Neurological Dysfunction in Coeliac Disease and Non-coeliac Gluten Sensitivity

Marios Hadjivassiliou, MD; Dasappaiah G. Rao, MD; Richard A. Grünewald, DPhil; Daniel P. Aeschlimann, PhD; Ptolemaios G. Sarrigiannis, MD; Nigel Hoggard, MD; Pascale Aeschlimann, BSc; Peter D. Mooney, MD; David S. Sanders, MD

Disclosures

Am J Gastroenterol. 2016;111(4):561-567. 

In This Article

Results

Comparison of CD (Group 1) vs. NCGS (Group 2)

Between 1994 and 2014, a total of 700 patients have been seen and assessed in a neurology clinic specializing in gluten sensitivity. Out of these, 562 patients were included in this report. The remaining patients were excluded for the following reasons: refused intestinal biopsy, HLA type not available, non-compliant with GFD with persistently positive serology, neurological manifestation developed, and patient referred after the diagnosis of CD was made (total of 139 patients). Of the 562 patients included in this report, 228 (41%) had evidence of enteropathy on duodenal biopsy (Group 1). Group 2 consisted of 334 patients (59%) with normal biopsies (NCGS). The mean age at the onset of neurological symptoms in Group 1 was 53 years (range 13–90) and in Group 2 it was 57 years (range 14–87). Patients in Group 1 developed neurological symptoms significantly earlier than Group 2 (P<0.01 by Kruskal–Wallis one-way analysis of variance). The mean age at diagnosis of CD of patients in Group 1 was 52.6±15.3 years. This compared with a mean of 43.8±15 years for patients diagnosed with CD presenting to the gastrointestinal department (P<0.0001 by Student's t-test). The mean duration of the neurological symptoms before the diagnosis of gluten-related disease was not significantly different among the two groups (P=0.06 by analysis of variance).

HLA Type

As in the case of patients with classical CD with gastrointestinal presentation, the HLA-DQ2 (DQA1*05:01–DQB1*02:01) was present in 214/228 (94%) of all patients in Group 1 and DQ8 (DQA1 03:01–DQB1 03:02) in 8/228 (4%). There were four patients with biopsy-proven enteropathy who had only one of the DQB1*02 alleles.

In Group 2, 148/333 (44%) of patients had the HLA-DQ2 and 60 (18%) had the HLA-DQ8. The prevalence of the HLA-DQ2 or -DQ8 in Group 2 was therefore 62%. The remaining patients had neither HLA-DQ2 nor -DQ8. All but six of these patients had the HLA-DQB1*06 or -DQB1*05 (both come under the umbrella of DQ1).

Type of Neurological Manifestation Per Group

In Group 1 (228 patients), the most common neurological manifestations were cerebellar ataxia 41%, followed by peripheral neuropathy 30% (of which 80% had sensorimotor axonal length-dependent symmetrical neuropathy and 20% had sensory ganglionopathy) and encephalopathy 21%. Less common manifestations included ataxia with myoclonus 11, myopathy 9, myelopathy 6, stiff person syndrome 3, neuromyotonia 1, and chorea 1 (some patients had more than one manifestation).

In Group 2 (334 patients), the most common neurological manifestations were peripheral neuropathy 54% (of which 69% had sensorimotor axonal length-dependent symmetrical neuropathy and 31% had sensory ganglionopathy), followed by cerebellar ataxia 46% and encephalopathy in 10%. Less common manifestations included myopathy 8, myelopathy 6, stiff person syndrome 5, chorea 3 and myoclonic ataxia 2, and epilepsy with occipital calcifications 1 (some patients had more than 1 manifestation).

Overall, the prevalence of ataxia was similar in the two groups, but there was an over-representation of encephalopathy in Group 1 and of neuropathy and ganglionopathy in Group 2 (P=0.002 by χ 2 test). Figure 1 summarizes the frequency of the neurological manifestations within the two groups.

Figure 1.

Distribution of the different types of neurological manifestations in the two groups. There is a greater proportion of patients with encephalopathy in Group 1 and a greater proportion of neuropathy and ganglionopathy in the patients in Group 2 ( P =0.002 by χ2 test).

Anti-gliadin Antibodies

In Group 1, the total number of patients with circulating IgG AGA was 78%, IgA AGA was 65%, and with 43% having both circulating IgG and IgA (Table 1). In Group 2, 68% had circulating IgG AGA, 53% for IgA and 21% for both. We compared these figures with 100 patients with newly diagnosed CD who presented to gastroenterology clinics (classic CD). In this group, 88% had IgG AGA, 75% IgA, and 63% had both. While by definition Groups 1 and 2 had to have circulating AGA to be included (i.e., 100% positivity), in the case of the 100 patients with newly diagnosed CD presenting to gastroenterologists, the total percentage with AGA positivity was 82%. Table 1 summarizes the above findings.

Anti-TG2 Autoantibodies

Baseline TG2 IgA antibodies were available in some but not all the patients included, as the availability of the assay for these antibodies was limited at the start of this study. In Group 1, 105/115 (91%) of patients had circulating antibodies against TG2 as compared with 67/229 (29%) in Group 2. The proportion of patients positive for TG2 IgA antibodies who also had biopsy-proven CD presenting to the gastroenterology department was 97% (based on 100 consecutive patients). This illustrates, as expected, that there is a high degree of correlation between enteropathy and circulating anti-TG2 antibodies. Table 1 summarizes the above findings.

Anti-TG6 Autoantibodies

The availability of TG6 antibody analysis/testing was limited as TG6 autoantibodies were not discovered until 2006, and their importance in neurological manifestations of GRD was not established until 2008. Testing for TG6 was therefore carried out in a smaller group of patients from each group and baseline samples were not available in all cases. Patients without baseline analysis and subsequently testing negative were excluded given that they were on GFD and hence no clear conclusion could be drawn. In Group 1, 36/54 (67%) of patients had circulating TG6 (IgG and or IgA) antibodies. In Group 2, 68/114 (60%) of patients had circulating TG6 antibodies. The prevalence of TG6 antibodies in patients with newly diagnosed CD presenting to gastroenterologists was 38/100 (38%). There was a significant difference in the prevalence of TG6 between the neurology groups and the patients with CD presenting to gastroenterologists (P<0.01 χ 2 test). Table 1 summarizes the above findings.

Severity of Neurological Manifestations Per Group

For the purpose of comparing the severity of the neurological manifestations between each group, we concentrated on the two most common types of manifestations, gluten ataxia and gluten neuropathy. The severity of ataxia was assessed at presentation, using a simple clinical rating scale: mild (patient able to walk unaided), moderate (patient needs walking aids/support to be able to walk), and severe (patient is wheelchair bound).[15] In Group 1, 69% of patients had mild ataxia, 17% moderate, and 14% severe. In Group 2, 77% had mild, 15% moderate, and 8% severe. There were no significant differences between the two groups.

The severity of neuropathy was assessed using neurophysiological parameters (neurophysiological abnormalities confined to lower limbs, mild, involvement of arms but sparing radial nerve, moderate, involvement of radial nerve as well, severe). In Group 1, 27% had mild, 40% moderate, and 33% severe neuropathy. In Group 2, 42% had mild, 22% moderate, and 36% severe neuropathy. Mild neuropathy was more common in Group 2 with moderate and severe neuropathy being more common in Group 1 (P<0.01 by χ 2 test). The above observations are summarized in Figure 2.

Figure 2.

Severity of ataxia and neuropathy in the two groups: Group 1 coeliac disease (CD) and Group 2 non-coeliac gluten sensitivity (NCGS). Moderate and severe neuropathy is more prevalent in Group 1 ( P =0.016 by χ2 test), but there is no difference in the severity of ataxia in any group.

Group 2 (NCGS) Comparison Between Patients With Positive and Negative TG2 Autoantibodies and Those With HLA-DQ2/DQ8 vs. Those Without

We also performed a comparison between those patients in Group 2 with (67) and those without (162) TG2 antibodies. The rationale for this was to establish if the presence or absence of such antibodies had any bearing on such neurological manifestations. We found no significant differences in the age at onset of neurological manifestations between those with and those without TG2 antibodies (56.7±16.3 vs. 56.3±14.4 years). Similarly, there were no substantial differences in the type and severity of neurological symptoms (Figure 3). Finally, we also compared those patients with the HLA-DQ2 and -DQ8 vs. those without. We again did not find any differences between the two subgroups (Table 1).

Figure 3.

Comparison between those patients in Group 2 with and without anti-tissue transglutaminase (TG2) antibodies. There were no significant differences between the two subgroups.

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