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Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aimof our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 +/- 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 +/- 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = -0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

Background Failed back surgery syndrome (FBSS) represents one main cause of chronic neuropathic or mixed pain, functional disability and reduced Health Related Quality of Life (HRQoL). Spinal Cord Stimulation (SCS) can be a value for money option to treat patients refractory to conventional medical management (CMM). We estimated from real-world data: 1) the amount of reduced levels of HRQoL of target patients compared to general population, 2) the relationship between pain intensity, functional disability, and overall HRQoL, and 3) the improvement of patients’ health from SCS intervention, and 4) we give some insights and make some suggestions on the selection of a battery of patients’ reported health instruments for use in routine clinical practice. Methods At recruitment (before SCS) and every 6 months for 2 years after SCS a battery of questionnaires/tests were completed: the generic EQ-5D and SF-36 for HRQoL, the specific Numerical Rating Scale (NRS) to measure pain intensity, and Oswestry Disability Index (ODI) to measure functional disability. We conducted multilevel regression analyses to investigate the association of HRQoL with the NRS and ODI indexes; multiple regression analyses to compare EQ-5D data with those of the general population adjusted for age, sex and education, and statistical tests to compare the changes of HRQoL, NRS and ODI estimates at baseline with those measured during the follow-up. Results Eighty patients (40% male, mean age = 58 years) participated. HRQoL was significantly worse in the patients than in the corresponding general population. Pain, functional disability and HRQoL significantly related each other during follow-up, Significant improvements (p

Background and aim: Peripheral neuropathy is a disorder with often unknown causes. Some drugs, including statins, are proposed to be among the causes of peripheral neuropathy. This study aimed at evaluating this condition by electrodiagnostic study among patients who had received statins. Methods: This case-control study was conducted in Shiraz, Iran in 2015, and included 39 patients aged 35-55 who had received statins for at least 6 months, and 39 healthy matched controls. Using electrodiagnosis, the sensory and motor wave features (amplitude, latency and nerve conduction velocity) of the peripheral nerves (Median, Ulnar, Tibial, Sural, and Peroneal) were evaluated among the subjects. Data were analyzed using SPSS software and p

Since the outbreak of the new coronavirus, healthcare systems around the world have witnessed not only COVID-19 symptoms but also long-term complications of the aforementioned, including neurological problems. We report a clinical case of an adult patient with bilateral facial nerve palsy and progressive ascending paresis of the limbs after contracting the novel coronavirus (COVID-19). Additionally, the systematic review aimed to identify and summarize specific clinical features, outcomes and complications of the studies focusing on bilateral facial diplegia as a sequela of COVID-19 infection. The total number of analyzed patients was 15. Only one patient was diagnosed with isolated bilateral palsy; the rest had Guillain-Barré Syndrome (GBS). With one exception, all the presented cases had favorable outcomes, with facial palsy recovery from slight to almost complete. In patients with a confirmed COVID-19 diagnosis, bilateral facial palsy may be an isolated symptom as well as a variant of GBS. Symptoms of cranial nerve damage during a COVID-19 infection may explain the appearance of facial nerve damage. In order to clarify the spectrum of neurological manifestations and a causal relation between SARS-CoV-2, COVID-19 vaccination and neurological symptoms, direct attention towards the study of this virus is crucial. It seems reasonable to recognize human coronavirus as another potential GBS trigger.

Objective To report morbidity and oncological outcomes in a consecutive series of lateral isolated recurrent gynecological cancer involving the pelvic side wall (PSW) including the iliopsoas muscle. Material and methods We retrospectively evaluated a consecutive series between 6/2013 and 12/2015 of lateral isolated recurrent gynecological malignancies treated with a lateral endopelvic resection (LEPR). LEPR was defined as an en-bloc lateral resection of a pelvic tumor with sidewall muscle, and/or bone, and/or major nerve, and/or major vascular structure. Post-surgical complications, quality of life (QoL) and survivals were computed. Results Seventy-four women with pelvic isolated relapse were admitted for surgery during the study period. Among them, 8 cases (10.8%) showed lateral isolated relapse involving the iliopsoas muscle and were treated with LEPR. R0 resection was achieved in 6/8 patients (75.0%), while the pathologic margins were microscopically and macroscopically positive in 1 patient (12.5%), respectively. There were no perioperative mortalities. Major postoperative complications occurred in 3 patients (37.5%) through peripheral neuropathies, thrombosis of the vascular graft and compartment syndrome of the leg. Median follow-up time was 21 months (range, 12–28). The 2-year overall survival (OS) was 88% improving up to 100% if R0 resection was achieved. In patients with positive pathologic margins (n = 2), the 2-year OS was 50%. All women showed an improved QoL after surgery. Conclusion LEPR with iliopsoas resection can be safely performed in selected cases with lateral isolated gynecological relapse involving the PSW and was associated with improved QoL and prolonged survival when an R0 resection was achieved.

Introduction Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a debilitating autoimmune neuropathy that is treated with intravenous immunoglobulin (IVIG). The aim of this retrospective study was to investigate the efficacy and safety of the sucrose-free IVIG Octagam® (Octapharma AG, Lachen, Switzerland) in patients with CIDP. Methods Data from 47 patients who received at least one dose of Octagam were collected from the records of 11 centres in France. Efficacy was assessed using Overall Neuropathy Limitation Scale (ONLS). Safety was evaluated using adverse event rates. Results Data from 24 patients who were IVIG naïve (n = 11) or had stopped IVIG ≥ 12 weeks before initiation of Octagam therapy (washout group; n = 13) were included in the efficacy analysis. At 4 months post-initiation of Octagam treatment, 41.7% of patients had improved their functional status (decrease of ≥ 1 ONLS score) with a significant change in the ONLS score from baseline (– 0.42; p = 0.04; signed test). Functional status was reduced in only two patients: one patient in the IVIG-naïve group and one patient in the IVIG-washout group. All 47 patients were included in the safety analysis, which showed that Octagam was well tolerated, with a frequency of 0.04 adverse events per Octagam course. The most common adverse drug reaction was headache. Conclusions These real-life results are consistent with the efficacy and safety of IVIG reported in randomised controlled studies. A long-term prospective study of Octagam in patients with CIDP is warranted. Funding Octapharma, France SAS.

International audience; BACKGROUND:Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.METHODS:We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).RESULTS:At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P

Neuromuscular choristoma (NMC) is a very rare, developmental malformation characterized by the endoneurial intercalation of mature muscle fibers among peripheral nerve fibers. NMC typically arises in the major proximal peripheral nerves, most commonly the sciatic nerve, and may involve the lumbosacral and brachial plexus. Patients present clinically with progressive neuropathy or plexopathy. NMC is strongly associated with development of a fibromatosis, histologically identical to conventional desmoid-type fibromatosis (NMC-fibromatosis). The development of NMC-fibromatosis is often precipitated by iatrogenic trauma (ie, biopsy). Desmoid-type fibromatosis is characterized by CTNNB1 exon 3 mutations, which result in aberrant nuclear β-catenin localization and dysregulated canonical Wnt signaling. In contrast, the pathogenesis of NMC and NMC-fibromatosis is unknown. Desmoid-type fibromatosis expresses estrogen receptors (ER), specifically the ER-beta isoform (ERβ), and endocrine therapies may be used in surgically unresectable cases. In contrast, the ER expression profile of NMC-fibromatosis is unknown. We evaluated a series of NMC and NMC-fibromatosis for CTNNB1 mutations, β-catenin expression, and ER isoform expression. Five NMCs occurred in 2 female and 3 male patients (median age: 14 y, range T (p.S45F) and 1 c.121 A>G (p.T41A). Four patients subsequently developed NMC-fibromatosis, and all 4 cases contained CTNNB1 mutations, including 1 p.T41A and 3 p.S45F mutations. In 3 patients, the NMC and NMC-fibromatosis had identical CTNNB1 mutations. Only 1 NMC had no detectable CTNNB1 mutation; however, the patient's subsequent NMCfibromatosis had a CTNNB1 p.T41A mutation. All NMC and NMC-fibromatosis showed aberrant nuclear localization of β-catenin, nuclear ERβ expression, and no ERα expression. The presence of CTNNB1 mutations both in NMC and NMC-fibromatosis may be a shared molecular genetic abnormality underlying their pathogenesis.

AIM: This study aimed to confirm the role of f VEGF gene 936 C/T polymorphism and Diabetic Polyneuropathy (DPN) in the Indonesian population as well as to investigate its relationship with VEGF-A level and the role of vascular risk factors. MATERIAL AND METHODS: This was a cross-sectional study involving 152 subjects. Clinical symptoms and signs of DPN were examined using DNE and DNS scoring followed by nerve conduction study. All subjects underwent anthropometric, clinical examination and laboratory procedures to obtain body mass index, HbA1C level, lipid profile, Polymorphism of +936 C/T VEGF gene (PCR-RFLP technique), and VEGF-A plasma level (ELISA). Statistical analysis using a t-test or Mann-Whitney was performed to assess continuous data and Chi-square for categorical data. Multivariate logistic regressions were also performed to determine the relationship between independent variables and DPN. RESULTS: Sixty-nine (45.4%) fulfilled the diagnostic criteria of DPN. There was a significant association between CT + TT genotype and DPN (OR 0.35 95%CI 0.16-0.79 p = 0.01). Multivariate logistic regression showed that plasma VEGF-A level (OR = 1.003; 95% CI = 1.000-1.007; p = 0.03), diabetes duration (OR = 1.108; 95% CI = 1.045-1.175; p = 0.001), and CT+TT genotype (OR = 0.347; 95%CI = 0.148-0.817; p = 0.013) were associated with DPN. Sub-group analysis on subjects with HbA1C level ≥7% showed that VEGF-A (OR = 1.011; 95%CI = (1.004-1.017; p = 0.03), diabetes duration (OR = 1.245; 95% CI = 1.117-1.388; p < 0.001), CT + TT genotype (OR = 0.259; 95%CI = 0.074-0.911p = 0.035), with an adition of HDL (OR = 0.916; 95% CI = 0.857-0.978; p = 0.009) were significant predictors of DPN while LDL (OR = 1.017; 95% CI = 1.000-1.035; p = 0.053) acted as modifying factor. CONCLUSION: It appeared that CT + TT genotype of VEGF +936 gene might act as a protecting factor for DPN while VEGF-A, diabetes duration, HDL, and LDL acted as risk factors especially on subjects with HbA1C level ≥ 7.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect of cancer treatment; however, the effects of CIPN on the daily life of individuals are not completely understood. CIPN can be induced by several types of drugs that are widely used in the treatment of solid and hematological malignancies. Our knowledge of the mechanisms underlying CIPN is incomplete, but structural properties of the various neurotoxic compounds might contribute to variations in the pathogenetic mechanisms of damage, in addition to the type of neurotoxicity, severity of the clinical condition, and incidence of CIPN. No drugs capable of preventing the occurrence of CIPN or ameliorating its long-term course are available, and chemotherapy schedule modification is often required to limit its severity, which could potentially prevent patients from receiving the most effective treatment for cancer. Moreover, symptomatic therapy is often largely ineffective in reducing CIPN symptoms. In this Review, the mechanistic and clinical aspects of this unpredictable condition are considered, along with the controversial aspects of CIPN, including the onset mechanisms associated with the different drug types, assessment of the patient's condition, and the current status of neuroprotection and treatment options.

Carpal tunnel syndrome (CTS) is a musculoskeletal condition that often impairs the fitness to work. Our aim is to retrospectively evaluate the association between physical exposures in meat processing industry in Northern Italy and the CTS, taking into account non-occupational factors.A cross-sectional study was performed to include 434 workers (236 males, 198 females, 37.0±10.6 years old, working age: 12.6±10.8 years) from meat processing industries. Signs and symptoms were collected at the compulsory occupational medical surveillance. Occupational risk factors were assessed through a questionnaire and direct assessment by investigators. Adjusted odds ratios (ORDiagnosis of the CTS was reported for 61 out of 434 subjects (14.1%) for an incidence of 11.3/1000 person- years. In general, signs and symptoms for the CTS were associated with the following demographic factors: smoking history (OR = 1.909, 95% confidence interval (CI): 1.107-3.293), previous traumas of the upper limb (OR = 3.533, 95% CI: 1.743-7.165), hypothyroidism status (OR = 7.897, 95% CI: 2.917-21.38) and, in the case of female participants only, previous pregnancies (OR = 2.807, 95% CI: 1.200-6.566) as well as a personal history of oral contraceptive therapy and/or steroidal replacement therapy (OR = 11.57, 95% CI: 4.689-28.56). The carpal tunnel syndrome cases were associated with the following occupational factors (4 h/day): forceful hand exertion (ORIncreasing levels of hand activity and force were associated with the increased CTS prevalence among participants. Recommendations have to be provided in order to reduce occupational exposure to these risk factors and improve medical surveillance. Med Pr 2017;68(2):199-209.Carpal tunnel syndrome (CTS) is a musculoskeletal condition that often impairs the fitness to work. Our aim is to retrospectively evaluate the association between physical exposures in meat processing industry in Northern Italy and the CTS, taking into account non-occupational factors.A cross-sectional study was performed to include 434 workers (236 males, 198 females, 37.0±10.6 years old, working age: 12.6±10.8 years) from meat processing industries. Signs and symptoms were collected at the compulsory occupational medical surveillance. Occupational risk factors were assessed through a questionnaire and direct assessment by investigators. Adjusted odds ratios (ORDiagnosis of the CTS was reported for 61 out of 434 subjects (14.1%) for an incidence of 11.3/1000 person- years. In general, signs and symptoms for the CTS were associated with the following demographic factors: smoking history (OR = 1.909, 95% confidence interval (CI): 1.107–3.293), previous traumas of the upper limb (OR = 3.533, 95% CI: 1.743–7.165), hypothyroidism status (OR = 7.897, 95% CI: 2.917–21.38) and, in the case of female participants only, previous pregnancies (OR = 2.807, 95% CI: 1.200–6.566) as well as a personal history of oral contraceptive therapy and/or steroidal replacement therapy (OR = 11.57, 95% CI: 4.689–28.56). The carpal tunnel syndrome cases were associated with the following occupational factors (4 h/day): forceful hand exertion (ORIncreasing levels of hand activity and force were associated with the increased CTS prevalence among participants. Recommendations have to be provided in order to reduce occupational exposure to these risk factors and improve medical surveillance. Med Pr 2017;68(2):199–209.

Objectives The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. Methods In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Results Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. Conclusions MTX may be effective and safe for remission-maintenance in AAV. Trial registration clinicaltrials.gov NCT00751517.

Peripheral neurotoxicity is a frequent complication limiting docetaxel chemotherapy in patients with cancer. We developed an experimental model that closely mimics the course of neuropathy in patients, aiming to investigate both the mechanisms of neurotoxicity at biochemical, functional and morphological levels and the potential neuroprotective role of neuroactive steroids. We demonstrated that treatment with dihydroprogesterone (DHP) or progesterone (P) counteracts docetaxel-induced neuropathy, preventing nerve conduction and thermal threshold changes, and degeneration of skin nerves in the foodpad. Neuroactive steroids also counteract the changes in gene expression of several myelin proteins and calcitonin gene-related peptide induced by docetaxel in sciatic nerve and lumbar spinal cord, respectively. Most nerve abnormalities observed during the treatment with docetaxel spontaneously recovered after drug withdrawal, similarly to what occurs in patients. However, results of midterm follow-up experiments indicated that animals cotreated with DHP or P have a faster recovery of the neuropathy compared with docetaxel-treated rats. Our study confirmed that neuroactive steroids exert a protective effect on peripheral nerves at different levels, suggesting that they might represent a new therapeutic frontier for patients with chemotherapy-induced neuropathy.

Background Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. Methods First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Results Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. Conclusions These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0732-2) contains supplementary material, which is available to authorized users.

Objectives Carpal tunnel syndrome (CTS) is the most common nerve entrapment syndrome, which since the beginning of the seventies has been linked to the keyboard and visual display unit (VDU). The objective of this study was to investigate the prevalence and personal factors associated with CTS in female VDU workers in Italy. Material and methods Participants in this study were female adult subjects, working ≥ 20 h/week (N = 631, mean age 38.14±7.81 years, mean working age 12.9±7.24 years). Signs and symptoms were collected during compulsory occupational medical surveillance. The binary logistic regression was used to estimate adjusted odds ratios for the factors of interest. Results Diagnosis of CTS was reported in 48 cases (7.6%, 11 of them or 1.7% after a surgical correction) for the incidence of 5.94/1000 person-years. In general, signs and symptoms of CTS were associated with the following demographic factors: previous trauma of upper limb (adjusted odds ratio (ORa) = 8.093, 95% confidence interval (CI): 2.347-27.904), history (> 5 years) of oral contraceptives therapy/hormone replacement therapy (ORa = 3.77, 95% CI: 1.701-8.354) and cervical spine signs/symptoms (ORa = 4.565, 95% CI: 2.281-9.136). Conclusions The prevalence of CTS was similar to the estimates for the general population of Italy. Among personal risk factors, hormone therapy, previous trauma of the upper limb and signs/symptoms of the cervical spine appeared to be associated with a higher risk of CTS syndrome. Eventually, the results reinforce interpretation of CTS in VDU workers as a work-related musculoskeletal disorder rather than a classical occupational disease. Int J Occup Med Environ Health 2016;29(6):927-936.

Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory small-diameter nerve fibers, which are affected early in peripheral neuropathies. The aim of this work was to provide normative reference data on the density of intraepidermal nerve fibers (IENFs) and Langerhans cells in the hindpaw footpad of Sprague-Dawley and Wistar rats. We also evaluated the sensibility of IENF density by comparing neuropathologic findings with neurophysiologic examination and the presence of peripheral neuropathy in two well-characterized animal models of neuropathy. IENF density was quantified in 22 Sprague-Dawley rats and 13 Wistar rats and compared with 19 age-matched Sprague-Dawley rats with streptozotocin-induced diabetic neuropathy and 30 age-matched Wistar rats with cisplatin- or paclitaxel-induced neuropathy. Antidromic tail sensory nerve conduction velocity (SNCV) was assessed in all animals. IENF and Langerhans cell densities were constant in healthy Sprague-Dawley rats at any age, and they were similar to those observed in healthy Wistar rats. In neuropathic rats, both SNCV and IENF density were significantly reduced with respect to controls. Quantification of IENF density was significantly correlated with changes in conduction velocity. Diabetic neuropathy rats alone showed a significantly higher density of Langerhans cells compared with controls. Our study demonstrated that IENF density quantification correlates with SNCV changes and suggests that this might represent a useful outcome measurement in experimental neuropathies. © 2005 Peripheral Nerve Society.

To evaluate nervous system involvement in a cohort of Italian patients with primary Sjogren’s syndrome (pSS), 87 unselected patients (83 female, and four male) observed consecutively at our institution over a period of 5 years were screened by clinical and instrumental (MRI, SPECT, electrophysiological testing, CSF analysis) investigations for peripheral and central neurological abnormalities. Seroimmunological parameters and extraglandular features other than neurological manifestations were also evaluated. Seven patients had central nervous system (CNS) disease (8%), mostly non-focal dysfunction, and 12 had peripheral nervous system (PNS) disease (13.8%), mostly mild or severe sensory or sensory-motor polyneuropathies. One patient had concomitant CNS and PNS involvement. Compared with CNS disease, PNS involvement occurred in older patients (450 years), independent of the disease duration. Patients with and without neurological abnormalities did not differ for seroimmunological parameters (including antiphospholipid antibodies) or extraglandular manifestations. From a statistical point of view, the only relevant finding was the detection of a slight increase in serum IgA and IgM levels (p50.05) in patients with an intact nervous system. Neurological involvement in pSS, be it central or peripheral, is not a rare finding. A careful clinical neurological evaluation, combined with a multiplicity of instrumental investigations, is recommended in the global assessment of pSS patients.

In the present study, we investigated the peripheral nervous system (PNS) (both in terms of its ultrastructure and in terms of its function) of rats made cobalamin (Cbl)-deficient either through total gastrectomy or through prolonged feeding on a Cbl-deficient diet. In both these types of Cbl-deficient neuropathies we found: (a) ultrastructurally, intramyelin and endoneural edema, with no or minimal axonal damage in the PNS, in dorsal root ganglia, and the ventral and dorsal rootlets of the spinal cord; (b) electrophysiologically, a significant reduction in the nerve conduction velocity, consistent with that reported in (a); (c) morphometrically, a significant reduction in the density of myelinated fibers both in the sciatic nerve and in the peroneal nerve. All these pathological changes were reversed by chronic postoperative administration of Cbl into totally gastrectomized (TGX)-rats, hinting at the specificity of the damage itself in relation to the permanent Cbl-deficient status of the TGX-rats. No signs of segmental demyelination or remyelination were found. We also observed a turning of type I fibers into type II fibers in the soleus muscle of all our Cbl-deficient rats, however the Cbl deficiency had been induced. This muscular change was still present in TGX- and Cbl-treated rats, and it cannot be related to a malnutrition status, since it has been observed also in rats fed a Cbl-deficient diet. All these results demonstrate that Cbl deficiency strongly affects rat PNS within different parameters.

To devise a rapid, sensitive method to quantify tactile threshold of finger pads for early detection and staging of peripheral neuropathy and for use in clinical trials.Subjects were 166 healthy controls and 103 patients with, or at risk for, peripheral neuropathy. Subjects were screened by questionnaire. The test device, the Bumps, is a checkerboard-like smooth surface with 12 squares; each square encloses 5 colored circles. The subject explores the circles of each square with the index finger pad to locate the one circle containing a small bump. Bumps in different squares have different heights. Detection threshold is defined as the smallest bump height detected. In some subjects, a 3-mm skin biopsy from the tested finger pad was taken to compare density of Meissner corpuscles (MCs) to bump detection thresholds.The mean (±SEM) bump detection threshold for control subjects was 3.3 ± 0.10 μm. Threshold and test time were age related, older subjects having slightly higher thresholds and using more time. Mean detection threshold of patients with neuropathy (6.2 ± 0.35 μm) differed from controls (p0.001). A proposed threshold for identifying impaired sensation had a sensitivity of 71% and specificity of 74%. Detection threshold was higher when MC density was decreased.These preliminary studies suggest that the Bumps test is a rapid, sensitive, inexpensive method to quantify tactile sensation of finger pads. It has potential for early diagnosis of tactile deficiency in subjects suspected of having neuropathy, for staging degree of tactile deficit, and for monitoring change over time.

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a frequent, potentially severe and dose-limiting side-effect of cancer treatment. Despite its clinical relevance that limits the use of several antineoplastic agents and even the future development of new anticancer drugs, several crucial aspects of CIPN remain unsolved, one of which is how to assess its occurrence and severity in the most effective and reliable way. CIPN severity is generally assessed using Common Toxicity Criteria (CTC) scales, although it is well known that significant inter-observer disagreement exists using these scales. Moreover, most CTC scores mix impairment, disability and quality of life measures, which could lead to misinterpretation of the results and unpredictable under- or overestimation of the effect. This uncertainty may lead to different interpretations of the results of the same clinical trials by clinicians and also by regulatory agencies. The use of other types of scale based on clinical and instrumental examinations, or the use of self-administered questionnaires for patients, has not yet really improved the accuracy of CIPN assessment, although some of these tools are promising and deserve to be further validated. As a result, there is a general recognition that CIPN has still not been properly assessed and that improvements should be made. In this review, the available data regarding the different tools used to assess CIPN will be revised and their features will be critically examined, with a special focus on their reliability and reproducibility across examiners and, when available, through direct comparison. © 2009 Elsevier Ltd. All rights reserved.

Cisplatin, paclitaxel and bortezomib belong to some of the most effective families of chemotherapy drugs for solid and haematological cancers. Epothilones represent a new family of very promising antitubulin agents. The clinical use of all these drugs is limited by their severe peripheral neurotoxicity. Several in vivo rat models have reproduced the characteristics of the peripheral neurotoxicity of these drugs. However, since only a very limited number of cancer types can be studied in immunocompetent rats, these animal models do not represent an effective way to evaluate, at the same time, the antineoplastic activity and the neurotoxic effects of the anticancer compounds. In this study, we characterized the neurophysiological impairment induced by chronic chemotherapy treatment in BALB/c mice, a strain suitable for assessing the activity of anticancer treatments. At the end of a 4-week period of treatment with cisplatin, paclitaxel, epothilone-B or bortezomib, sensory and sensory/motor nerve conduction velocities (NCV) were determined in the caudal and digital nerves and dorsal root ganglia (DRG) and sciatic nerves were collected for histopathological analysis. The electrophysiological studies revealed that all the compounds caused a statistically significant reduction in the caudal NCV, while impairment of the digital NCV was less severe. This functional damage was confirmed by the histopathological observations evidencing axonal degeneration in the sciatic nerve induced by all the drugs associated with pathological changes in DRG induced only by cisplatin and bortezomib. These results confirm the possibility to use our models to combine the study of the antineoplastic activity of anticancer drugs and of their toxic effects on the peripheral nervous system in the BALB/c mouse strain.

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

The role of Glutamate (Glu), one of the major excitatory neurotransmitters in the central nervous system, has been thoroughly investigated in animal models and in humans in several physiologic events, such as brain development and synaptic plasticity, but also in acute and chronic neurologic diseases and psychiatric disorders. Recently, it has been demonstrated that Glu is important for sensory input transduction, particularly along the nociceptive pathway. Glu involvement in peripheral neuropathies has also been suggested on the basis of experimental studies in animals, thus widening the spectrum of possible sites of action of this neurotransmitter from the central to the peripheral nervous system. This rather unexpected observation may have important therapeutic implications, provided that a complete characterization of the glutamatergic system in the peripheral nervous system is achieved and its changes under the different pathological conditions are investigated. This review will focus on the most recent advances in the research into the role of Glu and the glutamatergic system in the pathology of the peripheral nervous system.

Peripheral neuropathy, either inherited or acquired, represents a very common disorder for which effective clinical treatments are not available yet. Observations here summarized indicate that neuroactive steroids, such as progesterone, testosterone and their reduced metabolites, might represent a promising therapeutic option. Peripheral nerves are able to synthesize and metabolize neuroactive steroids and are a target for these molecules, since they express classical and non-classical steroid receptors. Neuroactive steroids modulate the expression of key transcription factors for Schwann cell function, regulate Schwann cell proliferation and promote the expression of myelin proteins involved in the maintenance of myelin multilamellar structure, such as myelin protein zero and peripheral myelin protein 22. These actions may result in the protection and regeneration of peripheral nerves affected by different forms of pathological alterations. Indeed, neuroactive steroids are able to counteract biochemical, morphological and functional alterations of peripheral nerves in different experimental models of neuropathy, including the alterations caused by aging, diabetic neuropathy and physical injury. Therefore, neuroactive steroids, pharmacological agents able to increase their local synthesis and synthetic ligands for their receptors have a promising potential for the treatment of different forms of peripheral neuropathy. © 2007 Elsevier B.V. All rights reserved.

This study examined the dose-dependent efficacy of erythropoietin (EPO) for preventing and/or treating cisplatin (CDDP) induced peripheral neurotoxicity (CINP), and its influence on tumour treatment and growth. Rats received eight intraperitoneal (ip) injections of 2 mg/kg CDDP twice weekly. EPO co-administered (50 or 10 microg/kg ip, three times/week) had a dose-dependent effect, partially preventing CINP, but 0.5 microg/kg ip was not effective. The neuroprotective effect lasted at least 5 weeks after the last dose of EPO and CDDP. In addition, EPO (50 microg/kg ip three times/week) after the last injection of CDDP still induced a significant recovery of CINP. In a separate experiment in rats bearing mammary carcinoma EPO treatment (50 microg/kg ip) given concurrently with CDDP (1.0 and 1.5 mg/kg twice a week for four weeks) was neuroprotective without influencing the effectiveness of the treatment or tumour growth. EPO thus appears to be an effective neuroprotectant that does not interfere with tumour treatment.

Background Cisplatin and several related antineoplastic drugs used to treat many types of solid tumours are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought. Objectives To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs. Search methods On 4 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and CINAHL Plus for randomised trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related drugs among human patients. Selection criteria We included randomised controlled trials (RCTs) or quasi-RCTs in which the participants received chemotherapy with cisplatin or related compounds, with a potential chemoprotectant (acetylcysteine, amifostine, adrenocorticotrophic hormone (ACTH), BNP7787, calcium and magnesium (Ca/Mg), diethyldithiocarbamate (DDTC), glutathione, Org 2766, oxcarbazepine, or vitamin E) compared to placebo, no treatment, or other treatments. We considered trials in which participants underwent evaluation zero to six months after completing chemotherapy using quantitative sensory testing (the primary outcome) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary outcomes). Data collection and analysis Two review authors assessed each study, extracted the data and reached consensus, according to standard Cochrane methodology. Main results As of 2013, the review includes 29 studies describing nine possible chemoprotective agents, as well as description of two published meta-analyses. Among these trials, there were sufficient data in some instances to combine the results from different studies, most often using data from secondary non-quantitative measures. Nine of the studies were newly included at this update. Few of the included studies were at a high risk of bias overall, although often there was too little information to make an assessment. At least two review authors performed a formal review of an additional 44 articles but we did not include them in the final review for a variety of reasons. Of seven eligible amifostine trials (743 participants in total), one used quantitative sensory testing (vibration perception threshold) and demonstrated a favourable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Furthermore the change measured was subclinical. None of the three eligible Ca/Mg trials (or four trials if a single retrospective study was included) described our primary outcome measures. The four Ca/Mg trials included a total of 886 participants. Of the seven eligible glutathione trials (387 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing but reported disparate results; meta-analyses of three of these trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. Similarly, none of the three eligible vitamin E trials (246 participants) reported quantitative sensory testing. The eligible single trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), oxcarbazepine (32 participants), and retinoic acid (92 participants) did not perform quantitative sensory testing. In all, this review includes data from 2906 participants. However, only seven trials reported data for the primary outcome measure of this review, (quantitative sensory testing) and only nine trials reported our objective secondary measure, nerve conduction test results. Additionally, methodological heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) ≥ 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766). Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity. Authors' conclusions At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results were negative and did not support the positive findings based on the qualitative measures. In summary, the present studies are limited by the small number of participants receiving any particular agent, a lack of objective measures of neuropathy, and differing results among similar trials, which make it impossible to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs.

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.

Skin biopsy has become a widely used tool to investigate small calibre sensory nerves including somatic unmyelinated intraepidermal nerve fibres (IENF), dermal myelinated nerve fibres, and autonomic nerve fibres in peripheral neuropathies and other conditions. Different techniques for tissue processing and nerve fibre evaluation have been used. In March 2004, a Task Force was set up under the auspices of the European Federation of Neurological Societies (EFNS) with the aim of developing guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathies. We searched the Medline database from 1989, the year of the first publication describing the innervation of human skin using immunostaining with anti-protein-gene-product 9.5 (PGP 9.5) antibodies, to 31 March 2005. All pertinent papers were rated according to the EFNS guidance. The final version of the guidelines was elaborated after consensus amongst members of the Task Force was reached. For diagnostic purposes in peripheral neuropathies, we recommend performing a 3-mm punch skin biopsy at the distal leg and quantifying the linear density of IENF in at least three 50-mum thick sections per biopsy, fixed in 2% PLP or Zamboni's solution, by bright-field immunohistochemistry or immunofluorescence with anti-PGP 9.5 antibodies (level A recommendation). Quantification of IENF density closely correlated with warm and heat-pain threshold, and appeared more sensitive than sensory nerve conduction study and sural nerve biopsy in diagnosing small-fibre sensory neuropathy. Diagnostic efficiency and predictive values of this technique were very high (level A recommendation). Confocal microscopy may be particularly useful to investigate myelinated nerve fibres, dermal receptors and dermal annex innervation. In future, the diagnostic yield of dermal myelinated nerve fibre quantification and of sweat gland innervation should be addressed. Longitudinal studies of IENF density and regeneration rate are warranted to correlate neuropathological changes with progression of neuropathy and to assess the potential usefulness of skin biopsy as an outcome measure in peripheral neuropathy trials (level B recommendation). In conclusion, punch skin biopsy is a safe and reliable technique (level A recommendation). Training in an established cutaneous nerve laboratory is recommended before using skin biopsy as a diagnostic tool in peripheral neuropathies. Quality control at all levels is mandatory.

A consecutive sample of 76 chronic alcoholic patients was studied clinically, biochemically and electrophysiologically to assess clinical and/or subclinical signs of alcohol-related neuropathy as well as the most important and disputed risk factors for neuropathy such as age, parental history of alcoholism, nutritional status, alcoholic disease duration and total lifetime dose of ethanol (TLDE). The results show that alcohol-related neuropathy, especially when subclinical, seems to be frequent and mostly characterized by axonal degeneration of peripheral nerve fibres with earlier and more frequent involvement of sensory fibres and lower limbs. Moreover, positive family history of alcoholism, but above all alcoholic disease duration and TLDE, could be more important factors than malnutrition in determining neuropathy.

Anti-sulfatide IgM antibodies have been recently associated with neuropathy but the clinical and electrophysiological correlations of this reactivity remains unclear. We reviewed the clinical and electrophysiological features of patients with high anti-sulfatide titers detected in our laboratory from 1991 to 1998. Of the 564 patients with different neurological diagnosis tested by enzyme-linked immunosorbent assay (ELISA), 11 had high anti-sulfatide IgM titers (>1/8000), 26 had titers of 1/8000 while 78 had titers of 1/4000. All patients with high anti-sulfatide IgM titers had a chronic, dysimmune, mostly sensorimotor neuropathy that in seven was associated with IgM monoclonal gammopathy. In most of these patients electrophysiological and morphological studies were consistent with a predominantly demyelinating neuropathy frequently associated with prominent axonal loss. Antibody titers of 1/8000, though always associated with neuropathy, did not correlate with a particular form or cause of neuropathy, while lower titers were equally distributed in patients with different neurological disorders. Our study indicate that high anti-sulfatide IgM titers (>1/8000) are highly predictive for a chronic, dysimmune, mostly demyelinating neuropathy often associated with IgM monoclonal gammopathy, and may therefore have potential diagnostic relevance.

Skin is a reservoir of sensory and autonomic nerve fibers that are potential indicators of peripheral nerve disease. Biopsies of skin have shown that sensory nerves in the most superficial layer of skin, the epidermal nerve fibers (ENFs), are reduced in patients with polyneuropathy. This report describes a minimally invasive skin blister method to isolate, image, and obtain quantitative analysis of ENFs. Blisters are made by applying a suction capsule to skin. The epidermal roof of the blister is excised, immunostained, whole mounted, and analyzed for ENF number and distribution. A reduction in number and abnormal distribution of ENFs are early indicators of peripheral nerve disease. Illustrations of skin blister and skin biopsy specimens from patients with different types of peripheral nerve disorders are included. These patients were chosen because their findings demonstrate the complementary information obtained by the blister and biopsy methods and the potential of the blister procedure to evaluate single nerve lesions and polyneuropathy and to follow the progress of ENF degeneration and regeneration.

In recent years several authors have described a close correlation between circulating antineuronal antibodies of different types and the occurrence of paraneoplastic neurological syndromes. Because this has not been widely accepted, we screened 300 serum samples from 181 ovarian cancer patients for the presence of circulating antineuronal antibodies by immunofluorescence. The findings were confirmed by immunoblotting. In 11 patients circulating antineuronal antibodies were detected. In 4 patients they were classified as anti-Yo and in 7 as anti-Ri, titres ranging from 1 : 400 to 1 : 204 800. All the patients underwent thorough neurological and neurophysiological investigations, with special regard to paraneoplastic syndrome. None of them had symptoms pointing to a paraneoplastic neurological syndrome, although patients were followed up to 2 years after the first examination. Thus the frequency of circulating antineuronal antibodies in ovarian cancer patients is higher than the frequency of paraneoplastic syndromes, and antibody positivity does not necessarily lead to the appearance of a neurological paraneoplastic syndrome.

The published information on glutamate levels in cere- brospinal fluid (CSF) and modifications in neurological disorders is controversial. In the present study, we demonstrated a metabolic instability of glutamate in untreated CSF and a spurious elevation of its levels by the current methods of CSF acidification. These findings may explain the discrepancies observed with different methods of CSF processing and analysis. We suggest a method of inactivating CSF enzymes that yields stable glutamate levels under different storage conditions. Use of such a method may be necessary for clinical studies

Background: Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate owing to publication of more relevant articles. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. Methods: Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30th, 2009. All pertinent articles were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. Results and Conclusions: Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (Recommendation Level A). Normative reference values are available for bright-field immunohistochemistry (Recommendation Level A) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (Recommendation Level A). Newly established laboratories should undergo adequate training in a well-established skin biopsy laboratory and provide their own stratified for age and gender normative values, intra- and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels, are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (Recommendation Level B).A reduced IENF density is associated with the risk of developing neuropathic pain (Recommendation Level B), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (Recommendation Level C). However, further studies are warranted to confirm its potential usefulness as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3-mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35 000 biopsies and a mere 0.19% incidence of non-serious side effects in about 15 years of practice (Good Practice Point).

The use of high doses of cisplatin (DDP) in the treatment of different solid tumors is often prevented by the onset of a disabling sensory neuropathy. In an attempt to minimize DDP-induced neurotoxicity different schedules of DDP administration have been tested. Moreover, during the past few years some putative neuroprotective drugs have been reported as reducing DDP neurotoxicity. In this prospective, randomized study we evaluated in a series of 33 patients affected by relapsing ovarian cancer the effect on the sensory pathway of a non-conventional schedule of DDP administration as monochemiotherapy or in combination with one of the neuroprotective drugs (i.e. glutathione). The results of the neurophysiologic examinations performed before and immediately after chemotherapy suggest that these schedules besides being safe and effective in the treatment of the ovarian cancer, have an extremely low peripheral neurotoxicity neurotoxicity of cisplatin

Background. Taxol is a new anticancer drug that acts as a tubulin polymeration enhancer. Its major toxicities are myelosuppression, hypersensitivity, and mucositis, but it also induces peripheral nerve damage. The use of taxol has recently been proposed for platinum-resistant cancers, but in these cases there is a possibility of cumulative toxicity in the peripheral nervous system. Methods. Twenty-two patients affected by a relapse of cisplatin-treated ovarian cancer were examined clinically and neurophysiologically to determine the evolution of taxol-induced peripheral somatic and autonomic neurotoxicity and the possible cumulative effect of a combination of taxol and cisplatin. Each patient was examined before, during, and after taxol treatment (using a dose of 135 or 175 mg/m2 in 3 hours every 3 weeks). Results. No patients were excluded from the study because of unacceptable toxicities of any kind. The serial examinations demonstrated that taxol induced onset of (or worsening of preexisting) neuropathic symptoms and signs in almost all the patients. The features were those of a distal, symmetrical, sensory polyneuropathy due to an axonopathy. Motor nerves and the autonomic nervous system were unaffected. Taxol neurotoxicity appeared early in the course of the treatment (i.e., after three courses) and was not severely disabling. In most cases after the early onset of peripheral neuropathy, stabilization of this side effect occurred. Conclusions. Considering the low doses of taxol used in this study, the sensory nerve damage was unexpectedly severe. It appears that a cumulative, but not dose-limiting, neurotoxic effect occurs using taxol in patients previously treated with cisplatin. Cancer 1995;75:1141–50.

A case of angioimmunoblastic lymphadenopathy with dysproteinaemia complicated by a subacute peripheral neuropathy is described. Clinically the neuropathy was mainly motor, but pain and paraesthesiae in the legs were also present. Sural nerve biopsy indicated decreased numbers of myelinated fibres, mainly the largest, without actual signs of degeneration or regeneration. However, the occurrence of denervation bands indicated that degeneration had led to loss of myelinated fibres.

3 peptic ulcer patients, treated for a few weeks with Trithiozine, developed polyneuropathy. The histopathological patterns in the 2 patients in whom sural nerve biopsy was done presented wallerian degeneration of the axons of the myelinated fibers, especially those of larger caliber. The evidence for a iatrogenic toxic etiology is discussed.

Following ingestion of marine fish in Thailand this patient complained of gastrointestinal and neurological disturbances, marked by severe, mainly motor, demyelinating polyneuropathy, which worsened on her return to Italy a few days later. The clinical pattern, electromyography, cerebrospinal fluid test and sural nerve biopsy by electronmicroscopy permitted the diagnosis of polyneuropathy secondary to ciguatoxin poisoning.

Electrophysiological examination of the peroneal nerve was performed in a group of individuals exposed for professional reasons to vapours of n-heptane. The results suggest a probably specific role of this hydrocarbon compound in provoking "minimal" peripheral nerve damage.