Dear Editor,

We read with great interest the review by Grossman on neurologic complications of celiac disease in a recent issue of Pract Neurol.(1)

Using an evidence-based approach, the author has carefully and critically analyzed articles published in the last decade on the most common neurologic manifestations associated with celiac disease, namely ataxia, epilepsy, and peripheral neuropathy. Grossman has rigorously dissected the evidence for, and against, the possible association of celiac disease with neurological manifestations.

The association, the review concludes, does not seem to hold up when referral bias is considered or when strict criteria are applied.

While still leaving open the possibility of an association between celiac disease and certain neurologic disorders, the author calls for well- controlled and prospective studies to help clarify the issue.

We would like to call attention to a 2-year prospective study, which was recently published.(2)

After a retrospective study of a cohort of celiac children, where we did not find a correlation between neurologic manifestations and improvement on gluten-free diet (3), we undertook a prospective study in an adult celiac population in order to evaluate the incidence of neurologic symptoms and examine the response to gluten-free diet. Our prospective study enrolled 71 patients with histologically proven celiac disease, who were prospectively followed for up to 28 months.

Of the 71 patients, 69 were consecutively referred to our centre from the university’s gastroenterology department, whereas 2 directly sought treatment at our clinic for neuropathic symptoms. Forty-two patients were on gluten-free diet at recruitment. Adherence to the diet was assessed by testing for anti-transglutaminase antibodies. All patients underwent neurological and electrophysiological evaluation at recruitment and at every follow-up visit.

The results of the prospective study showed that 3 patients were affected by sensory-motor polyneuropathy. However, 2 of the 3 patients with polyneuropathy had sought treatment at our clinic for neuropathic symptoms. Considering this referral bias, only one of the 69 celiac patients referred for evaluation was affected by neuropathy. Several other manifestations affecting the nervous system were detected in our celiac population (4 with headache, 4 with depression, 4 with entrapment syndromes, 1 with facial hemispasm, and one of the 3 patients with neuropathy was also affected by epilepsy). However, the relatively common occurrence in the general population of headache, depression, and entrapment neuropathies makes it difficult to conclude a likely association with celiac disease.

Antibody reactivity to neural antigens was detected in 30/71 (42.2%) patients, but there was no clear correlation between anti-neural reactivity and active neurologic dysfunction.

Follow-up of 62 patients during gluten-free diet did not reveal significant changes in electrophysiology. However, in 2 patients with neuropathy, improvement in symptoms did correlate with the diet.

In conclusion, the results of our prospective study do not seem to support a causal relationship between biopsy-proven celiac disease and neurologic disease in the studied group of patients. We agree with Grossman that further well-controlled studies are warranted in order to clarify the relationship, as well as the effect of diet.

The use of proper outcome measures should be considered when evaluating therapeutic efficacy of any intervention (e.g. diet) in such a heterogeneous disease.(4)

While further research may end up refuting an association between celiac disease and neurologic dysfunction, gluten sensitivity, as defined only on the basis of presence of anti-gluten antibodies, might prove to have a connection with certain neurologic and psychiatric deficits.(5)

The potential relevance and significance of elevated levels of these antibodies in the absence of celiac disease deserve proper attention as well and should not be overlooked.

References

1. Grossman G.
Neurological complications of coeliac disease: what is the evidence?
Pract Neurol. 2008;8:77-89.

2. Briani C, Zara G, Alaedini A, Grassivaro F, Ruggero S, Toffanin E, Albergoni MP, Luca M, Giometto B, Ermani M, De Lazzari F, D’Odorico A, Battistin L.
Neurological complications of celiac disease and autoimmune mechanisms: a prospective study.
J Neurommunol. 2008;195(1-2):171-5.

3. Briani C, Ruggero S, Zara G, Toffanin E, Ermani M, Betterle C, Guariso G.
Anti-ganglioside antibodies in children with celiac disease: correlation with gluten-free diet and neurological complications.
Alimentary Pharmacology and Therapeutics, 2004;20:231-235.

4. Hobart JC, Cano SJ, Zajicek JP, Thompson AJ.
Rating scales as outcome measures for clinical trials in neurology: problems, solutions, and recommendations.
Lancet Neurol. 2007;6:1094-105.

5. Briani C, Samario D, Alaedini A.
Celiac disease: from gluten to autoimmunity.
Autoimmun Rev. 2008;7(8):644-50.