Risk Factors For Peripheral Neuropathy Research Articles

Can chronoscopic reading in whole body reaction time predict peripheral neuropathy in type 2 diabetics? A case control study

Background: Type 2 diabetes is investigated as a risk factor for peripheral neuropathy. In whole body simple reaction time (WBSRT), the reaction time is split into two chronoscopic readings C1 and C2. C1 measures the time required for central processing which requires cognition and C2 measures total reaction time. C2-C1 measures the time required for peripheral motor response, i.e. the required for conduction of impulse in motor nerve fiber. We hypothesized that WBSRTC2-C1 will be delayed in diabetes and WBSRTC2-C1 will have predictive value in detecting peripheral neural dysfunction. Settings and Design: Hospital-based case control study. Materials and Methods: This study was conducted on 120 subjects using whole body reaction timers with the criteria of age (40-60 years) and type 2 diabetes and the results were compared with an equal number of age- and sex-matched controls. Statistical analysis was done by independent t-test and duration of diabetes was correlated with the time required for motor response (WBSRTC2-C1) using Pearson's correlation. Predictive value of WBSRTC2-C1 was calculated by using receiver operating characteristic (ROC) curve. Results: WBSRTC2-C1 (334 ± 67 ms) in diabetics was more delayed than WBSRTC2-C1 (297 ± 66 ms) in controls, indicating peripheral neural dysfunction in diabetes. There was no significant correlation between HbA1c, diabetic duration with WBSRTC2-C1 in diabetes. ROC curve for WBSRTC2-C1 to predict peripheral neuropathy was insignificant. Conclusion: Though WBSRTC2-C1 is delayed in diabetics, it alone cannot predict peripheral neural dysfunction in diabetics.

Prevalence and Risk Factors for the Peripheral Neuropathy in Patients with Peripheral Arterial Occlusive Disease.

Purpose:Peripheral neuropathy (PN) is known as a major contributor of the worsening of ischemic symptoms and the foot ulceration in patients with peripheral arterial occlusive disease (PAOD). However, there are few studies reporting the prevalence and risk factors for PN in PAOD. This study aimed to evaluate these issues for PN and to establish the importance of screening as additional treatment target for PN in PAOD.Materials and Methods:A total of 52 limbs with PAOD were enrolled from January 2011 to December 2012. PN was divided into radiculopathy, ischemic PN (IPN), and diabetic PN (DPN), based on electromyographic findings. We investigated the prevalence of overall PN and subtypes of PN and then analyzed the risk factors.Results:The prevalence of overall PN in PAOD was 43 of 52 limbs (82.7%). In terms of subtypes of PN, the prevalence rate of radiculopathy and IPN was 30.8% and 23.1%, respectively. DPN showed in 22 limbs (73.3%) among 30 diabetic limbs. There was no significant correlation between each type of PN and ischemic symptoms. Our analysis showed that coronary artery disease (CAD) was a significant risk factor (P=0.01) for IPN, however, did not identify any significant risk factors for DPN.Conclusion:This present study indicated that most patients with PAOD had PN and CAD was a risk factor for IPN. In particular, PAOD with diabetes represented a higher prevalence for DPN. Our study suggests that PN should be evaluated and considered as another treatment target in patients with PAOD.

A Retrospective Study to Evaluate the Incidence and Severity of Peripheral Neuropathy for Relapsed/Refractory Multiple Myeloma Patients upon Retreatment with Bortezomib

Background: Peripheral neuropathy (PN) is associated with multiple myeloma (MM) and often worsened with thalidomide (THAL) and vincristine (VCR) therapy. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of MM that has been also shown to cause PN. An increased risk of BTZ-induced PN has been associated with the presence of both PN and diabetes mellitus (DM) before treatment. However, the incidence and characteristics of BTZ-induced PN among MM patients (pts) retreated with another BTZ-containing regimen is unknown. We analyzed the incidence, severity and risk factors for PN after treatment of MM pts with a second BTZ-containing regimen.Methods: Retrospective chart analysis. MM pts that had progressed from at least one prior BTZ-containing regimen and had received treatment with another BTZ-containing regimen were eligible. Pts had to have experienced PN during the course of the first BTZ regimen and could not have received therapy with THAL or VCR. The protocol was later amended to allow inclusion of pts without PN during their first BTZ treatment and those who had received THAL or VCR. Statistical significance was assessed using Fisher’s or McNemar’s tests as appropriate. The relationship between comorbidities, prior THAL or VCR treatment and PN grade after BTZ treatment and re-treatment was analyzed using a multivariate logistics regression model. All statistical analyses were two-sided and were performed at the 0.05 level of significance.Results: As of July 3, 2014, 83 pts have been accrued to the retrospective analysis, and 58 chart reviews have been completed. The median age of pts included in the analysis was 64 years (range: 31-84 years); 57% of the pts were male and 69% were Caucasian. Pts had received a median of 2 prior regimens (range: 2-10); 43% of the pts had received prior regimens containing THAL and 15% of those had also received therapy with VCR. Prior to the protocol amendment, the eligibility criteria required pts to have experienced PN after the first BTZ treatment; therefore, most pts included in this analysis (88%) had PN.During their first BTZ treatment, the most severe grade of PN experienced by the majority of the pts was grade 1 (N=34), followed by grade 2 (N=13) and grade 3 (N=4). A comparison of the symptoms assessed when pts had their most severe grade of PN during this treatment and the severity reported at its onset showed that PN worsened in only 16% of pts. Nearly half (48%) of pts showed no change in PN whereas symptoms improved or resolved in 15% and 9% of the pts, respectively. During treatment with the second BTZ-containing regimen, a comparable proportion of pts (N=44; 76%) reported having experienced PN. Among those experiencing PN upon re-treatment, the most severe grade of PN experienced by the majority of the pts (N=29) was also grade 1, followed by grade 2 (N=12) and grade 3 (N=3). During the second BTZ treatment, a comparison of the symptoms that pts had when PN was at its worst and those recorded at its onset demonstrated that PN worsened in only 7% of the pts. PN showed no change in 47%, improved in 15%, or resolved in 7% of the pts.Interestingly, 17% of the pts (N=10) who had reported PN while receiving their first BTZ-containing regimen did not report this complication during their second BTZ treatment, while 7% of the pts (N=4) experienced PN only upon re-exposure. There was no association between the incidence of PN during the first BTZ treatment and its incidence during re-treatment (p=0.1213) or between the severity of PN (defined as worsening vs. not worsening) after first BTZ treatment and its severity after BTZ re-exposure (p=0.1306).Fifty-four percent of the pts presented with comorbidities, including DM (26%), hypertension (HTN, 22%) and peripheral vascular disease (PVD, 13%). There were no associations between PN grade after BTZ treatment and prior THAL or VCR exposure (p=0.5569) or between PN grade and comorbidities (DM, p=0.6657; HTN, p=0.9966; PVD, p=0.9966). Similar results were found for BTZ re-exposure (THAL or VCR, p=0.8672; DM, p=0.4137; HTN, p=0.2033; PVD, p=0.9954).Conclusions: Results from this retrospective study show that the severity and incidence of PN did not change with a second BTZ-containing regimen. Comorbidities or prior therapy with other PN-inducing agents such as THAL or VCR did not significantly increase the risk of PN after BTZ re-treatment. Enrollment into the study continues and updated results will be presented at the meeting. DisclosuresBerenson:Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tabbara:Millennium: Speakers Bureau. Lutzky:Millennium: Speakers Bureau. Ailawadhi:Millennium: Consultancy. Moezi:Millennium: Speakers Bureau.

Bortezomib‐ and thalidomide‐induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.

Charcot arthropathy of the foot and ankle in patients with idiopathic neuropathy.

Charcot neuroarthropathy in the developed countries is primarily associated with diabetic neuropathy. This study investigated a series of patients with Charcot arthropathy associated with idiopathic peripheral neuropathy to evaluate the natural history in these patients and to evaluate the efficacy of a treatment protocol used for diabetic Charcot joints. The records and radiographs of patients with Charcot arthropathy of the foot and ankle treated between 1986 and 2009 were retrospectively reviewed. Patients with known causes of or risk factors for peripheral neuropathy were excluded, identifying 82 feet in 59 patients with idiopathic neuropathy. Twenty-three (39%) were bilateral. The average age was 76 years and the average follow-up was 60 months. Data were analyzed for medical history and diagnoses, medications, anatomic classification of Charcot arthropathy, history of ulcerations, ambulatory status, shoe wear and bracing, and operative interventions. Patient care was based on previous published treatment algorithms, based on conservative management with operative intervention reserved for nonhealing ulcers, infection, and/or nonplantigrade, unbraceable feet. Therapeutic success was a plantigrade foot with healed soft tissue envelope that allowed weight-bearing. In all, 55% involved the midfoot (type 1), 34% the hindfoot (type 2), and 11% the ankle, (type 3A). Seventy-one of 82 feet were successfully treated at the time of last follow-up. Thirty-six feet (43%) were treated nonoperatively with success in 33 (92%). Forty-six of 82 feet required operative intervention, with success at last follow-up in 38 (83%). There were 8 operative failures resulting in 2 transtibial amputations and 6 feet with persistent ulceration. This series of patients with Charcot arthropathy associated with idiopathic neuropathy demonstrated a wider spectrum of Charcot arthropathy of the foot and ankle than has been previously recognized or documented. At the present time, heightened awareness is needed to promote accurate diagnosis and appropriate treatment in nondiabetic patients with Charcot arthropathy. Level IV, retrospective case series.

AB0495 Cutaneous Silent Period in Patients with Systemic Lupus Erythematosus without Neuropathic Symptoms

BackgroundSmall fiber neuropathy (SFN) is a peripheral nerve disorder affecting specifically small myelinated A Delta fibers and unmyelinated C fibers. SFN is one of the common causes of neuropathic pain...

Clinical assessment of peripheral neuropathy in HIV-infected children on antiretroviral therapy in rural South Africa

Peripheral neuropathy is a well-known side effect of antiretroviral therapy (ART) in adult patients and is particularly related to the use of nucleoside reverse transcriptase inhibitors. This class of drugs is included in all first-line paediatric ART regimens in Africa, but data on the prevalence of neuropathy in children are scarce. In this cross-sectional study, 182 HIV-infected children on ART in rural South Africa were assessed for peripheral neuropathy using the neuropathy symptom score (NSS) and neuropathy disability score (NDS). Peripheral neuropathy was defined as NSS ≥ 5 or NDS ≥ 3. Neurological assessment was completed for 174 children (96%). Symptoms of neuropathy were reported in NSS by 48 children (28%; 95% confidence interval (CI) 21-34%), and signs were observed in NDS in 25 children (14%; 95% CI 12-16%). A diagnosis of peripheral neuropathy was established in 42 children (24%; 95% CI 18-30%). Independent risk factors for peripheral neuropathy were co-trimoxazole prophylaxis (adjusted odds ratio 0.45; 95% CI 0.21-0.95, p = 0.036) and didanosine use (adjusted odds ratio 12; 95% CI 1.3-116, p = 0.030). Peripheral neuropathy as determined by clinical assessment is a common condition in African children on ART.

Clinical, neurophysiological, and skin biopsy findings in peripheral neuropathy associated with hepatitis C virus-related cryoglobulinemia

Hepatitis C virus (HCV)-related cryoglobulinemia commonly causes disabling complications including peripheral neuropathy and neuropathic pain. In this prospective clinical, neurophysiological, and skin biopsy study we aimed at assessing clinical characteristics and risk factors of peripheral neuropathy and neuropathic pain in patients with HCV-related cryoglobulinemia. We enrolled 69 consecutive patients with HCV-related cryoglobulinemia. We diagnosed neuropathic pain with the DN4 (Neuropathic Pain Diagnostic) questionnaire, and rated the various neuropathic pains with the Neuropathic Pain Symptom Inventory (NPSI). All patients underwent a standard nerve conduction study to assess Aβ-fiber function, laser-evoked potentials to assess Aδ-fiber function, and skin biopsy to assess C-fiber terminals. Of the 69 patients studied, 47 had a peripheral neuropathy, and 29 had neuropathic pain. Patients with peripheral neuropathy were older than those without (P < 0.0001). While peripheral neuropathy was significantly associated with the duration of HCV infection (P < 0.01), it was unrelated to the duration of cryoglobulinemia and cryocrit (P > 0.5). The severity of peripheral neuropathy significantly correlated with the duration of HCV infection (P < 0.05). Laser-evoked potential amplitudes were significantly lower in patients with than in those without neuropathic pain (P < 0.05). Conversely, no difference was found in nerve conduction study and skin biopsy findings (P > 0.05). Our findings show that peripheral neuropathy is related to age and HCV infection, rather than to cryoglobulinemia, and neuropathic pain is associated with damage to nociceptive pathways as assessed with laser-evoked potentials; this might be useful for designing more effective clinical interventions for these common HCV related-cryoglobulinemia complications.

Obesity Increases the Risk of Postoperative Peripheral Neuropathy After Minimally Invasive Colon and Rectal Surgery

Abdominal surgery in the obese can be a major challenge in the perioperative period. Peripheral neuropathy is an uncommon but well-described complication after abdominal surgery. Our aim was to evaluate the incidence of postoperative peripheral neuropathy after colorectal surgery and to identify its risk factors. A retrospective review of a prospectively maintained database of consecutive patients undergoing colorectal operations was performed. The incidence of postoperative nerve injury was compared between minimally invasive and open surgeries. BMI and other potential risk factors for developing peripheral neuropathy were evaluated. This investigation was conducted at a single institution. Over a 7-year period, 1514 colorectal operations were performed. 945(62.4%) of these operations were performed either laparoscopically or via hand-assisted laparoscopy, 166 (11.0%) were robotic assisted, and 403 (26.6%) were open procedures. Twenty-three patients (1.5%) developed peripheral neuropathy in the postoperative period. Forward stepwise logistic regression was used for multivariate analysis. All 23 of the patients with peripheral neuropathy had sensory deficits, and 1 patient had both sensory and motor deficits. All of the symptoms resolved without any residual neurologic deficits within 1 year. Twenty-two of the 23 patients with peripheral neuropathy were in the minimally invasive surgery group (incidence, 2%). One patient from the open group had peripheral neuropathy. By logistic regression analysis, only BMI was an independent predictor for peripheral neuropathy (p = 0.016) in minimally invasive surgery. A limitation of our study is that postoperative neuropathy identification depended on reporting of symptoms, and there was no objective method of assessment. In addition, because of the relatively small number of patients with postoperative neuropathy, the study may be underpowered to detect significant differences in potential risk factors for developing neuropathy. The incidence of postoperative peripheral neuropathy was 2.0% in minimally invasive surgery and 0.2% in open surgery. Minimally invasive surgery, age, lithotomy positioning, operative time, and Pfannenstiel incision all significantly increased the risk of peripheral neuropathy. However, only obesity was an independent risk factor for peripheral neuropathy in patients undergoing minimally invasive colorectal surgery. Preventive measures should be instituted and documented in obese patients undergoing minimally invasive colorectal procedures.

Elevated Plasma Level of Homocysteine is an Independent Risk Factor for Peripheral Neuropathy

Elevated Plasma Level of Homocysteine is an Independent Risk Factor for Peripheral Neuropathy

Concurrent Outbreaks of Cholera and Peripheral Neuropathy Associated with High Mortality among Persons Internally Displaced by a Volcanic Eruption

BackgroundIn October 2004, Manam Island volcano in Papua New Guinea erupted, causing over 10 000 villagers to flee to internally displaced person (IDP) camps, including 550 from Dugulaba village. Following violence over land access in March 2010, the IDPs fled the camps, and four months later concurrent outbreaks of acute watery diarrhea and unusual neurological complaints were reported in this population.Materials and MethodsA retrospective case-control study was conducted to identify the risk factors for peripheral neuropathy. Rectal swabs were collected from cases of acute watery diarrhea. Hair and serum metals and metalloids were analyzed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).ResultsThere were 17 deaths among the 550 village inhabitants during the outbreak period at a crude mortality rate 21-fold that of a humanitarian crisis. Vibrio cholerae O1 El Tor Ogawa was confirmed among the population. Access to community-level rehydration was crucial to mortality. Peripheral neuropathy was diagnosed among cases with neurological symptoms. A balanced diet was significantly protective against neuropathy. A dose-response relationship was seen between peripheral neuropathy and a decreasing number of micronutrient- rich foods in the diet. Deficiencies in copper, iron, selenium and zinc were identified among the cases of peripheral neuropathy.ConclusionsCholera likely caused the mostly preventable excess mortality. Peripheral neuropathy was not caused by cholera, but cholera may worsen existing nutritional deficiencies. The peripheral neuropathy was likely caused by complex micronutrient deficiencies linked to non-diversified diets that potentially increased the vulnerability of this population, however a new zinc-associated neuropathy could not be ruled out. Reoccurrence can be prevented by addressing the root cause of displacement and ensuring access to arable land and timely resettlement.

Prevalence and risk factors of diabetic peripheral neuropathy among type-2 diabetic patients presenting to SMIMS hospital, Kulasekharam, Kanyakumari district, Tamil Nadu, India.

Background: Diabetic Peripheral Neuropathy is a cause for significant morbidity and mortality. It includes mononeuropathies, polyneuropathies, plexopathies, and radiculopathies. Usually presents with sensory symptoms in the toes or feet, but in some patients there is loss of feeling mainly in hands. Aims & Objective: To estimate the prevalence and risk factors of peripheral neuropathy among Type-2 Diabetic patients presenting to SMIMS Hospital. Material and Methods: Study Design is Cross Sectional Study at SMIMS. Study Period is 10th September- 5th December 2011 & Sample Size is 283. A stratified random sampling and convenient sampling was done. The patients were questioned and Examined using a Pre-tested Questionnaire followed by a symptomatic history taking and Clinical Examination. Results: Prevalence of neuropathy among Diabetics is 33.33%. Hypertensive Diabetics, Diabetes with Dyslipidaemia have a higher risk of developing neuropathy. Conclusion: In this Study the prevalence of Diabetic-related Neuropathy is 33.33%. The study also shows risk factors for developing neuropathy such as Increasing duration of Diabetes, Comorbid diseases, Low Socio Economic Status.

パクリタキセル施行乳がん患者における末梢神経障害の発症頻度と危険因子に関する検討

Discontinuation of the treatment occurs in some cases for paclitaxel due to peripheral neuropathy. Although there have been several reports regarding the risk factors of peripheral neuropathy associated with this drug, there have been no such reports in Japan. Therefore, we conducted a retrospective survey to clarify risk factors of peripheral neuropathy among patients administered PTX.The subjects comprised all the patients in whom the administration of PTX was initiated at the Breast Center of Juntendo University Hospital between July 2004 and July 2008. PTX dosage, period of initial treatment, and severity of peripheral neuropathy were collected from the medical charts.Peripheral neuropathy developed in 82 out of 111 patients (73.9%), and 9 of them (8.1%) were assessed as Grade 3 or higher. A previous history of diabetes mellitus was identified as a risk factor of grade 3 or higher peripheral neuropathy (Hazard ratio 5.98, 95% confidence interval: 1.03-34.82; p=0.047).The rate of cases with peripheral neuropathy of Grade 3 or higher was lower than described in previous reports, and a history of diabetes mellitus was suggested as a risk factor. Because peripheral neuropathy is a problem for treatment, it is necessary to study treatment methods through a prospective controlled trial.

The Effect of Leflunomide on Cold and Vibratory Sensation in Patients with Rheumatoid Arthritis

ObjectiveTo evaluate the prevalence and risk factors of peripheral neuropathy in patients with rheumatoid arthritis (RA) treated with leflunomide (LEF) by quantitative sensory testing (QST).MethodA total of 94 patients were enrolledin this study, out of which 47 patients received LEF. The other 47 patients received alternative disease-modifying antirheumatic drugs and served as the control group. The demographic characteristics, laboratory findings, concomitant diseases, and medication history were evaluated at the time of QST. The cooling (CDT) and vibratory detection threshold (VDT) as the representative components of QST were measured.ResultsAge, gender, RA duration, ESR, and CRP did not show any significant differences between the two groups. VDT did not demonstrate any significant difference in both groups. However, CDT in LEF group was significantly higher than that of the control group (8.6±2.7 in LEF vs. 5.6±3.8 in control). The proportion of RA patients in the LEF group showing abnormally high CDT was over 2 times greater than that of the control group, but these findings were not statistically significant. Age, RA duration (or LEF medication in LEF group), ESR, and CRP did not show significant correlation with CDT in both groups. VDT significantly correlated with age in both groups.ConclusionLEF treatment in patients with RA may lead to abnormal CDT in QST. CDT value was not affected by age, RA duration, disease activity, or LEF duration. It remains to be determined whether QST may be a valuable non-invasive instrument to evaluate the early sensory changes in patients with RA taking LEF.

Sex Differences in the Incidence of Peripheral Neuropathy Among Kenyans Initiating Antiretroviral Therapy

Peripheral neuropathy (PN) is common among patients receiving antiretroviral therapy (ART) in resource-limited settings. We report the incidence of and risk factors for PN among human immunodeficiency virus (HIV)-infected Kenyan adults initiating ART. An inception cohort was formed of adults initiating ART. They were screened for PN at baseline and every 3 months for 1 year. We used the validated Brief Peripheral Neuropathy Screen (BPNS) that includes symptoms and signs (vibration perception and ankle reflexes) of PN. Twenty-two (11%) of 199 patients had PN at baseline screening. One hundred fifty patients without evidence of PN at baseline were followed for a median of 366 days (interquartile range, 351-399). The incidence of PN was 11.9 per 100 person-years (95% confidence interval [CI], 6.9-19.1) and was higher in women than men (17.7 vs 1.9 per 100 person-years; rate ratio, 9.6; 95% CI, 1.27-72, P = .03). In stratified analyses, female sex remained statistically significant after adjustment for each of the following variables: age, CD4 cell count, body mass index, ART regimen, and tuberculosis treatment. Stratifying hemoglobin levels decreased the hazard ratio from 9.6 to 7.40 (P = .05), with higher levels corresponding to a lower risk of PN. HIV-infected Kenyan women were almost 10 times more likely than men to develop PN in the first year of ART. The risk decreased slightly at higher hemoglobin levels. Preventing or treating anemia in women before ART initiation and implementing BPNS during the first year of ART, the period of highest risk, could ameliorate the risk of PN.

Alcohol consumption enhances antiretroviral painful peripheral neuropathy by mitochondrial mechanisms

A major dose-limiting side effect of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) chemotherapies, such as the nucleoside reverse transcriptase inhibitors (NRTIs), is a small-fiber painful peripheral neuropathy, mediated by its mitochondrial toxicity. Co-morbid conditions may also contribute to this dose-limiting effect of HIV/AIDS treatment. Alcohol abuse, which alone also produces painful neuropathy, is one of the most important co-morbid risk factors for peripheral neuropathy in patients with HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV/AIDS patients, the mechanisms by which alcohol abuse exacerbates highly active antiretroviral therapy (HAART)-induced neuropathic pain has not been demonstrated. In this study, performed in rats, we investigated the cellular mechanism by which consumed alcohol impacts antiretroviral-induced neuropathic pain. NRTI 2',3'-dideoxycytidine (ddC; 50 mg/kg) neuropathy was mitochondrial-dependent and PKCε-independent, and alcohol-induced painful neuropathy was PKCε-dependent and mitochondrial-independent. At low doses, ddC (5 mg/kg) and alcohol (6.5% ethanol diet for 1 week), which alone do not affect nociception, together produce profound mechanical hyperalgesia. This hyperalgesia is mitochondrial-dependent but PKCε-independent. These experiments, which provide the first model for studying the impact of co-morbidity in painful neuropathy, support the clinical impression that alcohol consumption enhances HIV/AIDS therapy neuropathy, and provide evidence for a role of mitochondrial mechanisms underlying this interaction.

A prospective double-blind, placebo-controlled study of thalidomide sensory symptoms in an elderly population with age-related macular degeneration

We aimed to determine the incidence of sensory symptoms (SS) that complicate thalidomide treatment of patients with age-related macular degeneration. In a double-blind prospective study, 38 patients were randomized to receive either thalidomide (100 mg twice per day) or placebo for 1 year. They were then followed for another year off drug. The SS (numbness, tingling, pins and needles) occurred in nine patients who took thalidomide (9/18; 50%) and in four who took placebo (4/20; 20%). Symptom severity was correlated with the time of onset, but not with cumulative dose. Five patients partially improved when the thalidomide was withdrawn, and three patients developed tremor with the neuropathy. The SS occurred shortly after thalidomide was introduced and we concluded that older patients with macular degeneration should be carefully screened for risk factors of peripheral neuropathy before thalidomide is used in their treatment.

Bortezomib-induced peripheral neuropathy in multiple myeloma: A comparison between previously treated and untreated patients

Peripheral neuropathy (PN), with neuropathic pain as main symptom, represents the dose-limiting toxicity of the proteasome inhibitor bortezomib. Aim of this study was to compare the incidence, risk factors, severity and outcome of PN and neuropathic pain in patient treated with bortezomib up-front or at relapse. We studied 55 patients with multiple myeloma (MM) who received bortezomib as first line therapy and 70 pre-treated patients who received bortezomib in relapse or progression. Regarding PN, no differences were found among untreated and pre-treated patients in the incidence (55% vs 52%, p = 0.43), severity (NCI grade 3–4 9% vs 14%, p = 0.27), and outcome (improved/resolved 90% vs 91%, p = 0.58). Concerning neuropathic pain, the incidence was lower (50% vs 81%, p = 0.008) and solved earlier (35 days vs 91 days, p = 0.02) in untreated compared with pre-treated patients. Untreated patients needed dose modification less frequently (36% vs 73%, p = 0.012). No correlation was found between development of PN and prior exposure to potentially neurotoxic drugs such as thalidomide, vincristine, and cysplatin. Age represented the main risk factor for PN ( p = 0.036) with an increase in risk of PN amounting to 6% per year of age. In conclusion, incidence, severity and outcome of bortezomib-related PN are similar in untreated and pre-treated MM patients except for neuropathic pain which has lower incidence and shorter duration in untreated patients with less frequent need for bortezomib discontinuation. Age emerges as the most relevant risk factor for peripheral neuropathy, with a risk increase for PN of 6% per year of age.

A prospective characterization of the resolution of ixabepilone induced peripheral neuropathy: data from a large registrational program in patients with metastatic breast cancer.

Abstract Abstract #6140 Background:&amp;#x2028; Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046, JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Similar to taxanes, dose-limiting peripheral neuropathy (PN) is a side effect associated with ixa treatment. Here we present the incidence rates, management of ixa-induced PN from 3 registrational studies in pts with MBC and an analysis of resolution time. Also, data on potential risk factors for PN are presented.&amp;#x2028; Methods:&amp;#x2028; Incidence of PN is summarized from a 2000 pt program from 3 multi-center clinical trials. In this program, almost 1100 pts with MBC received ixa either as a monotherapy (40 mg/m2 IV over 3h Q3w, N=126) in a phase II study, or in combination with C (1000 mg/m2 PO BID x14d Q3w) in 2 large phase III studies (N = 369 and N = 595). PN was evaluated every 4 weeks after completion of treatment until toxicity was resolved. Resolution of PN was defined as the time from onset of worst grade to baseline or grade 1. A Cox regression analysis was also performed on a dataset of 945 pts with different tumor types across multiple studies, receiving ixa as a monotherapy or in combination with C, to identify the potential risk factors for grade 3/4 PN.&amp;#x2028; Results:&amp;#x2028; Incidence rates of grade 3/4 PN and resolution time observed in 1 phase III study (046) and the phase II (081) have been published before (081: JCO, 25; 3407). Here we present the data from the final confirmatory phase III study (048).&amp;#x2028; &amp;#x2028; PN was effectively managed with dose reduction. After dose reduction, symptoms improved or did not worsen in the majority of pts, and a median of 2-3 additional treatment cycles were delivered. Pts with diabetes were at a higher risk of grade 3/4 PN (HR: 1.67 [1.00-2.78], p-value = 0.049).&amp;#x2028; Conclusions:&amp;#x2028; Incidence of ixa-associated PN was similar to that observed in trials of other T based regiments. Ixa-induced PN has a predictable median time to resolution of 5-6 weeks over 3 large studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6140.

Features and Risk Factors of Peripheral Neuropathy During Treatment with Bortezomib for Advanced Multiple Myeloma

BackgroundBortezomib is a first-in-class proteasome inhibitor with remarkable antitumor activity that is approved for the treatment of patients with multiple myeloma. Peripheral neuropathy (PN) is a frequent adverse event reported with bortezomib use. Patients and MethodsThe aim of this retrospective, single-center study was to determine the characteristics of bortezomib-associated PN in 100 patients with advanced myeloma. Peripheral neuropathy was evaluated by investigator's assessment. ResultsWith a median follow-up of 8 months (range, 0.1–32 months) from bortezomib initiation, bortezomib-associated PN was observed in 38 patients (38%; 95% CI, 28%–47%), with grade 3 and 4 PN occurring in 5 patients and 1 patient, respectively. Median time to onset of bortezomib-associated PN was 53 days (range, 11–182 days). Of the 38 patients with bortezomib-associated PN, resolution or improvement occurred in 20 patients (53%) at a median of 3 months (range, 1–8 months). In multivariate analysis, the total number of cycles of bortezomib (< 4 cycles or > 4 cycles; P = .03; odds ratio [OR], 2.6; 95% CI, 1.1–6.1) and a previous history of thalidomide therapy (P = .02; OR, 3.9; 95% CI, 1.2–12.6) were significantly associated with an increased incidence of bortezomib-associated PN. ConclusionWe conclude that, though relatively frequent, bortezomib-associated PN is reversible in a majority of patients. However, bortezomib-associated PN seems to be dependent on previous therapy with thalidomide, suggesting that bortezomib followed by thalidomide could be an optimal sequence of administration of these drugs in the salvage setting.