The small fiber neuropathy NaV1.7 I228M mutation: impaired neurite integrity via bioenergetic and mitotoxic mechanisms, and protection by dexpramipexole.

Gain-of-function variants in voltage-gated sodium channel NaV1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in 5-10% of patients with idiopathic small fiber neuropathy (I-SFN). Our previous in vitro observations suggest that enhanced sodium channel activity can contribute to a decrease in length of peripheral sensory axons. We have hypothesized that sustained sodium influx due to the expression of SFN-associated sodium channel variants may trigger an energetic deficit in neurons that contributes to degeneration and loss of nerve fibers in SFN. Using an ATP FRET biosensor, we now demonstrate reduced steady-state levels of ATP and markedly faster ATP decay in response to membrane depolarization in cultured DRG neurons expressing an SFN-associated variant NaV1.7, I228M, compared with wild-type neurons. We also observed that I228M neurons show a significant reduction in mitochondrial density and size, indicating dysfunctional mitochondria and a reduced bioenergetic capacity. Finally, we report that exposure to dexpramipexole, a drug that improves mitochondrial energy metabolism, increases the neurite length of I228M-expressing neurons. Our data suggest that expression of gain-of-function variants of NaV1.7 can damage mitochondria and compromise cellular capacity for ATP production. The resulting bioenergetic crisis can consequently contribute to loss of axons in SFN. We suggest that, in addition to interventions that reduce ionic disturbance caused by mutant NaV1.7 channels, an alternative therapeutic strategy might target the bioenergetic burden and mitochondrial damage that occur in SFN associated with NaV1.7 gain-of-function mutations.NEW & NOTEWORTHY Sodium channel NaV1.7 mutations that increase dorsal root ganglion (DRG) neuron excitability have been identified in small fiber neuropathy (SFN). We demonstrate reduced steady-state ATP levels, faster depolarization-evoked ATP decay, and reduced mitochondrial density and size in cultured DRG neurons expressing SFN-associated variant NaV1.7 I228M. Dexpramipexole, which improves mitochondrial energy metabolism, has a protective effect. Because gain-of-function NaV1.7 variants can compromise bioenergetics, therapeutic strategies that target bioenergetic burden and mitochondrial damage merit study in SFN.

Peripheral neuropathy in colorectal cancer survivors: the influence of oxaliplatin administration. Results from the population-based PROFILES registry.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of oxaliplatin which can negatively influence quality of life. We aimed to study the influence of cumulative dose, dose schedule and dose reductions of adjuvant oxaliplatin on long-term severity and prevalence of CIPN among colorectal cancer (CRC) survivors. MATERIAL AND METHODS: In total 207 patients, diagnosed with CRC between 2000 and 2009 who underwent adjuvant treatment with oxaliplatin, were included. They completed the EORTC QLQ-CIPN20 2-11 years after diagnosis. Data on oxaliplatin administration and acute neuropathy during treatment were extracted from the medical files. Subscales were analyzed with analysis of covariance and neuropathy symptoms with logistic regression analysis. RESULTS: Patients who received cumulative oxaliplatin dose of ≥ 842 mg/m(2) had a significantly worse EORTC QLQ-CIPN20 sensory score compared to those who received a low cumulative dose of < 421 mg/m(2) (mean 19 vs. 8; p = 0.02). They more often reported tingling toes/feet (13% vs. 2%, respectively; p = 0.01). Dose intensity and time delay did not influence the occurrence of CIPN. Patients receiving a dose reduction because of neuropathy (N = 50) reported a significantly worse sensory score at very similar cumulative doses, than those who did not receive a dose reduction because of neuropathy (N = 96) (mean 21 vs. 15; p = 0.01). CONCLUSION: Cumulative dose of oxaliplatin is associated with long-term CIPN. The risk of developing long-term CIPN could only be reduced by decreasing the cumulative dose, whereas delay probably is not beneficial. Patients receiving a dose reduction because of acute neuropathy are still at risk of developing long-term CIPN. Future studies should focus on identifying patients who are at risk of developing CIPN.

NaV1.7: stress-induced changes in immunoreactivity within magnocellular neurosecretory neurons of the supraoptic nucleus.

BACKGROUND: NaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a "peripheral" sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. However, occasional reports of patients with NaV1.7 gain-of-function mutations and apparent hypothalamic dysfunction have appeared. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress. RESULTS: Here we show that NaV1.7 is present within vasopressin-producing neurons and oxytocin-producing neurons within the rat hypothalamus, and demonstrate that the level of Nav1.7 immunoreactivity is increased in these cells in response to osmotic stress. CONCLUSIONS: NaV1.7 is present within neurosecretory neurons of rat supraoptic nucleus, where the level of immunoreactivity is dynamic, increasing in response to osmotic stress. Whether NaV1.7 levels are up-regulated within the human hypothalamus in response to environmental factors or stress, and whether NaV1.7 plays a functional role in human hypothalamus, is not yet known. Until these questions are resolved, the present findings suggest the need for careful assessment of hypothalamic function in patients with NaV1.7 mutations, especially when subjected to stress, and for monitoring of hypothalamic function as NaV1.7 blocking agents are studied.

Spinal cord stimulation in complex regional pain syndrome type I of less than 12-month duration.

INTRODUCTION: Complex regional pain syndrome type 1 (CRPS-1) has a 31% probability of becoming chronic. The early use of spinal cord stimulation (SCS) has been recommended as a strategy to prevent chronicity and functional impairment. METHODS: In a prospective study, we treated 74 CRPS-1 patients with a mean disease duration of 17 weeks with standard therapy consisting of physical therapy, topical dimethyl sulfoxide, analgesics, transcutaneous stimulation, and sympathetic blockade. Patients who did not respond to standard therapy were offered a treatment with SCS. In these patients, we investigated the impact on pain, quality of life, and function. RESULTS: Out of these 74 patients treated with standard therapy, six patients were included for early SCS treatment. The overall mean pain relief after one year was 35%. The mental component of the Short Form 36 improved; however, there was no effect on the physical component. None of the SCS treated patients showed a clear improvement in functional outcome. DISCUSSION: We conclude that the feasibility of performing a randomized controlled trial on early SCS therapy in CRPS-1 is low because of the good disease improvement with standard therapy in the first year after onset. This study raises questions about the need to use SCS early in the course of CRPS-1 because of the probable lack of additional benefit compared with SCS in chronic CRPS-1.

Electrical spinal cord stimulation in painful diabetic polyneuropathy, a systematic review on treatment efficacy and safety.

INTRODUCTION: Painful diabetic polyneuropathy is a common complication of diabetes mellitus. Drug therapies are ineffective in many patients. Therefore other treatment modalities should be considered, including spinal cord stimulation. We performed a systematic review to evaluate treatment efficacy and safety of spinal cord stimulation in painful diabetic polyneuropathy. SEARCH STRATEGY AND SELECTION CRITERIA: A systematic search with reference tracing was conducted in Pubmed and Embase from January 1980 to March 2010 to determine possible eligible articles. Reports were identified using the following keywords: (1) "diabetic neuropathies" AND "electric stimulation"; (2) "diabetic neuropathies" AND "spinal cord" and (3) "pain" AND "electric stimulation" AND "spinal cord". Subsequently, data were recruited on the efficacy and safety of spinal cord stimulation in this disorder. DATA COLLECTION AND ANALYSIS: The search strategy was designed by one reviewer. Study selection and data extraction were performed by two reviewers. Data for individual studies was reported and pooled data analysis was performed if appropriate. RESULTS: Three prospective case series and one retrospective cohort study were identified (including 25 patients). At 1 year spinal cord stimulation resulted in ≥ 50% pain relief in 63% of patients. After 1 year analgesics usage was reduced in most SCS-treated patients with complete withdrawal in 60%. No major adverse events were reported. CONCLUSION: Available literature shows promising results for the pain-relieving effect of spinal cord stimulation in painful diabetic polyneuropathy. The outcome of a randomized clinical trial is needed before spinal cord stimulation can be considered to be integrated in the standardized treatment algorithm.

Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome.

Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy is a pain syndrome with an unclear pathophysiology and unpredictable clinical course. The disease is often therapy resistant, the natural course not always favorable. The diagnosis of CRPS is based on signs and symptoms derived from medical history and physical examination. Pharmacological pain management and physical rehabilitation of limb function are the main pillars of therapy and should be started as early as possible. If, however, there is no improvement of limb function and persistent severe pain, interventional pain management techniques may be considered. Intravenous regional blocks with guanethidine did not prove superior to placebo but frequent side effects occurred.Therefore this technique receives a negative recommendation (2 A-). Sympathetic block is the interventional treatment of first choice and has a 2 B+ rating. Ganglion stellatum (stellate ganglion) block with repeated local anesthetic injections or by radiofrequency denervation after positive diagnostic block is documented in prospective and retrospective trials in patients suffering from upper limb CRPS. Lumbar sympathetic blocks can be performed with repeated local anesthetic injections. For a more prolonged lumbar sympathetic block radiofrequency treatment is preferred over phenol neurolysis because effects are comparable whereas the risk for side effects is lower (2 B+). For patients suffering from CRPS refractory to conventional treatment and sympathetic blocks, plexus brachialis block or continuous epidural infusion analgesia coupled with exercise therapy may be tried (2 C+). Spinal cord stimulation is recommended if other treatments fail to improve pain and dysfunction (2 B+). Alternatively peripheral nerve stimulation can be considered, preferentially in study conditions (2 C+).

Brush-evoked allodynia predicts outcome of spinal cord stimulation in complex regional pain syndrome type 1.

BACKGROUND: Spinal cord stimulation (SCS) has proven to be an effective however an invasive and relatively expensive treatment of chronic Complex Regional Pain Syndrome type 1(CRPS-1). Furthermore, in one third of CRPS-1 patients, SCS treatment fails to give significant pain relief and 32-38% of treated patients experience complications. The aim of the current study was to develop effective prognostic factors for prediction of successful outcome of SCS. METHODS AND RESULTS: The study population consisted of 36 chronic CRPS patients enrolled in a randomized controlled trial of SCS efficacy. We analyzed various prognostic factors in the group of patients treated with SCS and compared baseline values of possible predictors of outcome in the successfully treated and the not successfully treated group. Success was defined as Patient Global Perceived Impression of Change score of at least "much improved" and pain reduction of at least 2.5 on a visual-analogue scale (VAS score 0-10). Univariate analyses showed that patient age, duration of the disease, localization of the disease, intensity of the pain, and the presence of mechanical hypoesthesia did not predict SCS success. The mean and maximum value of brush-evoked allodynia proved to be statistically significant predictors of outcome. Using Receiver-Operating Characteristic (ROC) curve analyses of maximum allodynia values, the diagnostic sensitivity for successful SCS was 0.75 and the specificity 0.81. CONCLUSION: Brush-evoked allodynia may be a significant negative prognostic factor of SCS treatment outcome after 1 year in chronic CRPS-1.