Celiac disease (CD) or gluten-sensitive enteropathy, is an autoimmune gastrointestinal (GI) and systemic immune disorder. It is characterized by inflammation and tissue remodeling in the small intestine. Immune sensitivity to gliadin, a component of gluten, and its related proteins, is the hallmark of CD. Reduction of immunogenic gluten-related proteins from the diet leads to a reduction in anti-gliadin and anti-transglutaminase antibodies, coupled with improvement in GI symptoms. A majority of patients express the HLA-DQ2 and DQ8 MHC class II molecules, involved in the presentation of gliadin to naïve T-cells. There has been an increase in the incidence and prevalence of Celiac disease in the United States and around the world. Between 2000 and 2014, the Rochester Epidemiology Project found an increase in the incidence of CD from 8.1 per 100,000 person-years (2000-2002), to 21.5 per 100,000 person-years (2011-2014); with a similar increase in its prevalence from 0.10% in 2010, to 0.17% in 2014.
The disease is characterized by systemic manifestations that contribute to a complex clinical presentation of neurologic deficits, including peripheral neuropathy, dysautonomia, cerebellar ataxia and encephalopathy. An estimated 34% of patients present with classical CD symptoms, whereas 43% have non-classical CD; 23% diagnosed by screening asymptomatic high-risk patients. Altogether 36% of patients have evidence of complete villous atrophy, 51% have partial atrophy, and 11% have increased intraepithelial lymphocytes in intestinal biopsies. Two-thirds of patients have a normal body mass index, while 17% are overweight or obese, and 9% are underweight.
Extended gluten exposure may give rise to silent or subtle morphological and white-matter changes in the brain and impact the blood-brain barrier (BBB) with incipient disruption. One study examined 17 CD patients without any neurological involvement who underwent neurological evaluation and anatomical MRI acquiring individual gray- and white-matter, and subcortical structure volumes for automated volumetric analyses. Their findings showed a bilateral decrease in cortical gray-matter and caudate nuclei volumes in CD compared to controls. Another study of CD patients divided into subgroups based on their primary neurological complaint (balance disturbance, headache and sensory loss) underwent MRI to evaluate differences in brain grey matter density, cerebellar volume, and white matter abnormalities. The investigators noted reduced brain volume in the patient group compared to controls with significantly less grey matter density in multiple brain regions, both above and below the cerebellar tentorium. One-third of patients demonstrated white matter changes that were unexpected for the patient's age, with the highest incidence occurring in the headache subgroup. Seventy-one percent of CD patients in another study who underwent single photon emission computed tomography (SPECT) for the detection of perfusion defects across the BBB revealed SPECT abnormalities consistent with tandem CNS involvement, most significantly in the frontal brain regions that differed most notably from CD patients with autoimmunity but on unrestricted diets. Surprisingly, the prevalence of SPECT abnormalities was similar in CD patients with (74%) and without (69%) associated autoimmune disease.
A nationwide registry-based matched cohort study in Sweden of more than 10,000 children with CD and close to 12,000 of their siblings, studied frank neuropsychiatric illness in CD, noting that in comparison to the general population, those with CD had a 1.4-fold greater risk of future true psychiatric disorders. Childhood CD was a risk factor for mood disorders, anxiety disorders, eating disorders, behavioral disorders, attention deficit, autism spectrum disorder and intellectual disability. In addition, a previous diagnosis of a mood, eating, or behavioral disorder was more common before the diagnosis of celiac disease. Siblings of CD were at no increased risk for any of the investigated psychiatric disorders.
Treatment is focused first on removing gluten from the diet and then considering immune modulatory therapy employing a variety of agents to treat associated neurological involvement. Intravenous immunoglobulin is effective in treating cerebellar ataxia, and small and large fiber neuropathies associated with CD. Therapeutic plasma exchange has been used with success in those with CNS involvement manifesting as limbic encephalitis, leading to long disease-free period of time. Patients with autonomic involvement manifesting as orthostatic intolerance should be treated symptomatically.