**10. Dermatitis herpetiformis and EC**

Dermatitis herpetiformis (DH) was first described in 1885 by the French dermatologist Louis Duhring, and, indeed, is still known as Duhring's disease in some countries. In 1966, Marks et al. identified the presence of histological alterations in the small intestine of these patients that were identical to those observed in individuals with CD [74, 75].

The primary cutaneous lesions appear as erythematous papules, associated with liquid-containing vesicles in different areas of the body, especially those where there is rubbing, where they are distributed symmetrically on the extensor surfaces of the extremities. The vesicles produce a great deal of itching, causing patients to scratch themselves frequently, bursting their blisters, which releases their liquid content,

and causing erosions and abrasions. Subsequently, the papules become scabs that later detach, leaving a slightly hyperpigmented area. Generally, they predominate in young adults, but they can also affect children and older adults, especially atopic children. The vast majority of patients note the onset of symptoms during the warm months from the beginning of spring to the end of summer [76, 77].

The majority of patients with DH have no intestinal manifestations, or else only very mild ones. Sometimes patients only have iron deficiency anaemia. Males are more likely to be affected than are women (1.5–2:1) in contrast to CD, which clearly predominates in the female sex (2–4:1) [78].

The most characteristic histological finding is the presence of IgA-type granular deposits located in the papillae of the dermis and throughout the basement membrane, as can be demonstrated by direct immunofluorescence in skin biopsies. These accumulations promote an inflammatory response with infiltration of neutrophils around the vesicles of the affected areas [79]. The immunological basis of its development is linked to the pathogenesis of gluten intolerance in CD. The tTG-3 antibody is the main responsible auto-antigen, which is located in the skin of these patients, leading to the appearance and maintenance of the inflammatory response [80].

The main treatment for DH is the adoption of a GFD, which must be adhered to strictly and constantly throughout life. The skin lesions disappear several weeks after starting the GFD. Some cases may require a brief complementary treatment with Dapsone. This drug targets rashes by inhibiting neutrophil migration, and is used until the skin lesions have completely disappeared [81]. A Finnish study, carried out between 1971 and 2010, on the death rate and causes of death of 476 consecutive patients with DH, found significant reductions in all-cause mortality and cerebrovascular disease. The standardised mortality rate for all-cause mortality was significantly reduced to 0.70 (95% CI: 0.55–0.87). This value was similar in both sexes and was almost identical to that in dermatitis herpetiformis patients (0.73) without villous atrophy of the small intestine [82].

## **11. Cerebellar ataxia and EC**

This disease encompasses cases previously known as "idiopathic sporadic ataxia," which are accompanied by positive antibodies against gluten. It is a type of cerebellar ataxia that appears in patients with associated gluten intolerance.

The most common form of clinical presentation consists of balance and gait disorders with associated dysarthria. Less frequently, it manifests as diffuse or focal myoclonic contractions. It is accompanied by nystagmus and other ocular signs in more than 70% of cases. In general, it begins gradually, appearing in individuals aged over 50 years, and with equal prevalence in men and women. It usually has a slow evolution, with a stationary clinical course and intermittent episodes of aggravation. Most patients have a prior history of recurrent digestive symptoms, and many patients have not been previously diagnosed with CD or with associated NCGS.

The Sheffield group led by Dr. Hadjivassiliou was the first to describe this type of association, and has made significant contributions to the field since 1970 [83]. The diagnosis of gluten ataxia is confirmed by the presence of anti-gliadin antibodies (AGAs) [84] as well as anti-tTG- and, when available, anti-tTG-2–6.

Fewer than 40% of patients with gluten ataxia present anti-tTG-2-positive IgA. When combined with anti-tTG-6, it can attain a positivity of 85% [85]. Autoantibodies to tTG-6 have been identified in immune-mediated ataxia patients with gluten sensitivity, suggesting an important role for transglutaminase 6 in cortical and cerebellar neurons [86, 87]. Gluten ataxia occasionally presents a familial character, affecting several first-degree relatives [88].

**11**

*Introductory Chapter: Celiac Disease - An Overview DOI: http://dx.doi.org/10.5772/intechopen.82723*

**12. Neurogluten**

Gluten ataxia is considered an autoimmune disease characterised by the presence of cerebellar damage, mainly localised at the level of Purkinje cells, and the presence of circulating antibodies against gluten or related enzymes. Affected patients must follow a strict and sustained GFD. The degree of response to the withdrawal of gluten from the diet depends on the time elapsed between the appearance of the first signs of ataxia and the commencement of the GFD: the sooner it is established, the greater the chances of remission or recovery from the signs of ataxia. It is important to remember that coexisting nutritional deficiency and autoimmunity can also cause neurological dysfunction in CD. A wide variety of neurological phenotypes with different aetiologies was found in 68 gliadin-positive patients with CD or non-CD over a period of 10 years (2002–2012): cerebellar ataxia, neuropathy, dementia, myeloneuropathy, autoimmune disease, deficiencies of vitamin E, folate and copper, genetic disorders and metabolic or toxic syndrome, among others. The authors concluded that exposure to gluten can cause neurologi-

cal dysfunction even in those patients without established CD [89].

is not required in order for it to develop [90–93].

be the most widely recommended therapy [94, 95].

are less frequent [96–99].

become established.

as is the case in neurosyphilis [100, 101].

Non-celiac gluten sensitivity (NCGS) is a clinical entity related to the ingestion of gluten-containing food, but the patients are not affected by celiac disease (CD). NCGS does display the typical histology of CD, although it may share a low level of duodenal intraepithelial lymphocytosis, but not crypt hyperplasia or villous atrophy. Neither does NCGS have the typical serology of CD, in which anti-transglutaminase type 2 IgA antibodies are present in the serum. However, they have a low level of them, and sometimes they are positive for antigliadin IgG antibodies. The sensitivity and specificity of both processes are limited. NCGS may affect individual or familial cases, but unlike in CD, the HLA-DQ2/DQ8 haplotype

Like CD, NCGS is a common, chronic process, and often responds well to a GFD, even in severe cases. To date, in the absence of other biomarkers, the most specific method for confirming the diagnosis is a positive, self-reported response by the patient to a strict GFD, adhered to for a period of 6–12 months, and the verified improvement of the clinical signs when examined. To sustain the benefits, longterm or lifelong adherence, according to the severity of the syndrome, to a GFD will

NCGS gives rise to important neurological and neuropsychiatric disorders. The most frequent of these are gluten ataxia and peripheral neuropathy, which have both frequently been associated with depression and anxiety. All patients can improve with early adoption of a GFD. However, without that therapy, progressive neurological dysfunction and cerebellar atrophy, and axonal nerve injury appear in MRI and neurophysiological patterns, respectively. Cerebrospinal fluid alterations

Other cases have been described that are associated with CD, but these probably correspond more closely to NCGS. They are all grouped together as neurogluten, a term that evokes different disorders in the nervous system that have the same cause,

Controversy arises when neurological entities without a determined diagnosis are included and related to that cause by a functional improvement that has not been objectively verified over a sufficiently long period. Given the current convenience and availability of GFD, safer diagnostic criteria, based on expert consensus, are needed to make more accurate diagnoses until such times as reliable biomarkers

*Introductory Chapter: Celiac Disease - An Overview DOI: http://dx.doi.org/10.5772/intechopen.82723*

Gluten ataxia is considered an autoimmune disease characterised by the presence of cerebellar damage, mainly localised at the level of Purkinje cells, and the presence of circulating antibodies against gluten or related enzymes. Affected patients must follow a strict and sustained GFD. The degree of response to the withdrawal of gluten from the diet depends on the time elapsed between the appearance of the first signs of ataxia and the commencement of the GFD: the sooner it is established, the greater the chances of remission or recovery from the signs of ataxia.

It is important to remember that coexisting nutritional deficiency and autoimmunity can also cause neurological dysfunction in CD. A wide variety of neurological phenotypes with different aetiologies was found in 68 gliadin-positive patients with CD or non-CD over a period of 10 years (2002–2012): cerebellar ataxia, neuropathy, dementia, myeloneuropathy, autoimmune disease, deficiencies of vitamin E, folate and copper, genetic disorders and metabolic or toxic syndrome, among others. The authors concluded that exposure to gluten can cause neurological dysfunction even in those patients without established CD [89].
