Chiara Briani

Celiac disease: From gluten to autoimmunity

Celiac disease, also known as gluten-sensitive enteropathy and nontropical sprue, is a prevalent autoimmune disorder that is triggered by the ingestion of wheat gluten and related proteins of rye and barley in genetically susceptible individuals. The immune response in celiac disease involves the adaptive, as well as the innate, and is characterized by the presence of anti-gluten and anti-transglutaminase 2 antibodies, lymphocytic infiltration in the epithelial membrane and the lamina propria, and expression of multiple cytokines and other signaling proteins. The disease leads to inflammation, villous atrophy, and crypt hyperplasia in the small intestine. In addition to the intestinal symptoms, celiac disease is associated with various extra-intestinal complications, including bone and skin disease, anemia, endocrine disorders, and neurologic deficits. Gluten-free diet is currently the only effective mode of treatment for celiac disease, but better understanding of the mechanism of the disease is likely to add other choices for therapy in the future.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings

BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale

Abstract  Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute‐Common Toxicity Criteria (NCI‐CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI‐CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.

Update on idiopathic inflammatory myopathies

The inflammatory myopathies are a group of acquired diseases, characterized by an inflammatory infiltrate of the skeletal muscle. On the basis of clinical, immuno-pathological and demographic features, three major diseases can be identified: dermatomyositis (DM); polymyositis (PM); and inclusion body myositis (IBM). New diagnostic criteria have recently been introduced, which are crucial for discriminating between the three different subsets of inflammatory myopathies and for excluding other disorders. DM is a complement-mediated microangiopathy affecting skin and muscle. PM and IBM are T cell-mediated disorders, where CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I antigens, thus leading to fibre necrosis. In IBM, vacuolar formation with amyloid deposits are also present. This article summarizes the main clinical, laboratory, electrophysiological, immunological and histologic features as well as the therapeutic options of the inflammatory myopathies.

Multi‐center assessment of the Total Neuropathy Score for chemotherapy‐induced peripheral neurotoxicity

Abstract  The aim of this multi‐center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy‐induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute – Common Toxicity Criteria (NCI‐CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI‐CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI‐CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.

Clinical pattern and associations of oxaliplatin acute neurotoxicity: A prospective study in 170 patients with colorectal cancer

The objective of the current prospective, multicenter, international study was to trace the incidence and severity of acute oxaliplatin‐induced peripheral neuropathy (OXLIPN) and to determine its clinical pattern. The authors also specifically tested whether patients who had more symptoms of acute OXLIPN eventually would develop a more severe chronic, cumulative form of OXLIPN.

Carpal Tunnel Syndrome: ultrasound, neurophysiology, clinical and patient-oriented assessment

OBJECTIVE The aim of this study is twofold. First, to assess the relationships between the cross-sectional area (CSA) of the median nerve (MN) calculated at ultrasound (US) and: (1) patients perception of his/her symptoms and hand function; (2) clinical severity of CTS; (3) neurophysiological classification; (4) hand distribution of symptoms. Second, to assess the sensitivity of ultrasonography (US) and neurophysiology in the diagnosis of CTS using clinical measures as gold standard. METHODS We performed a prospective study by using multidimensional assessment: clinical (Historic and Objective scale, Hi-Ob), neurophysiological, patient-oriented measures (Boston Carpal Tunnel Questionnaire, BCTQ) and high-resolution US. The dominant hands of 54 consecutive patients who were referred to our neurophysiologic laboratory with clinical signs of CTS (43 females, mean age 53.3, range 30-80, SD: 13.1) were examined. RESULTS A statistically significant correlation was found between the CSA of the MN at wrist and (1) hand function (according to BCTQ, r=0.35, p=0.01), (2) clinical scale (Hi-Ob scale, r=0.51, p<0.00007), (3) neurophysiologic classification (r=0.80, p<0.0000001), and (4) hand distribution of symptoms (p=0.017). Neurophysiology showed higher sensitivity than US but in one of 3 cases with normal neurophysiological results, US showed data suggestive of CTS. CONCLUSIONS A positive correlation exists between US findings and all the conventional measures of CTS severity. The sensitivity of the combination of US and neurophysiology is higher than the sensitivity of neurophysiology or US alone. US is a useful complementary tool for CTS assessment. SIGNIFICANCE Information on the contribution of US in CTS and the interpretation of severity measurements in CTS.

Predictors of response to rituximab in patients with neuropathy and anti–myelin associated glycoprotein immunoglobulin M

Abstract  We evaluated the efficacy and safety of rituximab in an open‐label, uncontrolled study of 13 patients with polyneuropathy associated with antibodies to myelin‐associated glycoprotein (MAG) and correlated the response to therapy with clinical and laboratory features. One year after rituximab therapy, anti‐MAG immunoglobulin M (IgM) titers were significantly reduced. At that time, eight patients (62%) had improved in both the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore and the Medical Research Council sumscore for muscle strength and seven of them also in the INCAT disability score. The improvement in the mean INCAT sensory sumscore was significant at 12 months and correlated with lower anti‐MAG antibody at entry and at follow‐up. This study suggests that rituximab may be efficacious in patients with anti–MAG associated neuropathy and particularly on sensory impairment and in those with moderately elevated antibody titers. These findings suggest that antibody reduction below a critical level may be necessary to achieve clinical improvement.

Immune Cross-Reactivity in Celiac Disease: Anti-Gliadin Antibodies Bind to Neuronal Synapsin I

Celiac disease is an immune-mediated disorder triggered by ingestion of wheat gliadin and related proteins in genetically susceptible individuals. In addition to the characteristic enteropathy, celiac disease is associated with various extraintestinal manifestations, including neurologic complications such as neuropathy, ataxia, seizures, and neurobehavioral changes. The cause of the neurologic manifestations is unknown, but autoimmunity resulting from molecular mimicry between gliadin and nervous system proteins has been proposed to play a role. In this study, we sought to investigate the immune reactivity of the anti-gliadin Ab response toward neural proteins. We characterized the binding of affinity-purified anti-gliadin Abs from immunized animals to brain proteins by one- and two-dimensional gel electrophoresis, immunoblotting, and peptide mass mapping. The major immunoreactive protein was identified as synapsin I. Anti-gliadin Abs from patients with celiac disease also bound to the protein. Such cross-reactivity may provide clues into the pathogenic mechanism of the neurologic deficits that are associated with gluten sensitivity.

TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS : identification of two novel mutations

Background and purpose:  Increasing evidence suggests a direct role of the TAR DNA‐binding protein 43 (TDP‐43) in neurodegeneration. Mutations in the TARDBP gene, which codes for TDP‐43, have been recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases.