Chronic Peripheral Neuropathy Research Articles

Leprosy neuropathy: clinical presentations

Leprosy is a chronic infectious peripheral neuropathy caused by Mycobacterium leprae. The different clinical presentations of the disease are determined by the quality of the host immune response. Early detection of leprosy and treatment by multidrug therapy are the most important steps in preventing deformity and disability. Thus the early recognition of the clinical leprosy presentation is essential. Mononeuritis, mononeuritis multiplex (MM), polyneuritis (MM summation) are the most frequent. The frequent anesthetic skin lesions are absent in the pure neuritic leprosy presentation form. Isolated peripheral nerve involvement is common, including the cranial ones. Arthritic presentation is occasionally seen, usually misdiagnosed as rheumatoid arthritis. Attention should be given to autonomic dysfunctions in leprosy. There are clinical presentations with severe neuropathic pain - painful small-fiber neuropathy. Leprous late-onset neuropathy (LLON) clinical presentation should be considered facing a patient who develop an inflammatory neuropathy many years after a previous skin leprosy treatment.

83-Year-Old Man With Nausea, Constipation, and Peripheral Neuropathy

83-Year-Old Man With Nausea, Constipation, and Peripheral Neuropathy

Repeated Administration of Mirtazapine Attenuates Oxaliplatin-Induced Mechanical Allodynia and Spinal NR2B Up-Regulation in Rats

Chemotherapic drugs may elicit acute or chronic peripheral neuropathies. Mirtazapine, as an antidepressant, is also used for the treatment of neuropathic pain. The current study aimed to investigate the effect of mirtazapine on the oxaliplatin-induced neuropathy in rats as well as the underlying mechanism. A neuropathy model was established in Sprague-Dawley rats by intraperitoneal (i.p.) injection of oxaliplatin 4mg/kg twice a week for 4weeks. The therapeutic potential of mirtazapine 10, 20, and 30mg/kg/day per-orally for 28 consecutive days was evaluated. Subsequently, a dose of 1mg/kg of WAY100635 i.p., a selective antagonist of 5-HT1A receptor, was preadministrated before mirtazapine 20mg/kg/day per-orally in oxaliplatin-induced neuropathy. The behavioral tests and the expression of NMDA receptor subunit NR2B were determined. The results displayed that repeated administration of mirtazapine 20 or 30mg/kg/day for 28 consecutive days significantly attenuated the mechanical allodynia and the up-regulation of spinal cord NR2B but not the cold hyperalgesia in rats with oxaliplatin-induced neuropathy, which was reversed by WAY100635 preadministration. Our findings suggest that oxaliplatin-induced mechanical allodynia is associated with spinal NR2B up-regulation, which may be attenuated by mirtazapine administration.

Spinal NTS2 receptor activation reverses signs of neuropathic pain

Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and β-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.

P-0294 - Incidence of Cold-Induced Peripheral Neuropathy and Dose Modification Dm of Adjuvant Oxaliplatin - Based Chemotherapy for Patients with Colorectal Cancer

Background: Xelox (Oxaliplatin + Capecitabine) regimen is used for adjuvant treatment of colorectal cancer since 2005 at the department of oncology Hilleroed Hospital, Denmark. A well known side effect of Oxaliplatin which often leads to dose modification (DM), is acute and chronic peripheral neuropathy. Oxaliplatin induced acute neuropathy (AN) is provoked by cold. It could be expected that the degree of AN and thereby DM is more pronounced in the winter period compared to summer. This has never been studied before.

Authors' reply to the comment by Pazzaglia et al

Since the aetiologies of neuropathic pain are most often degenerative or age related, it is not surprising that these conditions are more common in the elderly (Ahmad and Goucke, 2002; Pickering and Capriz-Ribière, 2008). Neuropathic pain occurs and persists in a heterogeneous group of aetiologically different diseases, with various physio-pathological mechanisms (Cruccu and Truini, 2009; Baron et al., 2012). Patients with neuropathic pain present with various pain-related sensory abnormalities (Baron et al., 2012). Subgrouping patients with neuropathic pain on the basis of individual sensory profiles could guide the choice of pharmacological agents to be proposed to each patient (Bouhassira et al., 2004; Cruccu and Truini, 2009; Baron et al., 2012). We appreciate Pazzaglia et al.'s interest in our study on the characteristics of neuropathic pain in a population of sub-Saharan African elderly, followed for chronic pain of musculoskeletal origin (Lekpa et al., 2013). In this study, we choose to use the neuropathic pain diagnostic questionnaire DN4 (Bouhassira et al., 2005) instead of other validated instruments. Apart from its good discriminative properties for the identification of neuropathic pain, the DN4 questionnaire was easy to use, especially in our sample of elderly patients with a low level of education. Thus, we were able to show through this study that: (1) neuropathic pain existed in African elderly; (2) female gender, low educational status, manual professions, unemployment and diabetes mellitus were significantly associated with the presence of neuropathic pain; (3) chronic spine diseases and painful diabetic peripheral neuropathy are the main causes of neuropathic pain in our sample; and (4) neuropathic pain were neglected by physicians with a low rate of prescription drugs directed against neuropathic pain (Lekpa et al., 2013). In his comments, Pazzaglia et al. presented the methodology and results of a multicentre study they conducted among Italian elderly over 65 years, with peripheral neuropathy (Pazzaglia et al., 2013). The methodology used in our study was different from that used by these authors (musculoskeletal pain vs. peripheral neuropathy). Despite this difference, the results are broadly comparable. Indeed, these authors showed that (Pazzaglia et al., 2013): (1) neuropathic pain are also common in elderly; (2) the aetiologies are numerous; (3) the clinical profile or sensory profile, assessed with the Neuropathic Pain Symptom Inventory (NPSI) (Bouhassira et al., 2004), varies depending on the aetiology; and (4) also the low rate of prescription drugs targeting neuropathic pain. The use of NPSI (Bouhassira et al., 2004) would not have changed the results obtained in our study. However, it would have provided important additional information. We could have had a more accurate assessment of the clinical profile of our patients, differentiating subtypes of neuropathic pain. Indeed, the NPSI was developed and validated for the assessment of different symptoms of neuropathic pain. It is also a simple and easy-to-use instrument for daily practice and clinical studies. The NPSI allows discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain: burning (superficial) spontaneous pain, pressing (deep) spontaneous pain, paroxysmal pain, evoked pain and paraesthesia/dysaesthesia. One important feature of the NPSI is its sensitivity to treatment effects (Bouhassira et al., 2004). Subgrouping neuropathic pain in our study might have permitted us to make assumptions about the appropriate type of drug to offer to each of our patients, according to the sensory profile of the neuropathic pain presented by each patient, as suggested by Bouhassira et al. (2004), but it remains to be confirmed in controlled studies. Until then, it seems important to recommend the use of the NPSI or other neuropathic pain classification instruments (and the DN4 questionnaire) for the diagnosis and clinical assessment of neuropathic pain, both in daily practice and in further clinical studies.

Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) enrolled in two prospective trials

The purpose of this study was to assess the outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in 2 prospective, randomized, open-label clinical trials (1994–2005), with or without Five-Factor Score (FFS)-defined poor-prognosis factors, focusing on survival, disease-free survival, relapses, clinical and laboratory findings, therapeutic responses, and factors predictive of relapse. Forty-four patients with FFS ≥ 1 were assigned to receive 6 or 12 cyclophosphamide pulses plus corticosteroids and the seventy-four with FFS = 0 received corticosteroids alone, with immunosuppressant adjunction when corticosteroids failed. Patients were followed (2005–2011) under routine clinical care in an extended study and data were recorded prospectively. Mean ± SD follow-up was 81.3 ± 39.6 months. Among the 118 patients studied, 29% achieved long-term remission and 10% died. Among the 115 patients achieving a first remission, 41% experienced ≥1 relapses, 26.1 ± 26.8 months after treatment onset, with 57% of relapses occurring when corticosteroid-tapering reached <10 mg/day. Treatment achieved new remissions in >90%, but relapses recurred in 38%. Overall survival was good, reaching 90% at 7 years, regardless of baseline severity. Age ≥65 years was the only factor associated with a higher risk of death during follow-up. The risk of relapse was higher for patients with anti-myeloperoxidase antibodies and lower for those with >3000 eosinophils/mm3. Sequelae remained frequent, usually chronic asthma and peripheral neuropathy. In conclusion, EGPA patients' survival rate is very good when treatment is stratified according to the baseline FFS. Relapses are frequent, especially in patients with anti-myeloperoxidase antibodies and baseline eosinophilia <3000/mm3.

Progressive neurolymphomatosis with cutaneous disease: Response in a patient with mycosis fungoides

Peripheral neurolymphomatosis is a rare manifestation of advanced lymphoproliferative disorders. It is often associated with B cell lymphomas and rarely with cutaneous T cell lymphomas, such as mycosis fungoides and Sézary syndrome. In this case report, we present a 78-year-old male with a long-standing history of mycosis fungoides. The patient initially presented with chronic peripheral neuropathy in an ulnar nerve distribution. After an unsuccessful ulnar nerve transposition, the ulnar nerve was re-explored and a mass consistent with diffuse lymphomatous infiltration was diagnosed. Magnetic resonance (MR) imaging of the left brachial plexus and later of the sacral plexus demonstrated diffuse thickening and peripheral nodularity in keeping with neurolymphomatosis. The patient's clinical course rapidly deteriorated thereafter and the patient succumbed to his disease. Although uncommon, neurolymphomatosis may be considered in patients with chronic peripheral neuropathy and an underlying history of a lymphoproliferative disorder. US and MR may serve as helpful non-invasive adjuncts in making the diagnosis and identifying sites for biopsy.

Skin sympathetic fiber α-synuclein deposits

This study aimed to test whether peripheral α-synuclein staining might be useful for pure autonomic failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral autonomic neuropathy. We studied 21 patients with chronic peripheral autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons. Somatic and autonomic skin innervations were significantly decreased in patients with peripheral autonomic neuropathy compared to controls. No differences were found between acquired autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers. Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral autonomic neuropathy and may shed more light on the pathogenesis of PAF.

Erratum to: Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV

Erratum to: Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV

Comparison of Commercial Tests for Detecting Multiple Anti-Ganglioside Autoantibodies in Patients with Well-Characterized Immune-Mediated Peripheral Neuropathies

To assess the performance of commercial anti-ganglioside antibody assays, we determined anti-ganglioside antibody IgG and IgM isotype profiles of patients with acute and chronic well-characterized immune-mediated peripheral neuropathies by one immunodot assays (Zentec/Ingen: Dotzen Ganglio Profile Ab, Euroimmun/BioAdvance: Euroline ganglioprofile), two line-immuno assay (GA Generic Assays/Labodia: Anti-Gangli osid Dot, Euroimmun/BioAdvance: Euroline ganglioprofile), and one enzyme-linked immunosorbent assay (ELISA) (Bühlmann: GanglioCombi). Specific antibody profiles were compared with those obtained by our validated standard in-house immunodot assay (IDA). We selected 33 sera with high levels of IgG and IgM anti-ganglioside antibodies from 15 patients with Guillain-Barre syndrome (GBS) subtypes and variants, 12 patients with CANOMAD syndrome (chronic ataxic neuropathy with ophthalmoplegia, M-paraprotein, cold agglutinins, disialosyl antibodies), 5 patients with chronic motor peripheral neuropathies, and 1 patient with sensory neuropathy and a control group composed of 10 patients with non-autoimmune neuropathy. The 3 commercial IDAs employing hydrophobic membranes and the ELISA demonstrated different carbohydrate epitopes on 6 to 12 glycolipid antigens used for anti-ganglioside antibody detection. Comparison with the validated in-house IDA showed large variations in sensitivity between tests and a more diverse reactivity to gangliosides than expected. The test with the largest panel of glycolipids detecting 11 anti-ganglioside antibody reactivities (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b, and sulfatide) revealed the best concordance with our in-house assay. However, even with this test, differences were observed in the immunoreactivity against some gangliosides and weakly stained bands were not easy to interpret. Our data suggest an urgent need for standardization of commercial anti-ganglioside assays and the introduction of international anti-ganglioside antibody reference standards.

Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV

Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population. Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.

Calcium channel blockers reduce oxaliplatin-induced acute neuropathy: A retrospective study of 69 male patients receiving modified FOLFOX6 therapy

Oxaliplatin-based chemotherapy has been widely used for colorectal cancer. However, it causes severe acute and chronic peripheral neuropathies. Recently, we reported that calcium channel blockers prevent the oxaliplatin-induced cold hyperalgesia in rats. The purpose of this study was to determine whether the treatment with calcium channel blockers prevents the peripheral neuropathy during oxaliplatin therapy. The electronic medical charts for patients who received modified FOLFOX6 regimen from January 2008 to December 2010 were evaluated. Of the 200 patients who received modified FOLFOX6 therapy, 84 patients were excluded due to the exclusion criteria. Calcium channel blockers had been taken by 26 of 69 male patients, but only three of 47 female patients. Therefore, in the present analysis, the male data of the groups with and without calcium channel blockers (n=26 and 43, respectively) were compared. The cumulative incidence curve of acute neuropathy was significantly lower in the group with calcium channel blockers (P=0.0438, log-rank test), whereas there was no difference between these groups in the cumulative incidence curve of chronic neuropathy (P=0.4919, log-rank test). The present study indicated that calcium channel blockers inhibit the development of acute peripheral neuropathy in patients receiving modified FOLFOX6 therapy.

Dysautonomies des neuropathies périphériques

The mechanisms of dysautonomic disturbances are varied and mostly acquired. They can result from lesions of sympathetic or parasympathetic vegetative fibers located in the peripheral contingent, or in the somatic contingent by demyelination or axonal loss; or more rarely by cellular bodies in the sympathetic or parasympathetic ganglia. Several chronic peripheral neuropathies can be associated with dysautonomia. Only some causes need to be known because they can be clinically significant. Dysautonomia may be seen during chronic acquired neuropathies but also acute or subacute ones. The most frequent cause in the world is the dysautonomia of the diabetes; it affects all the systems; the cardiovascular dysfunction has an impact on the prognosis for survival when it is severe. Hereditary autonomic neuropathies are rare; they can declare themselves very early during the Riley-Day syndrome or very late during amyloid polyneuropathies due to transthyretin gene mutation. The diagnosis can be confirmed by molecular biology. The dysautonomia is frequent and often severe. These neuropathies justify symptomatic treatment to improve quality of life. For some of them, a specific treatment can be proposed to treat the causal affection to try to stop the progression of the disease.

527PD - Pharmacogenetic Predictors of Severe Chronic Peripheral Neuropathy in Stage II-III Colon Cancer (CC) Patients Treated with Oxaliplatin-Based Adjuvant Chemotherapy (CT). A Gemcad Study

ABSTRACT Background Oxaliplatin-based CT is now the standard adjuvant therapy after resection of stage III and selected high-risk stage II CC. However, this treatment is often associated with cumulative peripheral neuropathy. Predicting individual patient risk for developing severe neuropathy could improve the quality of care by allowing the individualization of treatment. Our aim is to identify single nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin sensitivity to predict severe (grade 2-3) oxaliplatin-induced chronic peripheral neuropathy (OXCPN) among stage II-III CC patients who received adjuvant CT. Methods DNA was extracted from formalin-fixed-paraffin-embedded samples from 202 surgically treated high-risk stage II (29.7%) and stage III (70.3%) CC patients receiving adjuvant oxaliplatin and fluoropyrimidines CT (25.24% FOLFOX, 74.75% CAPOX) from January 2004 to December 2008. Median follow-up was 51.4 months (7-96). Genotyping was performed for 35 SNPs in 18 genes involved in oxaliplatin metabolism (ERCC and XRCC groups), cell cycle and drug transport using MassARRAY (SEQUENOM) technology. A total of 177 stage II-III CC patients also treated with oxaliplatin-based CT were enrolled as a validation set. Results Forty-eight (23.8%) patients experienced grade 2-3 OXCPN. The cyclin H (CCNH) (rs2230641) C/C genotype was associated with a higher risk of severe OXCPN (57.1% C/C, 24.2% C/T, 21.3% T/T; RR: 5.197, p = 0.041). In addition, patients harboring the CCNH (rs2230641) C/C and/or ATP-binding cassette subfamily G member (ABCG2) (rs3114018) A/A haplotype had a higher risk of grade 2-3 OXCPN compared to the CCNH (rs2230641) any T and ABCG2 (rs3114018) any C haplotype (36.5% vs. 19.6%, respectively; RR:2.36; 95% CI, 1.17-4.78; p = 0.022). The ability to predict severe OXCPN of this combined analysis was then independently validated in the second cohort (RR: 2.82; 95% CI, 1.41-5.63; p = 0.003). Conclusions Our data suggest that SNPs in CCNH and ABCG2 can predict the development of severe OXCPN in stage II-III CC patients. The analysis of these SNPs may be useful in personalized adjuvant CT. Disclosure All authors have declared no conflicts of interest.

Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy

Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism—a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I-mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-l-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy-induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts.

Effect of different dosage of mecobalamin in treating 85 patients with chronic alcoholic peripheral neuropathy

Objective To observe the effect of different dosage of mecobalamin in treating patients with chronic alcoholic peripheral neuropathy.Methods 85 patients with chronic alcoholic peripheral neuropathy were randomly divided into group A(n =29),group B(n =28)and group C(n =28).Patients of all 3 groups were treated with conventional therapy.In addition,mecobalamin 1500 μg intravenously guttae once a day,mecobalamin 500 μg intravenously guttae once a day were given to patients in group A and B,respectively.Patients in group C were not given mecobalamin.After 4 weeks,improving and nerve conductive velocity were assessed for comparison.Results After 4 weeks' therapy,patients of all 3 groups were remarkably improved.Therapeutic effects of group A and B were better than group C ( all P ＜ 0.01 ),and group A was better than group B ( P ＜ 0.05).Nerve conductive velocity of patients in all 3 groups were raised markedly( P ＜0.05).Patients with mecobalamin therapy( patients in group A&B) showed significantly greater improvement in nerve conductive velocity( P ＜ 0.05 ) and high dose group( group A ) was better than group B(P ＜0.05).Conclusion Mecobalamin has a curative effect on chronic alcoholic peripheral neuropathy and high dose therapy is better than regular dose. Key words: Mecobalamin; Peripheral neuropathy, toxic, alcoholic ; Nerve conductive velocity

Cortical effect of oxaliplatin associated with sustained neuropathic pain: Exacerbation of cortical activity and down-regulation of potassium channel expression in somatosensory cortex

Oxaliplatin is a third-generation platinum-based chemotherapy drug that has gained importance in the treatment of advanced metastatic colorectal cancer. Its dose-limiting side effect is the production of chronic peripheral neuropathy. Using a modified model of oxaliplatin-induced sensory neuropathy, we investigated plastic changes at the cortical level as possible mechanisms underlying the chronicity of pain sensation in this model. Changes in gene expression were studied using DNA microarray which revealed that when oxaliplatin-treated animals displayed clinical neuropathic pain symptoms, including mechanical and thermal hypersensitivity, approximately 900 were down-regulated in the somatosensory cortex. Because of the known role of potassium channels in neuronal excitability, the study further focussed on the down-regulation of these channels as the possible molecular origin of cortical hyperexcitability. Quantification of the magnitude of neuronal extracellular signal-regulated kinase (ERK) phosphorylation in cortical neurons as a marker of neuronal activity revealed a 10-fold increase induced by oxaliplatin treatment, suggesting that neurons of cortical areas involved in transmission of painful stimuli undergo a chronic cortical excitability. We further demonstrated, using cortical injection of lentiviral vector shRNA against Kv2.2, that down-regulation of this potassium channel in naive animals induced a sustained thermal and mechanical hypersensitivity. In conclusion, although the detailed mechanisms leading to this cortical excitability are still unknown, our study demonstrated that a cortical down regulation of potassium channels could underlie pain chronicity in this model of chemotherapy-induced neuropathic pain.

Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant FOLFOX IV.

e14135 Background: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40% of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. Methods: 169 completely resected CRC patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcemia, hypomagnesaemia, hypoalbuminemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, B12 deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. Results: Incidence of neuropathy was found to be higher in patients with pretreatment anaemia (p=0.001), hypoalbuminemia (p=0.01) and hypomagnesemia (p=0.001) as well in those with habit to alcohol consumption (p=0.003). Neuropathy durations was conversely associated with age, being longer in younger patients (p=0.03), and again with hypoalbuminemia (p=0.04) and hypomagnesemia (p=0.002). No correlation was found with gender, hypocalcemia, diabetes and CRF. The correlation between vitamin B12 and folate levels and the development of neurotoxicity was not analysed because of the high number of missing data in the population. Conclusions: Age, anaemia, hypoalbuminemia, hypomagnesemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin induced neuropathy.

Neuropathies associated with oxaliplatin therapy

Neuropathies associated with oxaliplatin therapy