Neuropathy Total Symptom Score-6 Research Articles

Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis.

ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.

Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes.

Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22-49-fold) risk of neuropathy (rs2032930 and rs2032931 of recQ-mediated genome instability protein 2 (RMI2) gene), rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07-0.08-fold) risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p = 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus (p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant relationship between rs91778 and cold perception threshold (p = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.

Effects of Sensory and Motor Strategies for Recovery in Patients with Type 2 Diabetes Mellitus: A Quasi-experimental Study

Abstract Background: Among the late microvascular complications of diabetes mellitus, the growth and degeneration of such complications are responsible for much of the morbidity and mortality in terms of gangrene, diabetic ulcer, amputations, etc., Sensory and motor treatments are effective ways to cope up with complications. Aims and Objectives: To check the effect of sensory and motor strategies on type 2 diabetes mellitus (T2DM). Materials and Methods: There were 40 (n = 40) individuals who were diagnosed T2DM from the past 5 years. Participants were screened by monofilament testing, neuropathy total symptom score-6 (NTSS-6) scale, and manual muscle testing (MMT). Time up and go test was done before the intervention. Individuals were received transcutaneous electrical nerve stimulation (TENS) and sensory–motor exercises for 24 days. Result: After 4 weeks, outcome measures were assessed, the monofilament testing showed very positive impacts as all individuals were found negative after the intervention. The NTSS-6 (P &lt; 0.001) showed a substantial change between the pre- and postassessment. The MMT showed a significant difference in all individuals (P &lt; 0.001) and Time up and go test also showed significant improvement (P &lt; 0.001). Conclusion: TENS and sensory–motor exercises demonstrated effectiveness in enhancing of T2DM.

Udgharshana (an Ayurvedic therapeutic intervention) in improving vibration perception threshold in diabetic distal symmetric polyneuropathy: An observation

Diabetic Distal Symmetrical Polyneuropathy (DSPN), affects the sensation of vibration, a major risk factor for diabetic foot ulcers that raises the likelihood of lower limb amputation among the diabetic population. The effectiveness of existing therapeutic approaches in its management is limited, necessitating exploring alternative therapy approaches. A 61-year-old female, a known Type 2 Diabetic for five years, presented with complaints of numbness and tingling sensation in bilateral lower limbs below the knee joint associated with aching pain in the bilateral foot region for the last two years. On assessment, she was found to be positive on the Michigan Neuropathy Screening Instrument that indicates the probable diagnosis of diabetic DSPN. The patient was treated with an Ayurvedic topical therapeutic intervention, Udgharshana (~therapeutic coarse powder massage) with a combination of Triphala (~a polyherbal Ayurvedic formulation) powder and Dhanyamla (~fermented sour liquid prepared from gruel of husked grains). Improvement in clinical features was observed on Neuropathy Total Symptom Score-6 and in Semmes-Weinstein monofilament reading in the bilateral foot (right 7/10 vs. 9/10 and left 7/10-10/10). The intervention also improved the vibration perception threshold bilaterally (right 31.5V vs. 20.1V; left 30.5V vs. 22.8V). Inferring the observations, it is suggested that early disease management of diabetic DSPN with Ayurveda might arrest further disease progression and help in reversing the pathogenesis, with a positive effect on improving vibration perception threshold.

A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy of a Nerve Support Formula on Neuropathic Pain in Individuals Suffering from Type II Diabetes Mellitus.

The primary objective of the present study was to evaluate the effects of a Nerve Support Formula NeuropAWAY® on diabetic neuropathic pain. This double-blind, placebo-controlled, randomized trial was conducted between August 2020 and February 2021. Patients aged ≥40 and ≤65 years with a history of type 2 diabetes (T2D) with a confirmed diagnosis of diabetic neuropathic pain were included in the study. The primary efficacy endpoint was to assess the effect of the 42 days administration of the Nerve Support Formula on the neuropathic pain as assessed by the 11 point Pain Intensity Numeric Rating Scale (PI-NRS). The secondary objectives were to assess the effect on plasma vitamin B12 levels, nerve conduction velocity, blood flow velocity, Brief Pain Inventory, Neuropathy Total Symptom Score, and Insomnia Severity Index. The enrolled study population (n=59) was randomized in two study groups; the Investigational Product (IP) group - Nerve Support Formula (n=27) and placebo group (n=32). The mean age of these participants was 52.63 and 53.72 for IP and placebo group, respectively. The mean (SD) HbA1c levels for IP and placebo group were 8.37 (0.85) and 8.16 (0.86), respectively. By the end of the study (Day 42) the decrease in PI-NRS scores for the IP group was maximal (↓61.32%) and highly significant (p<0.001) in comparison to the placebo group (↑2.47%). Significant improvements (p<0.05) were also noted in the secondary efficacy variables after 42 days of IP intake. The formula was found to be significantly effective as compared to placebo in reducing pain and other sensory symptoms related to the diabetic peripheral neuropathy.

Demographic and Clinical Factors Associated with Depression in 140 Hospitalized Diabetic Patients with Distal Symmetric Polyneuropathy Evaluated Using Beck Depression Inventory and 6-Item Neuropathy Total Symptom Score Questionnaire.

BACKGROUND Diabetic distal symmetric polyneuropathy (DSPN) is one of the most common and costliest long-term complications. The pain and function limitations may lead to depression. This study aimed to assess the influence of demographic and clinical factors on the prevalence of depression among diabetic patients with distal symmetric polyneuropathy (DSPN). MATERIAL AND METHODS A total of 140 patients with diabetic DSPN completed the 21-item Beck Depression Inventory (BDI) measuring characteristic attitudes and symptoms of depression. The intensity of neuropathic complaints was assessed using the Neuropathy Total Symptom Score- 6 items (NTSS-6). Testing for peripheral neuropathy was performed. All patients completed questionnaires, which included anthropometric measures, social parameters, and medical aspects. Statistical analyses were done using STATISTICA 8 PL software. RESULTS Statistically significant relationships were found between the depression symptoms in diabetic patients and the intensity of subjective neuropathy symptoms evaluated by NTSS-6, body mass index (BMI), and education level. On average, each 1-point increase in NTSS-6 predicted a 16% increase in the risk of depression. Each 1 kg/m² increase in the BMI was associated with a 10% increase of depression risk. CONCLUSIONS The study showed the positive quantitative relationship between diabetic DSPN and depression symptoms. The BMI, severity of neuropathy symptoms, and lower level of education had a statistically significant association with the level of depression and may be useful in evaluating the risk of depression among DSPN patients.

A randomized placebo-compared study on the efficacy of classical ayurvedic pharmaceutical form versus aqueous alcoholic extracts of Phyllanthus niruri Linn. Plus Sida cordifolia Linn. in patients of diabetic sensory polyneuropathy

BackgroundIn routine, Ayurveda practitioners prefer classical pharmaceutical form of herbal medicines in compare to modern extracts. ObjectiveTo explore the difference of efficiency between whole drug powder of Phyllanthus niruri plus root decoction of Sida cordifolia and modern extracts of the same in compared to placebo in patients of diabetic poly-neuropathy. Material and methodsA randomized, partly-double-blinded, placebo-controlled trial evaluated the efficacy of two different pharmaceutical forms of herbal medicines over placebo in 90 patients (30 in each group) of diabetic sensory polyneuropathy for first three weeks period. After three weeks, active herbal medication groups were continued with their assigned medicaments for next 5 weeks period and all placebo-patients were randomized again into 2 groups of active medication and treated for next 8 weeks. Patients were assessed with Neuropathy Total Symptom Score 6 and sensation thresholds. ResultsSignificant effect of both form of herbal medicines over placebo was found in aching pain [F (2, 49) = 6.79, p = 0.002], allodynia [F (2, 59) = 6.74, p = 0.002], burning pain [F (2, 82) = 14.66, p < 0.0001], numbness [F (2, 77) = 16.37, p < 0.0001] and pricking pain [F (2, 50) = 14.23, p < 0.0001]. After the 8 weeks period, no significant difference was identified between the effect of both the herbal treatment on aching pain (U = 220, p = 0.03), allodynia (U = 421.5, p = 0.29), burning pain (U = 881.5, p = 0.846), numbness (U = 778, p = 0.92) and pricking pain (U = 260, p = 0.15). ConclusionBoth herbal groups have significant effect to reduce NTSS-6 score in compare to placebo. No significant difference found between the effect of two different pharmaceutical forms of Phyllanthus niruri and S. cordifolia.

A cross-sectional study describing peripheral neuropathy in patients with symptoms of gastroparesis: associations with etiology, gastrointestinal symptoms, and gastric emptying

BackgroundPeripheral neuropathy (PN) is present in diabetic gastroparesis but is not described in idiopathic gastroparesis.Aims(1) Determine prevalence of PN in idiopathic gastroparesis; (2) assess if patients with symptoms of gastroparesis and PN differ in gastric emptying and symptoms, both gastrointestinal and psychosocial, from patients without PN (nPN); (3) compare this relationship to that in other etiological groups.Methods250 patients with symptoms of gastroparesis underwent gastric emptying scintigraphy and answered questionnaires including severity of gastroparesis symptoms using the Gastroparesis Cardinal Symptom Index (GCSI) and presence of peripheral neuropathy using the Neuropathy Total Symptom Score-6 (NTSS-6).ResultsPN, defined by NTSS-6 > 6, was present in 70/250 (28%) patients: 22/148 (15%) idiopathic, 33/61 (54%) diabetic, and 11/32 (34%) postsurgical (p < 0.01). Among 148 patients with symptoms of idiopathic gastroparesis, defined as non-diabetic, non-postsurgical, and not caused by a known disorder such as Parkinson’s or connective tissue disease, symptoms of gastroparesis were more severe in PN than nPN: bloating (4.05 ± 1.17 vs. 2.99 ± 1.61, p < 0.01), abdominal distension (3.86 ± 1.49 vs. 2.45 ± 1.68, p < 0.01), and upper abdominal pain (3.64 ± 1.22 vs. 2.71 ± 1.78, p = 0.03). Ninety-nine idiopathic patients underwent gastric emptying scintigraphy: 7/43 (16%) patients with delayed gastric emptying and 9/56 (16%) patients with normal gastric emptying had PN. Among patients with idiopathic gastroparesis, abdominal distension (4.43 ± 0.53 vs. 2.89 ± 1.68, p = 0.01) was more severe in PN than nPN. The association of PN and worse gastrointestinal symptoms was not as apparent in patients with symptoms of diabetic or postsurgical gastroparesis.ConclusionsPN was present in 70/250 (28%) of patients with symptoms of gastroparesis and was present to a lesser extent in idiopathic than diabetic gastroparesis. The presence of PN in IG was associated with more severe gastroparetic symptoms than in nPN. Screening for PN may help identify a gastroparesis cohort with peripheral neuropathy who are more symptomatic.

Frequency of Neuropathic Sensory Symptoms Among Patients With Uncontrolled Diabetes Mellitus in Security Forces Hospital, Riyadh, Saudi Arabia.

BackgroundDiabetic peripheral neuropathy (DPN) is a chronic sensorimotor length-dependent and symmetrical polyneuropathy. Some peripheral neuropathies have painful presentations, and some are painless. DPN can have a potential impact on the patient's life.ObjectivesThis study was conducted in order to investigate the frequency of neuropathic sensory symptoms among patients with uncontrolled diabetes mellitus.MethodsThis is a cross-sectional study conducted in the Security Forces hospital using the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire. The questionnaire was administered by contacting patients through the phone. Patients with uncontrolled diabetes (HbA1C >9) were included in the study.ResultsThis study included 285 participants; 58.9% had type II diabetes and 41.1% had type I diabetes, 156 (54.7%) were females, and 129 (45.3%) were males. Most of the patients (51.1%) were 45-64 years old and the majority were non-smokers (77.9%). Patients with neuropathic pain were 182 (63.9%); 79 (43.4%) of them were males and 103 (56.6%) were females. The prevalence of neuropathic symptoms was much higher in females than in males.ConclusionThe prevalence of painful DPN is high among patients with long-term uncontrolled diabetes mellitus. Older, unemployed, and low-educated patients are at higher risk of developing painful DPN. Proper glycemic control and lifestyle modifications are essential in preventing the progression of this condition.

Efficacy of homoeopathic treatment for diabetic distal symmetric polyneuropathy: A multicentric randomised double-blind placebo-controlled clinical trial.

BackgroundIn course of diabetes, some 20–90% of individuals eventually develop diabetic neuropathy. Looking at the disease burden research studies in Homoeopathy were conducted and have shown positive results. These studies were not robust enough to prove the efficacy of individualized homoeopathy. ObjectiveTo assess efficacy of individualized homoeopathic medicines in management of DDSP. MethodsA multi-centric double-blind, placebo controlled, randomised clinical trial was conducted by the Central Council for Research in Homoeopathy at six centres with a sample size of 84. Based on earlier observational studies and repertorial anamnesis of DDSP symptoms 15 homoeopathic medicines were shortlisted and validated scales were used for evaluating the outcomes post-intervention. Primary outcome measure was change in Neuropathy Total Symptom Score-6 (NTSS-6) from baseline to 12 months. Secondary outcomes included changes in peripheral nerve conduction study (NCS), World Health Organization Quality of Life BREF (WHOQOL-BREF) and Diabetic Neuropathy Examination (DNE) Score at 12 months. ResultsData of 68 enrolled cases was considered for data analysis. Statistically significant difference (p<0.014) was found in NTSS-6 post intervention in the Verum group. Positive trend was noted for Verum group as per the graph plotted for DNE score and assessment done for NCS. No significant difference was found between the groups for WHOQOL-Bref. Out of 15 pre-identified homoeopathic medicines 11 medicines were prescribed in potencies in ascending order from 6C to 1M. ConclusionFurther studies must be taken up with larger sample size and defined parameters for NCS to assess the effectiveness of homoeopathy.

Effect of different exercise training intensities on musculoskeletal and neuropathic pain in inactive individuals with type 2 diabetes – Preliminary randomised controlled trial

AimsPeople with type 2 diabetes (T2D) have a greater prevalence of musculoskeletal and neuropathic pain. This exploratory analysis investigated whether exercise of different intensities leads to changes in self-reported musculoskeletal pain or symptoms of diabetic neuropathy in inactive individuals with type 2 diabetes. MethodsThirty-two inactive adults with T2D (59% male, mean age 58.7 ± 9.1yrs, median HbA1c 7.8%) were randomised to usual care (CON), supervised combined aerobic and resistance moderate-intensity continuous training (C-MICT), or supervised combined high-intensity interval training (C-HIIT). At baseline and 8-weeks, musculoskeletal and neuropathic pain were evaluated using a modified Nordic Musculoskeletal Questionnaire and the Neuropathy Total Symptom Score-6 respectively. Quantitative sensory testing was used to determine thermal, mechanical and vibration detection thresholds, as well as pain pressure thresholds. Adverse events were recorded throughout the intervention. ResultsCompared to CON, reduction in musculoskeletal pain intensity was significantly greater for C-HIIT (MD −5.4, 95% CI [−10.6 to −0.2], p = 0.04) and non-significantly greater for C-MICT (MD −5.9 [−12.4 to 0.7], p = 0.08). Changes in neuropathy symptoms were not different between C-HIIT and CON (MD 1.0 [−0.9 to 2.8], p = 0.31), or C-MICT and CON (MD 0.2 [−3.1 to 3.6], p = 0.89). No differences in sensory function were observed between groups. Similar rates of adverse events were seen in both exercise interventions (19 C-HIIT; 17 C-MICT), all but one of which were mild. ConclusionsPreliminary data suggests 8-weeks of high-intensity combined aerobic and resistance exercise may be safely prescribed for inactive individuals with T2D and may reduce musculoskeletal pain but not neuropathic symptoms.Trial Registration:ACTRN12615000475549.

Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy.

BackgroundThe association between long-term metformin use and low vitamin B12 levels has been proven. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed considerable variation among the studies. The potential of the deficiency to cause or worsen peripheral neuropathy in type-2 diabetes mellitus (T2DM) patients has been investigated with conflicting results. The aim of the study was to investigate: 1) the prevalence of vitamin B12 deficiency in T2DM patients on metformin; 2) the association between vitamin B12 and peripheral neuropathy; 3) and the risk factors for vitamin B12 deficiency in these patients.MethodsIn this cross-sectional study, consecutive metformin-treated T2DM patients attending diabetes clinics of two public hospitals in South Africa were approached for participation. Participation included measuring vitamin B12 levels and assessing peripheral neuropathy using Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire. The prevalence of vitamin B12 deficiency (defined by concentrations <150 pmol/L) was determined. Those with NTSS-6 scores >6 were considered to have peripheral neuropathy. The relationship between vitamin B12 and peripheral neuropathy was investigated when the two variables were in the binary and continuous forms. Multiple logistic regression was used to determine risk factors for vitamin B12 deficiency.ResultsAmong 121 participants, the prevalence of vitamin B12 deficiency was 28.1 %. There was no difference in presence of neuropathy between those with normal and deficient vitamin levels (36.8 % vs. 32.3 %, P = 0.209). Vitamin B12 levels and NTSS-6 scores were not correlated (Spearman’s rho =0.056, P = 0.54). HbA1c (mmol/mol) (OR = 0.97, 95 % CI: 0.95 to 0.99, P = 0.003) and black race (OR = 0.34, 95 % CI: 0.13 to 0.92, P = 0.033) were risk factors significantly associated with vitamin B12 deficiency. Metformin daily dose (gram) showed borderline significance (OR = 1.96, 95 % CI: 0.99 to 3.88, P = 0.053).ConclusionsClose to third of metformin-treated T2DM patients had vitamin B12 deficiency. The deficiency was not associated with peripheral neuropathy. Black race was a protective factor for vitamin B12 deficiency.

Nutritional management of patients with diabetic peripheral neuropathy with L-methylfolate-methylcobalamin-pyridoxal-5-phosphate: results of a real-world patient experience trial

Objective:Current therapies for diabetic peripheral neuropathy with pain mask the painful symptoms while the underlying pathology continues to progress. This study assessed changes in symptoms and quality of life in patients taking a novel prescription medical food, L-methylfolate-methylcobalamin-pyridoxal-5-phosphate (LMF-MC-PP, Metanx), intended to address the underlying metabolic needs of patients with diabetic peripheral neuropathy.Research design and methods:Between November 2010 and April 2012, patients rated their experiences before and after using LMF-MC-PP through an automated telephone system that included symptomatic items from the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire and questions related to quality of life and medication satisfaction.Results:A total of 544 patients participated in the study. Patients reported a mean reduction of 35% in NTSS-6 scores from after 12 weeks on LMF-MC-PP. Mean (standard deviation) score was reduced by 1.5 (1.8) at 12 weeks from a baseline of 4.3 (1.5) (p < 0.05). Patients achieved significant reductions in self-reported disruptions in work/school activities, social life, and family life, respectively. Overall pain rating decreased by 32% (p < 0.05). Patients previously treated with medications reported a 52% improvement in medication satisfaction (p < 0.05).Conclusions:In a real-world clinical setting, patients with diabetic peripheral neuropathy treated with LMF-MC-PP achieved significant improvements in total symptom score (NTSS-6) and in quality of life and functioning, together with greater medication satisfaction. A limitation of this study was the use of a survey instrument to collect data on patient outcomes.

A dietary intervention for chronic diabetic neuropathy pain: a randomized controlled pilot study.

Background:Diabetic neuropathy is a common and often debilitating condition for which available treatments are limited. Because a low-fat plant-based diet has been shown to improve glycemic control in individuals with type 2 diabetes, we hypothesized that such a diet would reduce painful symptoms of diabetic neuropathy.Methods:In this 20-week pilot study, individuals with type 2 diabetes and painful diabetic neuropathy were randomly assigned to two groups. The intervention group was asked to follow a low-fat, plant-based diet, with weekly classes for support in following the prescribed diet, and to take a vitamin B12 supplement. The control group was asked to take the same vitamin B12 supplement, but received no other intervention. At baseline, midpoint and 20 weeks, clinical, laboratory and questionnaire data were collected. Questionnaires included an analog ‘worst pain' scale, Michigan Neuropathy Screening Instrument, global impression scale, Short Form McGill Pain Questionnaire, Neuropathy Total Symptom Score, a weekly pain diary and Norfolk Quality of Life Questionnaire.Results:After 20 weeks, body weight change with the intervention was −6.4 kg (95% confidence interval (CI) −9.4 to −3.4, P<0.001) in an effect size analysis. Electrochemical skin conductance in the foot improved by an average of 12.4 microseimens (95% CI 1.2–23.6, P=0.03) with the intervention in an effect size analysis. The between-group difference in change in pain, as measured by the McGill pain questionnaire, was −8.2 points (95% CI −16.1 to −0.3, P=0.04). Michigan Neuropathy Screening Instrument questionnaire score change was −1.6 points (95% CI −3.0 to −0.2, P=0.03).Conclusions:Improvements were seen in some clinical and pain measures. This pilot study suggests the potential value of a plant-based diet intervention, including weekly support classes, for treating painful diabetic neuropathy.

Assessment of diabetic polyneuropathy and autonomic neuropathy using current perception threshold in korean patients with diabetes mellitus.

BackgroundThe current perception threshold (CPT) could be quantified by stimulating Aβ and C fibers at 2,000 and 5 Hz, respectively. C fibers play a role in the autonomic nervous system and are involved in temperature and pain sensation. We evaluated the usefulness of CPT for diagnosing distal polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) in diabetic patients.MethodsThe CPT was measured in the index finger (C7 level) and in the third toe (L5 level) in diabetic patients aged 30 to 69 years. We assessed DPN according to the neuropathy total symptom score-6 (NTSS-6) and 10-g monofilament pressure sensation. Subjects with a NTSS-6 >6 or with abnormal 10-g monofilament sensation were defined to have DPN. CAN was evaluated by spectral analysis of heart rate variability and by Ewing's traditional tests.ResultsThe subjects with DPN had significantly higher CPT at all of the frequencies than the subjects without DPN (P<0.05). Abnormal 10-g monofilament sensation and NTSS-6 >6 could be most precisely predicted by CPT at 2,000 and 5 Hz, respectively. However, only 6.5% and 19.6% of subjects with DPN had an abnormal CPT at 2,000 Hz at the C7 and L5 levels. Although CPT at 5 Hz showed a negative correlation with the power of low and high frequency in the spectral analysis (P<0.05), only 16.7% of subjects with CAN exhibited an abnormal CPT at the same frequency.ConclusionAlthough the CPT is significantly associated with neuropathic symptoms or signs corresponding to the nerve fiber stimulated, it provides little additional information compared with conventional evaluations.

Efficacy of homoeopathic treatment for diabetic distal symmetric polyneuropathy: A multicentric randomised double-blind placebo-controlled clinical trial

Background: There are limitations in the management of Diabetic Distal Symmetric Polyneuropathy (DDSP) in conventional system but in Homoeopathy the research studies have shown positive results. These studies were not robust enough to prove the efficacy of individualized homoeopathy, thus this protocol has been developed to assess the efficacy of these individualized homoeopathic drugs in this disease. Material and Methods: It shall be a double blind randomised placebo controlled clinical trial. On the basis of earlier observational studies and repertorial anamnesis of DDSP symptoms, 15 homoeopathic medicines have been identified. The validated scales are being used for evaluating the outcomes post-intervention. The primary outcome is change in Neuropathy Total Symptom Score-6 (NTSS-6) from baseline to 12 months. The secondary outcomes include the changes in HbA1c, peripheral nerve conduction test, World Health Organization Quality Of Life BREF (WHOQOL-BREF) and Diabetic Neuropathy Examination (DNE) Score at 12 months post intervention. Discussion: Results from this trial will help to construct a strategy for treating the patients with DDSP and for improving the quality of life of diabetic patients. Trial Registration: Clinical Trial Registry - India: CTRI/2013/07/003818.

Metanx in Type 2 Diabetes with Peripheral Neuropathy: A Randomized Trial

PurposeTo determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5′-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy. Research Design and MethodsThis multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5′-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B6 and B12, methylmalonic acid (MMA), and homocysteine. ResultsThere was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 μmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 μmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects. ConclusionsLMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful.

An observational study of the effect of metformin on B12 status and peripheral neuropathy

Aims Metformin is associated with lowering of vitamin B12 levels. We hypothesise that holotranscobalamin (holoTC) and methylmalonic acid (MMA) are more sensitive indicators of B12 deficiency in patients receiving metformin therapy, and that these correlate with declining peripheral neurological function. Methods Patients with type 2 diabetes were recruited and divided into those receiving metformin for greater than 6 months and a non-metformin group. Baseline characteristics were measured in both groups including vitamin B12, holoTC and MMA concentrations. Neurological function was assessed using neurothesiometry, monofilament, Neuropathy Total Symptom Score-6 questionnaire and the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs questionnaire. Results In total, 202 patients were recruited: 152 in the metformin group and 50 in the non-metformin group. Vitamin B12 levels were lower in the metformin group (219.1±105.4 ng/L, 281.4±95.1 ng/L, p&lt;0.001). HoloTC was significantly lower in the metformin group (54.8±30.5 pmol/L, 70.1±26.0 pmol/L, p=0.002). No significant difference in serum MMA was observed between the two groups (0.40±0.26 μmol/L, 0.35±0.22, p=0.23). No significant difference in neurological function was observed between the groups. Conclusion Although metformin therapy is associated with lower vitamin B12 status there does not appear to be any significant effect on peripheral neuropathy in those receiving metformin. We do not recommend changing current practice to routinely monitor or replace patients receiving metformin with vitamin B12 unless clinically indicated.

Role of nitrosative and oxidative stress in neuropathy in patients with type 2 diabetes mellitus

Objectives:Evidences of oxidative and/or nitrosative stress in type 2 diabetes mellitus were demonstrated in experimental and human studies. This study is aimed to assess the serum peroxynitrite and oxidized lipoproteins in patients with type 2 diabetes mellitus presented with clinical and laboratory evidences of peripheral neuropathy.Materials and Methods:Eighty four patients with type 2 diabetes mellitus (51 of them had neuropathy) and 31 apparent healthy subjects were studied in the unit of neurophysiology at the University Hospital of Medical College, Al-Nahrin University in Baghdad, Iraq. Neuropathy total symptom score (NTSS), neuropathy impairment score in the lower leg (NIS-LL), and nerve conduction velocity of sensory (ulnar and sural) and motor (ulnar and common peroneal) nerves were used to assess the neuropathy. Fasting venous blood was obtained from each participant for the determination of serum glucose and oxidized lipoproteins.Results:The electrophysiology study revealed significant decrease in conduction velocity of ulnar (sensory and motor components), sural, and common peroneal nerves in diabetic neuropathy compared to diabetics without neuropathy and healthy subjects. Significant high level of serum peroxynitrite was found in diabetic patients with or without neuropathy compared with non-diabetics. The changes in serum-oxidized lipoproteins in patients with diabetics with or without neuropathy were non-significantly differed from healthy subjects. Neither nitrosative stress nor oxidative stress indices correlated with the variables that are related to the neuropathy.Conclusion:It concludes that evidence of nitrosative and to less extent the oxidative stress is associated with neuropathy in type 2 diabetes mellitus and their indices not correlated with variables related to neuropathy.

Quality of Life and Objective Measures of Diabetic Neuropathy in a Prospective Placebo-Controlled Trial of Ruboxistaurin and Topiramate

The Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) is a validated comprehensive questionnaire designed to capture the entire spectrum of DN related to large fiber, small fiber, and autonomic neuropathy not captured in existing instruments. We aimed to determine if the Norfolk QOL-DN could be used to capture changes in QOL that correlate with nerve fiber-specific objective measures in a placebo-controlled trial of two agents that affect different nerve fibers. Sixty patients with DN were allocated to treatment on ruboxistaurin (RBX) (n = 18), topiramate (TPX) (n = 18), or placebo (n = 18). QOL-DN was administered and objective measures of nerve function were performed at entry and end of the study period. Total QOL scores improved significantly in the active treatment groups (RBX -9.56 ± 4.13; TPX -12.22 ± 2.76) but not in placebo (-5.56 ± 3.49). There were differences in nerve function improvement between treatments. Neurological symptom scores (NSS) improved with TPX from 5.5 (2.3) to 4.3 (0.65) (p = .007), sensory scores improved with TPX from 15.5 (1.79) to 8.3 (1.19) (p < .001), motor scores did not change, and sensory and motor impairment scores improved with TPX from 18.8 (2.15) to 12.1 (1.71) (p = .003). Total neuropathy scores (TNS) improved with TPX from 24.35 (2.61) to 16.35 (2.02) (p = .001). Neuropathy total symptom score-6 (NTSS-6) changes were significant for both treatments: RBX 4.38 (0.75) to 1.49 (0.38) (p < .001) and TPX 7.57 (1.3) to 4.26 (0.95) (p = .036). Changes in QOL-DN large fiber subscores correlated (Spearman's rank) significantly with changes in NTSS-6 (r = 0.55; p < .0001), NSS (r = 0.31; p < .04), neuropathy impairment score (NIS) (r = 0.35; p < .02), and TNS (r = 0.48; p < .0006). Changes in QOL-DN small fiber subscores correlated significantly with changes in NTSS-6 total scores (r = 0.40; p < .005) and intraepidermal nerve fiber density (IENFD) (r = -0.29; p < .05). Ruboxistaurin produced significant improvement in large fiber measures while TPX produced significant changes in small fiber measures. The Norfolk QOL-DN tool differentiated between these changes captured in the fiber-specific domains. Correlations were found between objective measures of neuropathy and total QOL, but those with nerve fiber domain scores were modest and reinforce the need to quantify QOL as an endpoint in neuropathy independent of other measures.