Marta Lucchetta

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.

Intra- and internerve cross-sectional area variability: new ultrasound measures.

Introduction: Nerve involvement in immune‐related neuropathies is non‐homogeneous, and therefore characterization of ultrasound (US) abnormalities is difficult. We developed two measures to quantify US abnormalities in immune‐related neuropathies. Methods: Intranerve cross‐sectional area (CSA) variability for each nerve was calculated as: maximal CSA/minimal CSA. Internerve CSA variability for each patient was calculated as: maximal intranerve CSA variability/minimal intranerve CSA variability. Six patients underwent US evaluation of the median, ulnar, and fibular nerves, and the abnormalities were scored with our newly developed measures. Results: The new measures were applicable to all nerves and patients. The highest degree of intra‐ and internerve CSA variability was observed in multifocal motor neuropathy, consistent with the asymmetric characteristics of this neuropathy. Conclusions: The application of intra‐ and internerve CSA variability measures allows us to quantify the heterogeneity of nerves and nerve segments and identify different US patterns in diverse immune‐related neuropathies. Muscle Nerve, 2012

Neurolupus is associated with anti-ribosomal P protein antibodies: An inception cohort study

OBJECTIVE Serum IgG antibodies (Abs) to phosphorylated ribosomal (P ribosomal) proteins have been inconsistently associated with neuropsychiatric manifestations in systemic lupus erythematosus (SLE). Our aim was to assess whether serum IgG Abs to ribosomal P proteins are associated with neuropsychiatric SLE. PATIENTS AND METHODS We examined an inception cohort of 219 SLE patients. Neuropsychiatric SLE manifestations were characterized using the American College of Rheumatology (ACR) definition. Serum Abs to P ribosomal proteins were searched for by immunoblotting. In a subgroup of patients, Abs were investigated also in cerebrospinal fluid (CSF). RESULTS Abs to P ribosomal proteins were detected in 45 (21%) patients, 23 of whom (51%) with neuropsychiatric involvement. Abs to P ribosomal protein were present both in serum and CSF. Abs to P ribosomal proteins significantly correlated with psychosis (p=0.017), mononeuropathy multiplex (p=0.040), malar rash (p=0.004), serum anti-Sm Abs (p=0.042), and lupus anticoagulant (p=0.036). SLE onset age was significantly younger in patients with Abs to P ribosomal proteins. Logistic regression analysis confirmed the relationship between Abs to P ribosomal proteins and psychosis, malar rash, SLE onset age and lupus anticoagulant. CONCLUSIONS Abs to ribosomal P proteins are associated with psychosis and might be associated with peripheral nervous system complications.

Sonographic features in hereditary neuropathy with liability to pressure palsies

Introduction: Diagnostic nerve ultrasound is becoming more commonly used by both radiologists and clinicians. The features of different neuromuscular conditions must be described to broaden our understanding and ability to interpret findings. Methods: Our study examines the sonographic features of 7 subjects with hereditary neuropathy with liability to pressure palsies (HNPP) in comparison to 32 controls by measuring the nerve cross-sectional area (CSA) of the median, ulnar and tibial nerves. Results: Significant differences (P < 0.05) in nerve size were found. The HNPP group had a larger CSA for the median nerve at the wrist and ulnar nerve at the elbow (entrapment sites), but not the forearms. The tibial nerve at the ankle was also larger in the HNPP group, suggesting possible concomitant tibial neuropathy at the ankle. Conclusion: These results will help shape imaging protocols to better detect conditions with non-uniform nerve enlargements. Muscle Nerve 2011

Nerve ultrasound findings in neuropathy associated with anti-myelin-associated glycoprotein antibodies

No systematic nerve ultrasound (US) studies on patients with neuropathy and anti‐myelin‐associated glycoprotein (anti‐MAG) antibodies are available.

Ultrasound evaluation of peripheral neuropathy in POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder associated with plasma cell dyscrasia whose main neurological feature is a demyelinating polyneuropathy. The aim of our study was to assess the pattern of ultrasound (US) nerve abnormalities in POEMS syndrome patients.

Antibodies to muscle and ganglionic acetylcholine receptors (AchR) in celiac disease.

Background: About 2.5% of patients with idiopathic peripheral neuropathy or idiopathic dysautonomia have underlying celiac disease (CD). Antibodies to ganglioside have been reported in CD patients with neuropathy. No data are so far available on the presence in CD of acetylcholine receptor (AChR) antibodies. Muscle AChR antibodies are found in patients with myasthenia gravis, and ganglionic AChR antibodies in patients with autoimmune autonomic neuropathy. Objective: To determine the frequency of AChR antibodies in CD patients and assess possible correlations with neurological manifestations. Methods: Seventy CD patients (16 M, 54 F, mean age 36 years) underwent neurological and electrophysiological evaluation. AChR antibodies were detected with radioimmunoprecipitation assay. Sera from 15 age-matched patients with systemic lupus erythematosus (SLE) and 10 with Sjogren syndrome were studied as controls. Results: None of our CD patients complained of autonomic symptoms or fatigable weakness. Borderline titres (0.03–0.05 nmol/l) of ganglionic AChR antibodies were present in 4 patients, one affected with type I diabetes and one with subclinical neuropathy. Three of the 4 patients underwent cardiovascular autonomic function tests, which showed no abnormalities. Low levels of ganglionic AChR antibodies (0.05–0.10 nmol/l) were found in 2 SLE control patients, one of whom had a severe sicca complex. Muscle AChR antibodies (>1.0 nmol/l) were found in two CD patient and one control patient with SLE. Neither had symptoms or signs of myasthenia gravis. Discussion and conclusions: CD is occasionally associated with neurologic disease, and with antibody reactivity to neuronal antigens. None of our CD patients had autonomic failure or significant levels of ganglionic AChR antibodies. Two CD patient and one control with SLE had muscle AChR antibodies without clinical evidence of myasthenia. The presence of antibodies in CD and in SLE patients may reflect a non-specific autoimmune response in these patients or may indicate subclinical autoimmune autonomic and neuromuscular involvement.

Anti-ribosomal P protein antibodies and neuropsychiatric systemic lupus erythematosus: cross-sectional vs. prospective studies.

Sir, Whether anti-ribosomal P (anti-P) antibodies have a prognostic value for neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE) remains a matter of debate. Anti-P antibodies are directed to the functional centre of ribosomal P (phospho) proteins. P proteins are post-translationally modified (dephosphorylated) during apoptosis, and a dysregulation in the normal clearance of apoptotic cells leads to aberrant exposure to the immune system of modified non self-antigens. This could be one of the triggering events for the development of anti-P autoimmune response in SLE. Haddouk et al. recently investigated the diagnostic value of anti-P in SLE patients and the relationship between anti-P antibodies, detected at disease onset, and SLE manifestations prospectively registered during a 5-year follow-up in a large cohort of Tunisian patients. Haddouk’s results confirmed our already published findings about anti-P antibody sensitivity and specificity for SLE and the relevant association with antiphospholipid antibodies. Indeed, the high specificity of anti-P antibody (99.3%) was confirmed in a recent international multi-centre study of 947 SLE patients and more than 1000 controls. Anti-P antibody positive/anti-dsDNA negative/ anti-Sm negative sera can occur in a significant proportion of SLE patients, further stressing the diagnostic relevance of this biomarker. Thus, we agree with the Authors on the fact that the American College of Rheumatology (ACR) criteria for SLE classification should be revised by including anti-P serology, due to its specificity and positive predictive value. Conversely, we suggest caution in interpreting the results of the second part of Haddouk’s study regarding the clinical correlates of anti-P antibodies. A number of limitations can be noted in their study, including the detection of anti-P antibodies at a single time point and the grouping of NPSLE manifestations in some sketchy clusters each one encompassing a broad spectrum of manifestations potentially induced by different pathogenic mechanisms. Since their first description in 1987, one of the most intriguing aspects of anti-P antibodies has been their possible pathogenic role in SLE psychosis and depression. It is worth noting that depressive features were induced in a lupus-prone mouse model by injecting affinity purified human anti-P antibodies into cerebral ventriculi. We have evaluated longitudinally both anti-P antibodies and NPSLE in an inception cohort of 219 SLE Italian patients, followed-up in a single centre for over 10 years. The method used for the anti-P assaying was as previously described and NPSLE involvement was carefully investigated according to ACR guidelines. In our study, anti-P antibodies were associated with psychosis both in univariate and multivariate analysis. We observed a significant variation of antibody levels in 27% of cases as well as a fluctuation between negative and positive results concomitantly with NPSLE events in some patients (Figure 1). In keeping with our results, a longitudinal study carried out on an international inception cohort of SLE patients applying a very stringent methodology showed a clear association between anti-P antibodies and NPSLE episodes. Thus, a prospective study longitudinally investigating both anti-P antibody and NPSLE occurrence should certainly be more appropriate and informative for NP attribution and outcome (Table 1).

Lenalidomide in patients with chemotherapy-induced polyneuropathy and relapsed or refractory multiple myeloma: results from a single-centre prospective study.

Lenalidomide, an immunomodulatory drug used in myeloma therapy, has been claimed to be less neurotoxic than thalidomide, but evidence is still weak. We prospectively assessed lenalidomide safety in myeloma patients to evaluate whether it would induce or modify a previously ensued chemotherapy‐induced peripheral neuropathy (CIPN). Thirty consecutive patients (17 men, mean age 63.7 ± 9.4) previously treated with bortezomib and/or thalidomide and starting on lenalidomide (25 mg/day for 21‐day cycles) for relapsed or refractory myeloma were assessed at baseline, 6, and 12 months from the beginning of lenalidomide with Total Neuropathy Score clinical version (TNSc), Eastern Cooperative Oncology Group (ECOG) performance status, and numeric rating scale (NRS) for pain. TNSc >2 was considered significant for CIPN. TNSc changes of at least 4 points from baseline value were considered clinically relevant. At baseline 16 of the 30 patients (53.3%) had CIPN (mean TNSc 5.8, range 3–15). After 6 months, 13 patients were unchanged, 1 improved, and 2 worsened. After 12 months the patient who had improved persisted stable, and the two who had worsened returned to TNSc baseline value. The 14 patients without CIPN at baseline did not develop neuropathy. NRS and ECOG performance status persisted unchanged. Our results demonstrate lenalidomide safety and very low neurotoxicity also in patients with pre‐existing CIPN treated for 1 year.

Ultrasound diagnosis of peroneal nerve variant in a child with compressive mononeuropathy

We report on a 6-year-old child presenting with subacute foot drop. Neurophysiologic and radiologic studies revealed a peroneal nerve compression secondary to fibular exostosis. Before undergoing surgical removal of the exostosis, the patient underwent further neurophysiologic and ultrasonographic evaluation that showed the presence of an accessory peroneal nerve branch that caused gastrocnemius involvement. Findings at surgery confirmed the supposed anatomical variant. Both nerve components were carefully preserved during the operative procedure. The association of ultrasonographic and neurophysiologic studies was crucial in identifying the etiopathologic mechanism and anatomical picture and provided clinicians and surgeons with important information in planning the procedure.