Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6

Abstract

BACKGROUND & AIMS:Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS:We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS:Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS:In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

Cognitive Impairment in Coeliac Disease with Respect to Disease Duration and Gluten-Free Diet Adherence: A Pilot Study

“…Imaging studies of CD have been integral in characterising the brain tissue injury found in CD. Lowered brain volume in the cerebellum (whole cerebellar grey matter) and thalamus has been found in patients with TG6 positivity [24], while white matter changes affecting the tract connecting those regions (spinothalamic) in addition to the corpus callosum have been reported as a more general finding [14]. These brain locations are known to hold associations with the cognitive functions found to be impaired in the current study.…”

“…Circulating antibodies against gluten products are thought to be the primary cause of underlying brain pathology in gluten-related conditions. Transglutaminase 6 (TG6), an antibody common in gluten ataxia and also present in CD patients at a rate of approximately 40% [24], is expressed in a number of brain regions and particularly the cerebellum [25]. This may explain the characteristic patchy loss of cerebellar Purkinje cells observed in gluten ataxia [7].…”

Brain fog and non-coeliac gluten sensitivity: Proof of concept brain MRI pilot study

“…The brain has been shown to be affected in a number of gluten-related disorders, from blunt neurological conditions like gluten ataxia [25] to "classical" CD [16,17,26,27]. In the current study neurological symptoms during typical gluten reactions of "classic" NCGS patients were reported at high rates, including headaches and brain fog each in approximately half of the group, as well as feeling off-balance in a third of subjects and sensory symptoms in a fifth.…”

“…White matter lesions are a non-specific brain pathology known to occur during normal aging [29]. However, they appear with greater size and frequency in a number of conditions such as vascular dementia [30] and multiple sclerosis [31], and have also been reported as an outcome in CD [16] (potentially linking with the increased risk of vascular dementia which CD is known to carry [32]). Similarly, low NAA/Cr is also known to be present in CD [17] and other neurological gluten conditions such as gluten ataxia [33].…”

“…The physiological basis of these symptoms may offer new brain-based biomarkers, which would complement others focused on the gut and immune response [13] for use in future trials. Potential candidates for these may be similar to those already reported for CD which would include pathologies such as white matter lesions [15] or altered cerebellar biochemistry [16], as well as "dynamic" variables such as cerebral blood flow (CBF) [17] which may change by measurable degrees alongside symptom onset following a gluten challenge. Brain imaging has never been conducted on classic NCGS patients, meaning pilot data would be very valuable.…”