Marios Hadjivassiliou

Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria.

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts’ recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally.

Clinical and Immunologic Features of Ultra-Short Celiac Disease

BACKGROUND & AIMSnThe clinical effects of gluten-sensitive enteropathy with villous atrophy limited to the duodenal bulb (D1) have not been delineated in adults with celiac disease. We investigated the sensitivity of D1 biopsy analysis in the detection of celiac disease, the number and sites of biopsies required to detect ultra-short celiac disease (USCD, villous atrophy limited to D1), and the clinical phenotype of USCD.nnnMETHODSnWe performed a prospective study of 1378 patients (mean age, 50.3 y; 62% female) who underwent endoscopy at a tertiary medical center in the United Kingdom from 2008 through 2014; routine duodenal biopsy specimens were collected from D1 and the second part of the duodenum (D2). Quadrantic D1 biopsy specimens were collected from 171 consecutive patients with a high suspicion of celiac disease (mean age, 46.5 y; 64% female). Clinical data from patients diagnosed with USCD, based on biopsy analysis, were compared with those from patients with conventional celiac disease (CCD) (villous atrophy beyond D1) and individuals without celiac disease (controls). The number of intraepithelial lymphocytes (IELs) and immune phenotypes were compared between D1 vs D2 in patients with celiac disease.nnnRESULTSnOf the 1378 patients assessed, 268 (19.4%) were diagnosed with celiac disease; 9.7% of these patients had villous atrophy confined to D1 (USCD; P < .0001). Collection of a single additional biopsy specimen from any D1 site increased the sensitivity of celiac disease detection by 9.3%-10.8% (P < .0001). Patients with USCD were younger (Pxa0= .03), had lower titers of tissue transglutaminase antibody (Pxa0= .001), and less frequently presented with diarrhea (Pxa0=xa0.001) than patients with CCD. Higher proportions of patients with CCD had ferritin deficiency (Pxa0= .007) or folate deficiency (Pxa0= .003) than patients with USCD or controls. Patients with celiac disease had a median of 50 IELs/100 enterocytes in D1 and a median of 48 IELs/100 enterocytes (Pxa0= .7) in D2. The phenotype of IELs from patients with D1 celiac disease was indistinguishable from those of patients with D2 celiac disease.nnnCONCLUSIONSnCollection of a single additional biopsy specimen from any site in the D1 intestine increases the sensitivity of detection for celiac disease. Patients with USCD may have early stage or limited celiac disease, with a mild clinical phenotype and infrequent nutritional deficiencies.

Chronic idiopathic axonal polyneuropathy: a systematic review.

Chronic idiopathic axonal polyneuropathy (CIAP) is a term describing neuropathies with both sensory and motor involvement in a length dependant distribution where neurophysiology reveals axonal damage, neuropathy onset is insidious and shows slow or no progression of the disease over at least 6xa0months with no aetiology being identified despite appropriate investigations. This entity merits further consideration given how common it is, the absence of clarity regarding aetiopathogenesis, natural history and therapies. A systematic computer-based literature search was conducted on PubMed database. We used two Medical Subject Headings terms in title. Term A was “axonal”, “cryptogenic”, “idiopathic” or “unknown” and Term B was “neuropathy” or “polyneuropathy”. This search strategy resulted in the identification of 658 articles. After eligibility assessment, 48 papers were used for this review. CIAP is usually diagnosed in the sixth decade of life and it is more prevalent in males (ratio 3:2). It is usually slowly progressive. Some data support a potential role of autoimmunity in CIAP and further larger prospective studies are required to address such potential link and any treatment implications. CIAP is a common type of polyneuropathy but the least studied. Increasing awareness and research into this entity may result in better understanding and in the development of treatment strategies.

Transglutaminase 6 antibodies in gluten neuropathy

BACKGROUNDnTG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies).nnnMETHODSnThis was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy.nnnRESULTSnTwenty-eight patients were recruited (mean age 62.5±13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy.nnnCONCLUSIONSnWe found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN.

Peripheral neuropathy in idiopathic Parkinson's disease: A systematic review

BACKGROUNDnParkinsons disease (PD) has been associated with peripheral neuropathy (PN). PN has been demonstrated in some rare genetic forms of PD (e.g. PARK2 mutations) but has also been linked to levodopa exposure.nnnOBJECTIVEnThe aim of this systematic review is to clarify any evidence of peripheral nervous system involvement in idiopathic PD.nnnMETHODSnA systematic computer-based literature search was conducted on PubMed database.nnnFINDINGSnThe pooled estimate of the prevalence of large fiber PN in PD was 16.3% (based on 1376 patients). The pooled estimate of the prevalence of biopsy-proven small fiber neuropathy was 56.9% (based on 72 patients). Large fiber PN in PD is in the majority of cases distal, symmetrical, axonal and predominantly sensory. There are, however, few reports of chronic idiopathic demyelinating polyneuropathy and very occasional cases of acute neuropathies. Although nerve conduction studies have been performed in the majority of the studies, they included only a limited number of nerves, mainly in the lower limbs. There is little evidence to support a direct link between levodopa treatment and the development of PN in idiopathic PD. In the majority of the cases PN has been linked to abnormalities in vitamin B12, methylmalonic acid or fasting homocysteine levels. Additional aetiological risk factors for PN may be responsible for any apparent link between PD and PN.nnnCONCLUSIONSnLarge-scale prospective studies with long-term follow-up with detailed baseline assessments are needed in order to understand the natural history of PN in PD, both on clinical and neurophysiological parameters.

Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis

IntroductionParaneoplastic neurological syndromes (PNS) consist of a heterogeneous group of neurological disorders triggered by cancer. The aim of this systematic review is to estimate the reported prevalence of pain in patients with paraneoplastic peripheral neuropathy (PPN).MethodsA systematic computer-based literature search was conducted on PubMed database.ResultsOur search strategy resulted in the identification of 126 articles. After the eligibility assessment, 45 papers met the inclusion criteria. Full clinical and neurophysiological data were further extracted and involved 92 patients with PPN (54.5% males, mean age 60.0xa0±xa012.2xa0years). The commonest first manifestation of PPN is sensory loss (67.4%), followed by pain (41.3%), weakness (22.8%), and sensory ataxia (20.7%). In 13.0% of the cases, pain was the sole first manifestation of the PPN. During the course of the PPN, 57.6% of the patients may experience pain secondary to the neuropathy.ConclusionsPain is very prevalent within PPN. Pain specialists should be aware of this. Detailed history-taking, full clinical examination, and requesting nerve conduction studies might lead to an earlier diagnosis of an underlying malignancy.

Test for coeliac disease first

In their overview of investigating fatigue in primary care, Hamilton and colleagues conclude that the prevalence of fatigue in patients with coeliac disease is unknown and that coeliac serology should …

Cerebellar ataxia with sensory ganglionopathy; does autoimmunity have a role to play?

Background and purposeCerebellar ataxia with sensory ganglionopathy (SG) is a disabling combination of neurological dysfunction usually seen as part of some hereditary ataxias. However, patients may present with this combination without a genetic cause.MethodsWe reviewed records of all patients that have been referred to the Sheffield Ataxia Centre who had neurophysiological and imaging data suggestive of SG and cerebellar ataxia respectively. We excluded patients with Friedreich’s ataxia, a common cause of this combination. All patients were screened for genetic causes and underwent extensive investigations.ResultsWe identified 40 patients (45% males, mean age at symptom onset 53.7u2009±u200914.7xa0years) with combined cerebellar ataxia and SG. The majority of patients (40%) were initially diagnosed with cerebellar dysfunction and 30% were initially diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5u2009±u20098.9xa0years (range 0–44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%).Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients. Six patients had malignancy, which was diagnosed within 5xa0years of the neurological symptoms. Only 3 patients (7.5%) were classified as having a truly idiopathic combination of cerebellar ataxia with SG.ConclusionOur case series highlights that amongst patients with the unusual combination of cerebellar ataxia and SG, immune pathogenesis plays a significant role.

PTU-157 The clinical and phenotypic assessment of ultra-short coeliac disease

Introduction Data suggests that an additional duodenal bulb (D1) biopsy may increase the diagnostic yield for coeliac disease (CD) by up to 10%. However no consensus exists on necessity of D1 biopsy. One reason may be that it is not clear if these patients with Ultra-Short Coeliac Disease (USCD) have the same phenotype or are at risk of the same consequences as conventional CD. We aimed to assess the clinical phenotypes of patients with USCD compared to those with conventional disease. Method All patients attending a specialist CD endoscopy list were invited to take part. All patients had duodenal biopsy taken as routine. Patients had standard quadrantic biopsies taken from the second part of the duodenum (D2) and at least one biopsy taken from D1. Biopsies were analysed separately according to the Marsh classification system. Marsh 3 disease was required to diagnose CD. Patients had concurrent tissue tranglutaminase (tTG) and endomysial antibodies (EMA) and total IgA. All patients with VA were followed up in the CD specialist clinic where routine haematology, biochemistry, HLA typing and DXA scans were requested. Presenting symptoms and immunology were compared for all presentations. Haematology and biochemistry results were compared to a control group of patients that had CD excluded with normal serology and histology. Results 1378 new presentations (62% female; mean age 50.3) underwent duodenal biopsy. 268 (19.4%) new diagnoses of CD were made (66% female; mean age 41.6). CD patients were significantly younger than controls (p < 0.0001). 25/268 (9.3%) of new CD patients had USCD. Univariate analysis showed fewer USCD patients had diarrhoea than conventional CD (3.8 vs 24.0%, P < 0.0001). Decision tree analysis to identify USCD showed the absence of diarrhoea was the single discriminating factor (Adj P = 0.018). Rates of osteoporosis (p = 0.78) and anaemia (p = 0.14) were equal. Ferritin deficiency (P = 0.007) and folate deficiency (P = 0.003) rates were higher in conventional CD than USCD and controls. On multivariate analysis, patients with USCD were younger than those with conventional CD 36.6 vs. 42.1 (AOR 0.97 (0.94–0.998) P = 0.03), had lower tTG titres (AOR 0.89 (0.81–0.98) P = 0.02) and had higher folate levels (AOR 1.17 (1.01–1.36) P = 0.03) compared to conventional disease. Conclusion USCD appears to represent early disease with younger age and lower tTG titres and may represent a milder form of CD with lower rates of diarrhoea and folate deficiency. Long term follow up of patients with USCD is required to fully assess the clinical impact of diagnosis. Disclosure of interest None Declared.

PTU-159 Comparison of three commercially available point of care tests for coeliac disease: Abstract PTU-159 Table 1

Introduction Coeliac disease (CD) remains underdiagnosed. A rapid point of care test (POCT) may increase uptake of serological testing in appropriate patient groups. 3 POCTs are commercially available in the UK and in continental European pharmacy outlets: Biocard an IgA tissue tranglutaminase (tTG) test (BHR pharmaceuticals); Celiac Quick Test (Biohit Healthcare) detecting IgA, IgG and IgM tTG and Simtomax (Tillotts Pharma) which detects IgA and IgG antibodies against deamidated gliadin peptides (DGP). A fourth POCT has also been developed but not marketed (Xeliac Test Pro, Personal Diagnostics), with availability being solely from the manufacturer and no published data existing supporting its validity. Of the 3 commercially available POCTs, there is a limited evidence base with significant ascertainment bias. For this reason we decided to compare 3 commercially available tests in an endoscopic setting. Method Patients referred with a positive endomysial antibody (EMA) for duodenal biopsy to confirm CD were recruited. All patients had repeat serum EMA, tTG and immunoglobulins and were tested simultaneously with the 3 POCTs as per the manufacturers’ instructions. All patients had quadrantic duodenal biopsies from the second part of the duodenum as well as a duodenal bulb biopsy. Demonstration of villous atrophy (VA) was required to diagnose CD. Results 82 patients (51.2% female, mean age 41.0) have been recruited. In 10 patients the EMA had normalised on repeat testing. None of these patients had VA on duodenal biopsy. 9 of these patients were referred with a weak EMA and had a negative tTG. One patient had a tTG of 10 times the upper limit of normal, and subsequent gluten challenge revealed a positive EMA and VA. Of the remaining 72 patients 59 new cases of CD were confirmed with the presence of villous atrophy, of the 13 EMA positive patients without VA 8 had Marsh 1 or 2 changes present with the remaining 5 patients having normal histology. Full sensitivity, specificity PPV and NPV for all of the tests compared to VA on duodenal biopsy are shown in Table 1.Abstract PTU-159 Table 1 Test Sensitivity (%) Specificity (%) PPV (%) NPV (%) Serum tTG 98.3 (89.7–99.9) 34.8 (17.2–57.2) 79.5 (68.1–87.7) 88.9 (50.7–99.4) Biocard 72.9 (59.5–83.3) 65.2 (42.8–82.8) 84.3 (70.9–92.5) 48.4 (30.6–66.6) Celiac Quick Test 71.2 (57.7–81.9) 52.2 (31.1–72.6) 79.2 (65.5–88.7) 41.4 (24.1–60.9) Simtomax 96.6 (87.3–99.4) 30.4 (14.1–53.0) 78.1 (66.6–86.6) 77.8 (40.2–96.1) Conclusion In this pilot data set Simtomax appears to be the most sensitive of the POCTs when compared to histology with similar results to serum tTG as screening test. Further work is required in larger cohorts and lower prevalence populations to confirm the utility of these tests in adult CD. Disclosure of interest P. Mooney: None Declared, S. Wong: None Declared, M. Burden: None Declared, M. Kurien: None Declared, M. Hadjivassiliou: None Declared, D. Sanders Grant/ Research Support from: BHR pharmaceuticals; Tillotts Pharma for investigator led studies.