controls. (Table 1-4) Recently, it has been estimated that GA accounts for 22% of patients that present with sporadic ataxia.() Table 1-5 Table 14 Prevalence of antigliadin antibodies in patients with idiopathic sporadic ataxia* Sporadic Ataxias (%) Familial Ataxias (%) Healthy Controls (%) Reference 3/24 (13) 12/104 (12) 7/26 (27) 4/24 (17) 13/98 (13) 6/32 (19) 59/143 (41) 5/14 (36) 12/33 (36) 0/23 (0) NP 9/24 (38) NP 1/15 (6) 63 (8-15) 8/59 (14) 1/27 (4) NP NP 5% NP 2% 5% 6/73 (8) 149/1200 (12) 1/47 (2) NP () () () () () () () () () * Based on previously published data.(). NP = (data) not provided. All of the studies have methodological flaws: almost all were retrospective and varied in their use or inclusion of control groups; different gold standards for the definition of study populations were used; independent and blinded assessments of biopsy samples or measurements of disease outcome were rarely performed; data were largely accrued from tertiary referral centres and were thus subjected to referral bias; and studies attempting to disprove the association had inadequate sample size.()
absent in healthy individuals.() Whether these antibodies are a result of epitope spreading or whether they truly are directed towards the specific transglutaminase is unclear. TG2, TG3 and TG6 are encoded on the same chromosome in humans (20q11-12) and all three can specifically deamidate gluten T cell epitopes, albeit with subtle functional differences.(; ) Given the overall homology between transglutaminases, autoantibody cross-reactivity and epitope spreading is worth consideration.() However, current evidence is conflicting in this regard. A recent report using ELISA and immunohistochemistry showed cross-reactivity between anti-TG2 antibodies and the isozymes TG3 and TG6.() This contrasted earlier studies reporting an absence of cross-reactivity between different transglutaminase isoforms, although these observations were based on competitive inhibition ELISAs, which can prevent the detection of very low affinity transglutaminase Also, cross-reactivity does not explain why some patients have antibodies exclusive to one transglutaminase isozyme.() It is apparent that current literature has addressed some of the criteria (albeit at differing levels of evidence) that suggest antibodies against gluten-related peptides mediate a neurological disease. (Box 1) Very recently, Hadjivassiliou and colleagues conducted a prospective cohort study to investigate the role of TG6 antibodies in diagnosing GA.() Patients were recruited from the ataxia, gluten/neurology, CD, and movement disorders clinic at Royal Hallamshire Hospital, Sheffield, UK, and also from the Tampere University Hospital (Finland). Patients were divided into two groups: (1) those with idiopathic sporadic ataxia negative for antigliadin antibodies (AGA), TG2 antibodies, and endomysial antibodies (EMA) and (2) patients with GA based on the original definition of an idiopathic cerebellar ataxia with positive antigliadin IgA and/or IgG antibodies irrespective of positivity for TG2 and EMA. Neurologic control groups included patients with genetically confirmed neurologic and
deep/subcortical WMAs may be appreciated as punctate, early confluent or confluent changes.() Figure 1-22 Figure 122 Classification of subcortical and deep white matter abnormalities on MR imaging Axial T2-weighted MR images demonstrate (a) Mild (grade 1), punctate lesions predominantly in the parietal lobe at the level of the corona radiata in a 42-year-old male with GA; (b) moderate (grade 2), early confluent WMAs in the peritrigonal regions from a 69-year-old male with a clinical presentation of ataxia and; (c) severe (grade 3), extensive confluent white matter hyperintense signal changes at the level of the basal ganglia in a 65-year-old male with “gluten encephalopathy”. (Images courtesy of Dr. Nigel Hoggard, University of Sheffield, UK). Prevalence In population-based studies, the prevalence of any WMA varies between 45% and 95%.() Table 1-9 displays the frequency of different types of WMAs, as shown on MR imaging in the community-dwelling (asymptomatic) Austrian Stroke Prevention Study.() Table 19 Prevalence of different types of WMAs in 993 participants (age range 45-87 years) from the Austrian Stroke Prevention Study* Periventricular WMAs Deep/subcortical WMAs Age (years) Caps/lining (N=632) N (%) Halo (N=61) N (%) Punctate (N=586) N (%) Early confluent (N=150) N (%) Confluent (N=76) N (%) <55 (N = 128) 55-64 (N = 344) 66 (55.5 203 (59.0) 0 (0) 5 (1.4) 76 (59.3) 236 (68.6) 3 (2.3) 17 (4.9) 0 (0) 9 (2.6)
between patients with GA and patients with ACAA (with and without serological evidence of sensitivity to gluten). Methods Subjects and Controls A retrospective review of all patients attending the ataxia clinic, Royal Hallamshire Hospital, Sheffield, UK was performed. Patients with a diagnosis of GA and ACAA were sought (see Chapter 3 for details). All patients from the two groups that had undergone the exact same MR imaging protocol of the brain were selected for MR imaging analysis. The clinical notes of these patients were assessed to obtain the duration and severity of ataxia symptoms at the time of MR imaging (as outlined in Chapter 3). Evidence of CD (in the form of positive duodenal biopsies) was also sought in both patient groups. Age- and sex-matched control data were acquired from a group of 55 healthy volunteers as detailed in Chapter 4.() All controls and subjects underwent the exact same imaging protocol. MR imaging outcome measures Outcome measures comprised of: (a) CV:TIV; (b) NAA/Cr and Cho/Cr ratios in the cerebellar vermis and hemisphere and (c) grey matter ‘density’ as indicated by VBM. In each case, subjects’ data were compared to control data matched for age and sex. Imaging protocol and analysis Details of structural MR imaging and 1H MR spectroscopy, as well as imaging analysis can be found in Chapter 3. %CV:TIV was estimated using the modified method. Results Over a 15-year period, 904 patients with progressive cerebellar ataxia attended the specialist ataxia clinic at the Royal Hallamshire Hospital, Sheffield, UK. Of these, 104 patients were diagnosed with ACAA and 159 patients with GA. 61% of the ACAA group and 70% of the GA group had the HLA DQ2/DQ8 genotype, compared to 30% in healthy local blood donors.() 44% of patients