Immunological Causes of Neurologic Disease From Gut to Brain Priv. Doz. Dr. Sylvia Boesch Univ. Klinik für Neurologie, Innsbruck September 2011
Immunological Causes of Ataxias autoimmune mediated ataxias GAD antibody pos Ataxia Celiac Disease/Gluten Ataxia Thyroid antibody pos Ataxia paraneoplastic ataxias Onconeural antibodies (Yo, Hu, Tr, Ri, ) Absent onconeural antibodies
Epidemiology Prevalence: healthy population about 1% neurological manifestations unclear, 10%-22.5% BUT: retrospective data only
Manifestations of CD Zelnik, N. et al. Pediatrics 2004;113:1672-1676
General considerations Most patients with neurological manifestations of gluten sensitivity have no GI symptoms Gluten sensitivity cannot be diagnosed on a clinical basis alone Untreated patients have circulating antibodies to gliadin and to one or more type of transglutaminase IgG antigliadin antibodies have little value for coeliac disease, but may be crucial for extraintestinal manifestations Detection of deamidated gliadin peptides (DGP) is more specific for detection of coeliac disease than are classic AGA assays (IgG anti- DGP 100% sensitivity in CD, BUT only 25% in patients with ataxia without GI manifestation and positive testing for antibodies to transglutaminase-2 or 6)
In practice: Testing for gliadin antibodies Testing for DGP antibodies Testing for IgA and IgG autoantibodies to TG2 CAVE: TG2 antibodies may be absent in patients without GI manifestation Anti-TG6 and anti -TG3 testing : TG3 antibodies in patients with dermitis herpetiformis TG6 antibodies in patients with neurologic manifestations BUT: these tests are not yet widely available
Enteropathy Gold Standard of CD diagnosis BUT: Enteropathy is NOT prerequisite for the diagnosis of gluten sensitivity with predominantly neurological manifestations Gluten sensitivity causes a range of small bowel mucosa changes histologically normal full blown enteropathy MARSH classification pre-lymphomatous state
Celiac Disease and the intestinum Malabsorption Vitamine B Vitamine E Hypokaliämie Hypocalziämie
Pathological findings in CD - intestinal Duodenal biopsy. Routine HE stain revealed no relevant duodenal atrophy (A). In contrast to a moderate CD3 lymphocytic population, a much stronger duodenal infiltration of CD8+ lymphocytes (B; Marsh I) Effector cells in gluten ataxia 93; 2009
CD is heritable 40% load MHC class II association white population:>90% CD HLA DQ2.5 (DQA1*05 - DQB1*02) alternatively: HL-DQ8 (DQA1*03-DQB1*0302) High frequency of the HLA genotype for CD patients with predominantly neurological manifestations DQ8 substantially more common (Sheffield cohort) 17% (ccd<6%)
Non-HLA Loci of Celiac Disease Susceptibility GWAS, genome-wide association study; SNP, single nucleotide polymorphism. Loci identified CELIAC 2 5q31-q33 CELIAC 3 2q33 Type of study used for identification linkage analysis Candidate gene approach CELIAC 4 19p13.1 linkage analysis Netherland Origin of the cohort(s) Italy, Finland, Scandinavia, Europe (meta-analysis) France, The Netherlands, Sweden, Norway Candidate genes (function) Reference Unknown [36], [40], [43] and [45] CTLA4 (T cell response) [38], [41] and [48] Myosin IXB (Rho family guanosine triphosphatase) 44 CELIAC 5 15q11-q13 linkage analysis (microsatellite) Finland Unknown 49 CELIAC 6 4q27 CELIAC 7 1q31 GWAS (SNPs) GWAS (SNPs) United Kingdom, Netherland, Ireland, Italy, United States, Scandinavia United Kingdom, Netherland, Ireland, Italy, United States KIAA1109 TENR (ADAD1) IL2 IL21 [31], [33], [35], [39] and [47] CLOSE RGS1 (B-cell activation) [31], [33], [39] and [47] CELIAC 8 2q11-q12 GWAS (SNPs) United Kingdom, Netherland, Ireland IL18RAP IL18R1 [31], [33] and [42] CELIAC 9 3p21 GWAS (SNPs) United Kingdom, Netherland, Ireland, Spain CCR1 (chemokines) CCR2 CCRL2 CCR3 CCR5 XCR1 [31], [33] and [37] CELIAC 10 3q25-q26 GWAS (SNPs) United Kingdom, Netherland, Ireland, Italy, United States IL12A [31], [33], [39] and [47] CELIAC 11 3q28 GWAS (SNPs) United Kingdom, Netherland, Ireland, Italy, United States LPP (zinc binding protein) [31], [33], [39] and [47] CELIAC 12 6q25.3 GWAS (SNPs) United Kingdom, Netherland, Ireland, Italy TAGAP (T cell activation) [31], [33] and [47] CELIAC 13 12q24 GWAS (SNPs) United Kingdom, Netherland, Ireland, Italy, United States SH2B3 (TLR intracellular adaptor, T-cell activation) [31], [33], [39] and [47]
Gluten ataxia Gluten neuropathy Gluten encephalopathy Rare manifestations Epilepsy Myopathy Myelopathy Multiple sclerosis?? Stiff-man syndrome Myoclonic ataxia
Celiac Disease Ataxia in CD
Celiac Disease - Ataxia in CD
Celiac Disease Ataxia in CD Macroscopical and histological findings Severe widening of the cerebellar folia (KB staining). Neuropathology (Hadjivassiliou et al., 1998) Loss of cerebellar Purkinje-cells Degeneration of spinothalamic tracts Perivascular infiltrations in both
Celiac Disease Ataxia in CD Sporadic cerebellar ataxia associated with gluten sensitivity (Bürk, Bösch et al., Brain 2001) Results 12/104 Ataxia patients positiv for AGA/EA antibodies (11.5%) Gender: m/f = 5/7 Age: 55.5 ± 17.4 years (range 30-76) Onset of ataxia: 44.8 ± 23.2 years (range 2-68) Duration of disease: 10.7 ± 8.2 years (range 2-32) Antibodies: 11 AGA positiv ( 5 IgG-AGA, 2 IgA-AGA), 1 IgA-EA Intestinal biopsy: 2 patients with Marsh type 3, 5 patients with focal lymphocytic mucosal infiltration (Marsh type 1)
Celiac Disease Ataxia in CD Sporadic cerebellar ataxia associated with gluten sensitivity (Bürk, Bösch et al., Brain 2001) Inclusion criteria 104 patients with progressive sporadic ataxia No family history for inherited ataxias Negative genetic screening for Friedreich Ataxia, ADCAs (SCA1, 2, 3, 6, 7) Normal Screening for vitamin ( Vitamin B12, E) No hepatic disease
Celiac Disease Ataxia in CD Sporadic cerebellar ataxia associated with gluten sensitivity (Bürk, Bösch et al., Brain 2001) Immunological Results HLA Typisierung: 7/10 HLA-DQB1*0201 (typical susceptibility for CD) 3/10 negativ for HLA-DRB1*04 und DQB1*0302 (alternativ locus for CD) CSF: normal, no antibodies, no oligoclonal antibodies
Celiac Disease Ataxia in CD Sporadic cerebellar ataxia associated with gluten sensitivity (Bürk, Bösch et al., Brain 2001) Results Ataxia Stance/gait ataxia 100 % Dysarthria 100 % Hemispheric ataxia 91.7% Gaze-evoked Nystagmus 66.7% Dysphagia 41.7% Double vision 16.7% Gastrointestinal symptoms 16.7% Neuropathy 58.3%
Celiac Disease Ataxia in CD Sporadic cerebellar ataxia associated with gluten sensitivity (Bürk, Bösch et al., Brain 2001) Results MRI: marked cerebellar atrophy, no atrophy of other brain structures Evoked potentials: pathological (VEP 39%, BEAP 10%, SSEP tib. 58.3%) EMG/NLG: sensomotor axonal neuropathy 16.7%, motor axonal neuropathy 8.3%, demyelinating neuroptahy 16.7%
Celiac Disease - Ataxia in CD The prevalence of antigliadin antibodies in ataxia and control groups. FA = Friedreich's ataxia; SCA = spinocerebellar ataxia, MSA-C = cerebellar variant of multiple system atrophy
Celiac Disease Ataxia in CD Quantitative IgG antigliadin antibody titre 30 patients with gluten ataxia, 13 patients with coeliac disease without neurological illness 12 healthy control subjects
Celiac disease Ataxia in CD
GLUTEN NEUROPATHY Most common manifestation
Celiac Disease rare neurological manifestations and CD Multifocal Encephalopathy (Kepes et al., Neurology 1975) Epilepsy (Chapmann et al., Br Med J 1978) Dementia (Collin et la., Neurology 1991) Myoclonus (Bathia et al., Brain 1995)
62/424 patients (36%) Migraine like headache Resemble vascular lesions Resolve with diet
Celiac Disease-Ataxia in CD Therapy Diet life long especially since the incidence of intestinal lymphomas is 40 times higher in CD 7S-Immunglobulins (intravenous) Ann Neurol. 2001 Dec;50(6):827-8. Effectiveness of intravenous immunoglobin therapy in cerebellar ataxia associated with gluten sensitivity. Bürk K, Melms A, Schulz JB, Dichgans J. 4 ataxia patients (without mucosal infiltration/atrophy, positive AGA) 0.4g/kg/day Immunglobulin for 5 days. Out-come: benefit in all cases within 2-3 weeks, marked ongoing benefit in 1 person, no benefit after 10-12 weeks in 1 patient. (Bürk, Melms et al., 2001)
Autoimmune Ataxias - Therapy Immunoglobulins Improvement of ataxia Improvement of cerebellar and cerebral perfusion
Coeliac disease (CD) and Neurology Danke für Ihre Aufmerksamkeit