Peripheral Nervous Alterations Research Articles

Sensitivity of Ultrasound in Detection of Neuropathic Changes in Chronic Kidney Disease Patients

Abstract Background Neurological complications secondary to the uremic state, contribute largely to morbidity and mortality in patients with renal failure. The prevalence of peripheral neuropathy remains high in advanced renal dysfunction. Recently Sonographic alterations of peripheral nerves in chronic kidney disease disease have become a concern for early diagnosis of neuropathy in such patients hence decrease morbidity for these patients. The current study aims to investigate sensitivity of nerve ultra-sound in detection of uremic neuropathy in comparison to nerve conduction study. Objective To investigate the sensitivity of nerve US in detecting peripheral neuropathy by measuring CSA in CKD patients in comparison to nerve conduction velocity. Patients and Methods The present study is acase control study which was conducted at the Neurosonography unit in Ain Shams University Hospital, on patients of chronic kidney disease visiting outpatient nephrology clinic. We enrolled 30 patients (60 arms and legs) and 25 controls (50 arms and legs) in the study. The aim of our study to assess sensitivity of ultrasound in detection of neuropathic changes in CKD patients and to correlate the extent of nerve damage to renal dysfunction as measured by laboratory investigations. Results To the best of our knowledge, most recent studies that evaluated use of US in uremic neuropathy, focused on dialysis patients and including diabetic patients, most of these studies focused on carpal tunnel syndrome as a common comorbidity in end stage renal disease (ESRD) patients. Few studies evaluated the use of nerve ultrasound in CKD patients pre-dialysis, excluding other risk factors for neuropathy (like diabetes mellitus, autoimmune diseases, etc…) in comparison to nerve conduction studies. Conclusion Mean age of patients was 44 years with males constituting 53.3%% of the sample. The present study demonstrated increased cross-sectional area of nerves in uremic neuropathy by ultrasound. The results in our study showed that nerve ultrasound is a useful diagnostic tool for diagnosis of peripheral neuropathy in pre-dialytic chonic kidney disease patients. It was observed that normal CSA by US in the majority of nerves corresponded to normal NCS. Increased CSA was correlated to demylinating neuropathy more than axonal neuropathy. In axonal neuropathy, majority of nerves showed decreased CSA but normal and high CSA was found in nerves with axonal neuropathy.

Peripheral Nerve Ultrasound for the Differentiation between ALS, Inflammatory, and Hereditary Polyneuropathies.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.

SSEA-4 positive dental pulp stem cells from deciduous teeth and their induction to neural precursor cells

BackgroundStage-specific embryonic antigen-4 (SSEA-4) is a marker for the identification of multipotent embryonic cells. It is also positive in neuroepithelial cells, precursor neural cells (NPC), and human dental pulp cells. The aim of this study was to evaluate the potential morphodifferentiation and histodifferentiation to NPC of SSEA-4 positive stem cells from human exfoliated deciduous teeth (SHED).MethodsA SHED population in culture, positive to SSEA-4, was obtained by magnetic cell separation. The cells were characterized by immunohistochemistry and flow cytometry. Subsequently, a neurosphere assay was performed in a medium supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF); afterward, cells were neurodifferenciated with a neurobasal medium. Finally, indirect immunohistochemistry was performed to identify neuronal markers.ResultsThe morphological and histological changes in the SSEA-4 positive SHEDs were observed after induction with epidermal and fibroblast growth factors in neurobasal culture medium. At the end of induction, the markers Nestin, TuJ-1, and GFAP were identified.ConclusionsThe findings show that SSEA-4 positive SHEDs have a behavior similar to neuronal precursor cells. Our findings indicate that the dental pulp of deciduous teeth is a promising source for regeneration therapies associated with neurodegenerative diseases or peripheral nerve alterations.

Peripheral nerve morphology and intraneural blood flow in chronic kidney disease with and without diabetes.

Introduction/AimsSonographic alterations of peripheral nerves in pre‐dialytic kidney disease are yet to be determined. We aimed to assess peripheral nerve cross‐sectional area (CSA) and intraneural blood flow in patients with pre‐dialytic chronic kidney disease (CKD) and diabetic kidney disease (DKD).MethodsSubjects with CKD (n = 20) or DKD (n = 20) underwent ultrasound to assess CSA of the median and tibial nerves as well as intraneural blood flow of the median nerve. Blood flow was quantified using maximum perfusion intensity. Neuropathy was assessed using the Total Neuropathy Score. A 6‐m timed walk test was also performed. Healthy controls (n = 28) were recruited for comparison.ResultsThe DKD group had more severe neuropathy (p = .024), larger tibial nerve CSA (p = .002) and greater median nerve blood flow than the CKD group (p = .023). Blood flow correlated with serum potassium in disease groups (r = 0.652, p = .022). Disease groups had larger tibial nerve CSA than controls (p < .05). No blood flow was detected in controls. Tibial nerve enlargement was associated with slower maximal walking speeds in disease groups (r = −0.389, p = .021).DiscussionSubjects with DKD demonstrated enlarged tibial nerve CSA and increased median nerve blood flow compared to those with CKD. Elevations in serum potassium were associated with increased blood flow. Sonographic alterations were detectable in pre‐dialytic kidney disease compared to controls, highlighting the utility of ultrasound in the assessment of nerve pathology in these patient groups.

P 51. Sonographical study on morphological alterations of the peripheral nerves in a cohort of patients with Parkinson's Disease

Introduction . The reported prevalence of axonal polyneuropathy (PNP) in patients with Parkinsońs Disease (PD) is about 55%. Alpha synuclein pathology as well as levodopa exposure are discussed as the main driving factors [Doppler et al. 2010; Toth et al. 2010]. The aim of this study was to evaluate morphologic alterations of peripheral nerves in PD- PNP using nerve ultrasound. A recent study of our group showed alterations mostly in entrapment sites [Kühn et al. 2020]. We investigated this observation in a larger cohort. Patients/Methods. Peripheral nerves of 85 patients with PD were evaluated with nerve ultrasound. The cohort had a mean age of 71 years and a mean disease duration of seven years. The cross-sectional-area (CSA) was measured at 14 different anatomical points, of which five were typical entrapment sites (median nerve at carpal tunnel, ulnar nerve at loge de Guyon and cubital tunnel, fibular nerve at the fibular head, tibial nerve at the ankle) and nine non entrapment sites (median nerve at forearm and upper arm, ulnar nerve at forearm and upper arm, radial nerve, vagal nerve, fibular nerve at popliteal fossa, tibial nerve at popliteal fossa and sural nerve). The values were compared with reference values of our group [Kerasnoudis et al. 2013]. Results. Regarding the stated entrapment sites eight patients had an enlarged CSA (cut-off value of 12.57 mm 2 ) of the median nerve at the carpal tunnel. 26 patients of the ulnar nerve at the Guyon loge (cut-off value of 7.22 mm 2 ) and 38 at the cubital tunnel (cut-off value of 8,13 mm 2 ). The CSA of the fibular nerve at the fibular head was enlarged in 57 patients (cut-off value of 13,9 mm 2 ). 56 patients showed an enlargement of the CSA of the tibial nerve at the ankle (cut-off value of 9,26 mm 2 ). A much lower number of nerves with CSA increase were found at the non-entrapment sites. At each site no more than 10 patients had CSA-values larger than the cut off value. Conclusion/Discussion. Our results could demonstrate a non symptomatic nerve damage at sites with a higher mechanical burden in the case of PNP in PD. To what extend enhanced structural vulnerability due to the alpha-synuclein pathology contributes to this finding remains to be examined. Longitudinal examination is necessary to reveal dynamic alterations in different disease stages. Table 1. CSA values at the different measured sites. Fig. 1.

Textural markers of ultrasonographic nerve alterations in amyotrophic lateral sclerosis.

Ultrasound has revealed cross-sectional nerve area (CSA) reduction in amyotrophic lateral sclerosis (ALS), but little is known about the sonographic nerve texture beyond CSA alterations. In a large cohort of 177 ALS patients and 57 control subjects, we investigated the covariance and disease-specific signature of several sonographic texture features of the median and ulnar nerves and their relationship to the patients' clinical characteristics. ALS patients showed atrophic nerves, a loss of the intranerve structures' echoic contrast, elevated coarseness, and a trend toward lower cluster shading compared with controls. A reduction in intranerve echoic contrast was related to longer disease duration and poorer functional status in ALS. Sonographic texture markers point toward a significant reorganization of the deep nerve microstructure in ALS. Future studies will be needed to further substantiate the markers' potential to assess peripheral nerve alterations in ALS.

A Histological Study on Platelet Poor Plasma versus Platelet Rich Plasma in Amelioration of Induced Diabetic Neuropathy in Rats and the Potential Role of Telocyte-like Cells

Background: Diabetic neuropathy (DN) is a major chronic diabetes complication characterized by functional and structural alterations in peripheral nerves. Platelet rich plasma (PRP) is an encouraged biological blood derivative that has gained publicity in diverse applications and proved its efficacy.Aim of Work: Evaluate the probable ameliorating effect of platelet poor plasma (PPP) versus PRP on induced DN in rats.Materials and Methods: This study included 48 male adult albino rats, 10 to obtain PRP and PPP. Thirty eight were divided into 4 groups; group I (control). Group II (DN group): received a single intraperitoneal STZ (60 mg/kg) injection and were left till the end of the experiment. Groups III (PRP group) and IV (PPP group) received subcutaneous PRP or PPP 0.5 mL/kg, 2 times a week for 3 weeks after 60 days diabetes. Body weight, blood glucose and miR-146a and nerve conduction velocity (NCV) were assessed, as well as tissue MDA, TNFα, NGF, ZO-1 and claudin-1. Right sciatic nerve specimens were taken and processed for HandE, toluidine blue stains, S100, CD34 and caspase-3 immunohistochemical stains and TEM. Number of CD34 immunopositive cells and area percent of S100 and caspase-3 immunoreaction were measured, in addition to G-ratio and capillary luminal area. This was followed by statistical analysis.Results: DN group showed altered biochemical and histological features; axonopathy, Schwannopathy and angiopathy, with affected NCV and telocyte-like cells (TLCs). PRP and PPP groups showed comparable results to each other and to the control. They revealed almost normal biochemical and histological features and NCV. In addition, they revealed significant increase in S100 and CD34 immunoexpression with significant decrease in area percent of caspase-3 versus DN group.Conclusion: PPP and PRP proved to exert ameliorative effect on DN through improving the biochemical and histopathological altera‌tions and TLCs preservation.

Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice.

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.

Oxidative and histopathological effects of the application of electrosurgical devices to the penile tissue of rats

This study was performed to evaluate the oxidative and histopathological changes that occur following the application of electrosurgical devices (monopolar or bipolar cautery) to penile tissue. Eighteen Wistar albino male rats were randomly distributed into three groups. In the control group (CG, n=6), all penile tissues were sampled without any additional process following the administration of anesthesia. In the monopolar cautery group (MPG, n=6), a 15-W cauterization process lasting 5s was performed on an approximately 2mm2 area of the ventral side of the penile shaft, 0.5cm proximal to the edge of the glans in the midline. Bipolar cautery was practiced in the third group (BPG, n=6) using the same techniques outlined in the previous statement. Penile tissues consisted of the cautery application area, the edge of the glans, and dorsal side of the penis and were sampled after 90min; then, histopathological evaluation and biochemical examination involving malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) measurements were performed. Histopathologically, the MPG and BPG demonstrated increased inflammation, fibrosis, and epithelial loss in the urethra in the areas to which cautery was applied as compared to the CG (P<0.05). The vascular structures of the corpus cavernosa were significantly decreased in the cautery application area of both the MPG and the BPG as compared to the CG (P<0.05). In the Masson's trichrome stained samples, significant collagen deposition was observed in the cautery application area both in the MPG and the BPG as compared to the CG (P<0.05). However, S-100 staining was decreased in these groups as compared to the CG (P<0.05). S-100 staining was also decreased in the MPG as compared to the BPG on the edge of the glans (P<0.05). Biochemically, MDA values were significantly increased in the MPG as compared to the CG and the BPG (P<0.05). Monopolar and bipolar cautery both did cause oxidative changes and triggered inflammatory, vascular, and peripheral nerve alterations in the cautery application area while bipolar cautery did not cause any distant effects.

Electrophysiologic alterations in the excitability of the sciatic and vagus nerves during early stages of sepsis.

BackgroundNonspecific and delayed diagnosis of neurologic damage contributes to the development of neuropathies in patients with severe sepsis. The present study assessed the electrophysiologic parameters related to the excitability and conductibility of sciatic and vagus nerves during early stages of sepsis.Materials and methodsTwenty-four hours after sepsis induced by cecal ligation and puncture (CLP) model, sciatic and vagus nerves of septic (CLP group) and control (sham group) rats were removed, and selected electric stimulations were applied to measure the parameters of the first and second components of the compound action potential. The first component originated from fibers with motor and sensory functions (Types Aα and Aβ fibers) with a large conduction velocity (70–120 m/s), and the second component originated from fibers (Type Aγ) with sensorial function. To evaluate the presence of sensorial alterations, the sensitivity to non-noxious mechanical stimuli was measured by using the von Frey test. Hematoxylin and eosin staining of the nerves was performed.ResultsWe observed an increase of rheobase followed by a decrease in the first component amplitude and a higher paw withdrawal threshold in response to the application of von Frey filaments in sciatic nerves from the CLP group compared to the sham group. Differently, a decrease in rheobase and an increase in the first component amplitude of vagal C fibers from CLP group were registered. No significant morphologic alteration was observed.ConclusionOur data showed that the electrophysiologic alterations in peripheral nerves vary with the fiber type and might be identified in the first 24 h of sepsis, before clinical signs of neuromuscular disorders.

P 26 Evaluation of clinical, electrophysiological, sonographic and MRI characteristics of the CIDP spectrum disorder

Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with a wide spectrum of clinical presentation and treatment response. Electrophysiological studies constitute the gold standard used to characterise CIDP patients and contribute to treatment decisions. However, mostly at late stages electrophysiological methods show a pronounced axonal damage and are not able to distinguish CIDP subtypes. Therefore, therapeutic decisions have to be based solely on the clinical course. We investigated the applicability of nerve ultrasound and magnetic resonance imaging (MRI) in a cohort of CIDP patients at a late stage with a variable clinical presentation and correlated our findings to electrophysiological parameters. Methods We systematically examined the median, ulnar, radial, tibial, fibular and sural nerves as well the brachial plexus with high resolution ultrasound (US) and the lumbar roots and tibial, fibular, median, ulnar and radial nerve of eighteen CIDP patients with high-resolution 3 Tesla MRI (including 18 healthy controls) additionally to the nerve conduction studies. Results The mean cross sectional area (CSA) measured in MRI and US of the CIDP patients was increased compared to the healthy controls. A symmetrical clinical presentation correlated with a symmetrical increase of the CSA of the lumbar and cervical plexus. CSA in MRI correlated with the conduction velocity and amplitude. An increase of T2 signal and CSA of the plexus and peripheral nerves which correlated with a marked increase of the sonographical CSA corresponded to patients with an aggressive disease course, which were candidates fon an escalation treatment. Conclusions Nerve ultrasound and MRI findings at late CIDP stages can contribute to the therapeutic decisions and unmask aggressive CIDP patients. Both of them in combination are required to give a complete picture of peripheral nerve alterations in CIDP.

Peripheral Nerve Ultrasonography in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy: Correlations with Clinical and Neurophysiological Data.

Objective. This cross-sectional study analyzes the pattern of ultrasound peripheral nerve alterations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) at different stages of functional disability. Material and Methods. 22 CIDP and 10 MMN patients and a group of 70 healthy controls were evaluated with an ultrasound scan of the median, ulnar, peroneal, tibial, and sural nerves. Results were correlated with clinical disability scales and nerve conduction studies. Results. Patients with intermediate functional impairment showed relatively larger cross-sectional areas than subjects with either a milder (p < 0.05) or more severe impairment (p < 0.05), both in CIDP and in MMN. In addition, MMN was associated with greater side-to-side intranerve variability (p < 0.05), while higher cross-sectional areas were observed in CIDP (p < 0.05) and in nerve segments with predominantly demyelinating features (p < 0.05). Higher CSA values were observed in nerves with demyelinating features versus axonal damage (p < 0.05 for CIDP; p < 0.05 for MMN). Discussion and Conclusions. Greater extent of quantitative and qualitative US alterations was observed in patients at intermediate versus higher functional disability and in nerves with demyelinating versus axonal damage. CIDP and MMN showed differential US aspects, with greater side-to-side intranerve variability in MMN and higher cross-sectional areas in CIDP.

Comparison of clinical, electrophysiological, sonographic and MRI features in CIDP

IntroductionWe investigated the applicability of nerve ultrasound and magnetic resonance imaging (MRI) in chronic inflammatory demyelinating polyneuropathy (CIDP). MethodsWe systematically examined several nerves with ultrasound and the lumbar roots and tibial nerve in the popliteal fossa of nine CIDP patients with MRI additionally to the nerve conduction studies. ResultsPatients with overall disability sum score (ODSS) 2–3 were characterised by normal fascicular structure in MRI and ultrasound. Patients with higher ODSS showed isolated enlarged fascicles and increased cross sectional area (CSA) of the peripheral nerves and of the diameter of the cauda equina and L5 root, whereas two of them showed atrophic fascicles in both imaging techniques. ConclusionsNerve ultrasound and MRI findings show the same morphological fascicle alterations in peripheral nerves in correlation to ODSS. Nerve ultrasound as an affordable tool, easy and quick to perform, could replace MRI in daily routine for monitoring peripheral nerve morphology.

Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 — mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.

Prospective assessment of peripheral neuropathy in Duodopa-treated parkinsonian patients

Although peripheral neuropathies (PN) have been described in patients with Parkinson's disease (PD) treated with oral dopaminergic therapies, anecdotal reports of subacute severe PN have been reported during treatment with enteral levodopa/carbidopa infusion (Duodopa). We prospectively assessed clinical and electrophysiological data of 15 consecutive patients with PD treated with Duodopa for a mean follow-up of 9 months. Nerve conduction studies and a clinical evaluation with a standardized battery of peripheral neuropathy scales were performed at baseline and after a mean follow-up of 9 months. At baseline, mild signs of PN were observed in three subjects, and vitamin B12 serum levels were found to correlate with the amplitude of sural sensory action potentials. Follow-up data were available for 10/15 subjects: one patient developed a subacute sensory-motor PN and three subjects with pre-existing PN showed a moderate worsening of electrophysiological and clinical features. Subclinical electrophysiological alterations of peripheral nerves were observed in two subjects. No significant changes were observed in vitamin B12, folate, homocysteine and methylmalonic acid levels. In this consecutive series of patients treated with Duodopa, we observed one subacute sensory-motor PN and few length-dependent alterations of peripheral nerves, similar to those described during oral levodopa treatment.

Peripheral nerve alterations after spinal cord injury in the adult rat

To assess if spinal cord injury (SCI) can produce alterations in axons of peripheral nerves emerging caudal to the injury. Mild/severe contusion or complete transection was performed at T8 in adult rats. The function and morphology of the sciatic nerve were assessed 3 months after the lesion. There was a decrease in the amplitudes of muscle responses in nerve conduction tests. The number of myelinated fibers was maintained, but some of them presented structural abnormalities. SCIs cause alterations in peripheral axons not affected by the injury. Preservation of the peripheral components is essential for potential regenerative and rehabilitation therapies. Thus, special care has to be taken to avoid secondary complications, due to compressions or immobility, in SCI humans.

23 Peripheral neuropathy in Parkinson’s disease patients treated with Duodopa: A 9 months clinical and electrophysiological follow-up study

Background Sensory-axonal peripheral neuropathies (PN) have been described in Parkinson’s disease (PD) patients treated with oral dopaminergic therapies. Moreover, few cases of subacute severe PN were reported in parkinsonian patients treated with enteral levodopa/carbidopa gel infusion (Duodopa), suggesting that this particular mean of levodopa administration could be associated with a higher risk of developing PN. In this study we report the follow-up clinical and electrophysiological data of 15 consecutive PD patients treated with Duodopa infusion between July 2010 and September 2011. Methods Patients were evaluated by means of a clinical and electrophysiological assessment, both before the placement of Duodopa intestinal tube and after a mean follow-up duration of 9 months. Results A higher rate of electrophysiological alterations in peripheral nerves was found at follow-up, comparing to the baseline evaluation. Two main patterns of PN were observed; the first one was characterized by a severe sensory-motor PN with a subacute onset (1 patient), while the second one was characterized by a mild sensory dominant axonal impairment (4 patients). Conclusions Two different patterns of PN were observed in PD patients treated with Duodopa therapy: a more aggressive subacute sensory-motor PN, which may be potentially triggered by immune-mediated responses or by vitamin adsorption deficiency, and a milder sensory axonal length-dependent PN, which share many similarities with the typical electrophysiological pattern described in PD patients treated with oral dopaminergic therapies. Taken together these data suggest that serial electrophysiological assessment may be advisable in PD patients under Duodopa treatment.

Allopregnanolone prevents and suppresses oxaliplatin-evoked painful neuropathy: Multi-parametric assessment and direct evidence

Oxaliplatin (OXAL) is a platinum-based drug used for the treatment of colorectal, lung, breast and ovarian cancers. OXAL does not cause renal or hematologic toxicity. However, OXAL induces neuropathic pain which hampers the chemotherapy success. Attempts with neuroprotective agents including anticonvulsivants and antidepressants were made to prevent OXAL-induced painful neuropathy but the clinical data are controversial and the tested neuroprotectors are able to evoke themselves undesirable effects. Here, we demonstrated that the natural neurosteroid allopregnanolone (3α,5α-THP), known to be devoid of toxic side-effects in humans and experimental models, prevented and suppressed OXAL-induced painful neuropathic symptoms. Indeed, 3α,5α-THP repaired OXAL-evoked neurochemical and functional alterations in peripheral nerves and intra-epidermal nerve fibers (IENF). Behavioral analyses showed that prophylactic or corrective 3α,5α-THP treatment (4mg/kg/2days) respectively prevented or abolished OXAL-induced cold allodynia, mechanical allodynia and hyperalgesia by reversing to normal decreased thermal and mechanical pain thresholds of OXAL-treated rats. Electrophysiological investigations revealed that 3α,5α-THP restored control values of sciatic nerve conduction velocity and action potential peak amplitude drastically reduced by OXAL-treatment. Furthermore, immunohistochemistry and confocal microscopic quantifications demonstrated that 3α,5α-THP repaired OXAL-induced neurochemical/cellular alterations by restoring IENF control density and normal level of neurofilament 200kDa that was strongly repressed by OXAL in dorsal root ganglion neurons and sciatic nerve axons. OXAL showed no toxicity for the non-compact myelin protein 2′,3′-cyclic-nucleotide-3′-phosphodiesterase whose expression level was similarly increased by 3α,5α-THP in controls and OXAL-treated rat nerves. Together, these results may be interesting for the development of natural or safe neurosteroid-based neuroprotective strategy against anticancer drug-evoked painful neuropathy.

Neurological adverse events associated with anti-tumor necrosis factor alpha treatment

Anti-tumor necrosis factor alpha (TNF-alpha) drugs have been successfully used for the treatment of rheumatic autoimmune diseases including rheumatoid arthritis (RA), psoriatic arthritis, psoriasis, ankylosing spondylitis (AS), juvenile chronic arthritis, and Crohn's disease. However, they have been associated with different neurological disorders, including alterations of peripheral nerves, multiple sclerosis (MS), optic neuritis (ON) and acute transverse myelitis (ATM). This article reviews the most current aspect regarding neurological adverse events associated with anti-TNF-alpha drugs with emphasis on the possible explanations for this relation and the pathogenic mechanism of TNF-alpha in neurological disorders.

Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy.

Painful neuropathy is a major side-effect limiting cancer chemotherapy. Therefore, novel strategies are required to suppress the neuropathic effects of anticancer drugs without altering their chemotherapeutic effectiveness. By combining biochemical, neuroanatomical/neurochemical, electrophysiological and behavioral methods, we demonstrated that progesterone-derived neurosteroids including 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone suppressed neuropathic symptoms evoked in naive rats by vincristine. Neurosteroids counteracted vincristine-induced alterations in peripheral nerves including 2',3'-cyclic nucleotide 3'-phosphodiesterase, neurofilament-200 kDa and intraepidermal nerve fiber repression, nerve conduction velocity, and pain transmission abnormalities (allodynia/hyperalgesia). In skin-tumor rats generated with carcinosarcoma-cells, vincristine, which suppressed the skin tumor and restored normal blood concentration of vascular endothelial growth factor (VEGF), reproduced neuropathic side-effects. Administered alone, neurosteroids did not affect the tumor and VEGF level. Combined with vincristine, neurosteroids preserved vincristine anti-tumor action but counteracted vincristine-induced neural side-effects. Together, these results provide valuable insight into the cellular and functional mechanisms underlying anticancer drug-induced neuropathy and suggest a neurosteroid-based strategy to eradicate painful neuropathy.