Coeliac disease, epilepsy and cerebral calcifications

doi:10.1016/j.braindev.2004.05.003

Brain and Development

Volume 27, Issue 3, April 2005, Pages 189-200

https://doi.org/10.1016/j.braindev.2004.05.003 Get rights and content

Abstract

Coeliac disease, epilepsy and cerebral calcifications (CEC) syndrome is a rare clinical condition. One hundred and seventy-one patients have been reported in the literature. Patients are mostly from Italy, Spain, and Argentina, suggesting a geographically restricted condition. Epilepsy is more frequently characterized by occipital seizures. It may be benign or drug-resistant, sometime evolving into severe epileptic encephalopathy. Gluten free diet (GFD) efficacy seems to be inversely related to the duration of epilepsy and the young age of the patient. Patients with cerebral calcifications (CC) and coeliac disease (CD) without epilepsy are considered as having an incomplete form of CEC syndrome. Some patients with epilepsy and CC without CD are supposed to have a CEC syndrome with silent or latent CD.

Whether CEC syndrome is a genetic condition, or whether epilepsy and/or CC are a consequence of an untreated CD is unknown yet. Since histopathological findings seem to be the expression of vascular calcifyied malformation, CEC syndrome may be considered a genetically determined entity, such as a type of Sturge-Weber-like phacomatosis. Moreover, CEC, as well as CD, is associated with HLA-DQ2 and HLA-DQ8 phenotype and genotype. The progressive growth and late occurrence of CC before beginning a GFD, the demonstration of anti-gliadin antibodies in the cerebro-spinal fluid and the association with HLA class II genes, suggest that an immune reaction originating from the jejunal mucosa, triggered by gliadin in gluten intolerance predisposed subjects (HLA phenotype) may be responsible for seizures and CC. Moreover, a long-lasting untreated CD folic acid deficiency may cause calcifications.

Probably, CEC is considered a genetic, non-inherited, ethnically and geographically restricted syndrome associated with environmental factors.

Section snippets

Historical perspective and definition

Coeliac disease (CD) is an autoimmune disease characterized by chronic inflammation in the wall of the small intestine [1] due to a permanent intolerance to gluten protein (gluten intolerance, GI). CD is defined by crypt hyperplasia, jejunal mucosa villous atrophy, and inflammatory infiltrate in the lamina propria associated with an increased number of intraepithelial lymphocytes; resolution of villous atrophy and clinical improvement on gluten-free diet (GFD); and relapse of clinical symptoms

Typical CEC syndrome

In typical CEC syndrome CD may appear at any time during a lifetime and it can evolve in silent or paucisymptomatic forms. Epilepsy is a localization-related epilepsy, usually occipital in type. CT-scan features consist of bilateral cortico-subcortical occipital calcifications without contrast enhancement, and brain atrophy.

Laboratory investigations

The diagnosis of CD in all IWG patients was made according to the most recent ESPGAN (European Society Pediatric Gastroenterology Hepatology and Nutrition) criteria [70], and so they underwent a xylose load test, and determination of serum folic acid, antigliadin IgG and IgA antibodies, and antiendomysium antibodies (EmA). The gliadin antibodies IgA or IgG were positive in 78.8% of the patients, EmA positive in 100%, serum folic acid low in 82.1%, and xylose afterload test positive in 62.5% [57]

CD and CC without epilepsy

Ten anecdotal CD patients with CC of otherwise unknown origin and without epilepsy.

CD and epilepsy without CC

Sixty-nine patients were reported up to 1996 [56], and one-third of them had partial occipital epilepsy. The evolution of seizures was benign in a half of the patients, and drug resistant in the others. Some of these patients were supposed to have a form of benign occipital epilepsy. In two patients occipital epilepsy was progressive towards epileptic encephalopathy. In 2001, Labate et al. [80] investigated

Criteria for diagnosis

All the patients with epilepsy (especially with occipital seizures), and CC (mainly, but not only, located in the occipital area) had to be investigated for CD following the ESPGAN criteria [70] in order to identify patients with silent or latent CD at an early stage. Anti-transglutaminase, antiendomysial antibodies [83] and HLA have also to be tested. In fact, in the case of negative gliadin or EmA antibody, the lack of DQ2α/β heterodimer or DR4 allele can rule out CD. On the other hand,

Differential diagnosis

Differential diagnosis has to rule out any disease associated with posterior CC. Clinical history may easily differentiate pathological conditions such as encephalitis [84], purulent meningitis [85], [86], and ossifying meningoencephalopathy [87]. Other conditions associated with similar CC are congenital folate malabsorption [88], and treatment with methotrexate, antifolate agents and radiotherapy in leukaemic children [89], [90], [91].

Differential diagnosis has also to be made between SWS

Treatment (GFD)

It has been demonstrated that the chances of seizure control after GFD seem to be significantly inversely related to the duration of epilepsy before GFD and to the age at the beginning of GFD [41]. Based on retrospective evidence, another Italian study [98] suggested that early CD identification and treatment would prevent or reverse the tendency to epilepsy. In an extension and follow-up of the IWG study of 1992, Del Giudice et al. [99] demonstrated that the number of years with gluten

Epidemiology

In CD patients an increased prevalence of epilepsy, ranging between 1 and 21.5%, was reported by several authors [20], [21], [22], [100], but Hanly et al. [101] reported that the frequency was equal to that in the controls. This prevalence is higher than observed in the general population. Vascotto and Fois [79] demonstrated that the prevalence of epilepsy (and CC) increases from 0.79% of cases with typical CD diagnosed at the mean age of 5.9 years to 3.5% (1.7% for cerebral calcifications) of

Ethiology and pathogenesis

Whether the association between CD and epilepsy and CC is merely a coincidence or a genetic condition, or whether epilepsy and/or CC are a consequence of an untreated CD has still to be demonstrated. The specific involvement of the occipital lobe is an another unresloved issue.

Conclusions

CEC syndrome is a rare condition characterised by CD, epilepsy and CC. The three symptoms of the disease are not always present at the same time, because they may start at different ages. CD disease is rarely present at the onset in its typical active picture. More frequently it is silent and even latent, and neuroradiological signs and epilepsy may be its presenting symptoms. Epilepsy is occipital in most cases with the onset in childhood, and has variable outcome, ranging from cases with an

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