Case-Control Study of Paresthesia Among World Trade Center-Exposed Community Members.

OBJECTIVE: To investigate whether paresthesia of the lower extremities following exposure to the World Trade Center (WTC) disaster was associated with signs of neuropathy, metabolic abnormalities, or neurotoxin exposures. METHODS: Case-control study comparing WTC-exposed paresthesia cases with "clinic controls" (WTC-exposed subjects without paresthesias), and "community controls" (WTC-unexposed persons). RESULTS: Neurological histories and examination findings were significantly worse in cases than controls. Intraepidermal nerve fiber densities were below normal in 47% of cases and sural to radial sensory nerve amplitude ratios were less than 0.4 in 29.4%. Neurologic abnormalities were uncommon among WTC-unexposed community controls. Metabolic conditions and neurotoxin exposures did not differ among groups. CONCLUSIONS: Paresthesias among WTC-exposed individuals were associated with signs of neuropathy, small and large fiber disease. The data support WTC-related exposures as risk factors for neuropathy, and do not support non-WTC etiologies.

Development and Validation of the Norfolk Quality of Life Fatigue Tool (QOL-F): A New Measure of Perception of Fatigue.

OBJECTIVES: To design a questionnaire to evaluate and distinguish between cognitive and physical aspects of fatigue in different age groups of "nondiseased" people and guide appropriate prevention and interventions for the impact of frailty occurring in normative aging. STUDY DESIGN AND PARTICIPANTS: The Norfolk QOL-Fatigue (QOL-F) with items of cognitive and physical fatigue, anxiety, and depression from validated questionnaires including items from the Patient-Reported Outcomes Measure Information System (PROMIS) databank was developed. The preliminary QOL-F was administered to 409 healthy multiethnic local participants (30-80 years old) in 5 age groups. METHODS: The authors distilled the item pool using exploratory (EFA) and confirmatory factor analysis (CFA). EFA identified 5 latent groups as possible factors related to problems due to fatigue, subjective fatigue, reduced activities, impaired activities of daily living (ADL), and depression. RESULTS: CFA demonstrated good overall fit [χ2(172) = 1094.23, P < .001; Tucker-Lewis index = 0.978; root mean square error of approximation = 0.049] with factor loadings >0.617 and strong interfactor correlations (0.69-0.83), suggesting that fatigue in each domain is closely related to other domains and to the overall scale except for ADL. The 5-factor solution displayed good internal consistency (Cronbach α = 0.78-0.94). Total and domain scores were fairly equivalent in all age groups except for the 40 to 49-year-old group with better overall scores. In addition, 70 to 79-year-olds had better ADL scores. In item response analysis, factor scores in different age groups were similar, so age may not be a significant driver of fatigue scores. Fatigue scores were significantly higher in females than in males (P < .05). CONCLUSIONS AND CLINICAL IMPLICATIONS: The developed Norfolk QOL-F tool demonstrated fatigue as a perceived cognitive phenomenon rather than an objective physical measure, suggesting mandatory inclusion of cognitive as well as physical measures in the evaluation of people as they age. QOL-F is able to distinguish QOL-F domain scores unique to different age groups, proposing clinical benefits from physical, balance, and cognitive interventions tailored to impact frailty occurring in normative aging.

Clinical measures in transthyretin familial amyloid polyneuropathy.

INTRODUCTION: This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed. RESULTS: Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease. CONCLUSIONS: NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017.

Delay between Onset of Symptoms and Seeking Physician Intervention Increases Risk of Diabetic Foot Complications: Results of a Cross-Sectional Population-Based Survey.

We present a post hoc analysis of 17,530 questionnaires collected as part of the 2012 screening for neuropathy using Norfolk Quality of Life tool in patients with diabetes in Romania, to assess the impact on foot complications of time between the onset of symptoms of diabetes/its complications and the physician visit. Odds ratios (ORs) for self-reporting neuropathy increased from 1.16 (95% CI: 1.07-1.25) in those who sought medical care in 1-6 months from symptoms of diabetes/its complications onset to 2.27 in those who sought medical care >2 years after symptoms onset. The ORs for having a history of foot ulcers were 1.43 (95% CI: 1.26-1.63) in those who sought medical care in 1-6 months and increased to 3.08 (95% CI: 2.59-3.66) in those who sought medical care after >2 years from symptoms of diabetes/its complications onset. The highest ORs for a history of gangrene (2.49 [95% CI: 1.90-3.26]) and amputations (2.18 [95% CI: 1.60-2.97]) were observed in those who sought medical care after >2 years following symptoms onset. In conclusion, we showed that waiting for >1 month after symptoms onset dramatically increases the risk of diabetic foot complications. These results show the need for accessible educational programs on diabetes and its chronic complications and the need to avoid delays in reporting.

Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study.

BACKGROUND: This 52-week study evaluated the long-term safety and tolerability of capsaicin 8% w/w (179 mg) patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy (PDPN). METHODS: Phase 3, multinational, open-label, randomised, controlled, 52-week safety study, conducted in Europe. Patients were randomised to capsaicin 8% patch repeat treatment (30 or 60 min; 1-7 treatments with ≥ 8-week intervals) to painful areas of the feet plus SOC, or SOC alone. The primary objective was the safety of capsaicin 8% patch repeat treatment (30 min and 60 min applications) plus SOC versus SOC alone over 52 weeks, assessed by changes in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) total score from baseline to end of study (EOS). Secondary safety endpoints included Utah Early Neuropathy Scale (UENS) assessments and standardised testing of sensory perception and reflex function. RESULTS: Overall, 468 patients were randomised (30 min plus SOC, n = 156; 60 min plus SOC, n = 157; SOC alone, n = 155). By EoS, mean changes in Norfolk QOL-DN total score from baseline [estimated mean difference versus SOC alone; 90% CI for difference] were: 30 min plus SOC, -27.6% [-20.9; -31.7, -10.1]; 60 min plus SOC, -32.8% [-26.1; -36.8, -15.4]; SOC alone, -6.7%. Mean changes [difference versus SOC alone] in UENS total score by EoS versus baseline were: 30 min plus SOC, -2.1 [-0.9; -1.8, 0.1]; 60 min plus SOC, -3.0 [-1.7; -2.7, -0.8]; SOC alone, -1.2. No detrimental deterioration was observed in any of the Norfolk or UENS subscales by EoS with capsaicin. Also, no worsening in sensory perception testing of sharp, warm, cold and vibration stimuli was found with capsaicin by EoS. Capsaicin treatment was well tolerated and the most frequent treatment-emergent adverse events were application site pain (30 min, 28.2%; 60 min, 29.3%), burning sensation (30 min, 9.0%; 60 min, 9.6%) and application site erythema (30 min, 7.7%; 60 min, 8.9%). CONCLUSION: In patients with PDPN, capsaicin 8% patch repeat treatment plus SOC over 52 weeks was well tolerated with no negative functional or neurological effects compared with SOC alone. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT01478607 . Date of registration November 21, 2011; retrospectively registered.

Epidemiology of Diabetic Foot Ulcers and Amputations in Romania: Results of a Cross-Sectional Quality of Life Questionnaire Based Survey.

This is a post hoc analysis of quality of life in diabetic neuropathy patients in a cross-sectional survey performed in 2012 in Romania, using the Norfolk QOL-DN in which 21,756 patients with self-reported diabetes were enrolled. This current analysis aims to expand research on the diabetic foot and to provide an update on the number of foot ulcers found in Romania. Of the 21,174 patients included in this analysis, 14.85% reported a history of foot ulcers and 3.60% reported an amputation. The percentage of neuropathy patients with foot ulcers increased with age; the lowest percentage was observed in the 20-29-year age group (6.62%) and the highest in the 80-89-year age group (17.68%). The highest number of amputations was reported in the 70-79-year age group (largest group). Compared to patients without foot ulcers, those with foot ulcers had significantly higher scores for total DN and all its subdomains translating to worse QOL (p < 0.001). This analysis showed a high rate of foot ulcers and amputations in Romanian diabetic patients. It underscores the need for implementation of effective screening and educational programs.

Walking-Induced Fatigue Leads to Increased Falls Risk in Older Adults.

BACKGROUND: For older adults, falls are a serious health problem, with more than 30% of people older than 65 suffering a fall at least once a year. One element often overlooked in the assessment of falls is whether a person's balance, walking ability, and overall falls risk is affected by performing activities of daily living such as walking. OBJECTIVE: This study assessed the immediate impact of incline walking at a moderate pace on falls risk, leg strength, reaction time, gait, and balance in 75 healthy adults from 30 to 79 years of age. Subjects were subdivided into 5 equal groups based on their age (group 1, 30-39 years; group 2, 40-49 years; group 3, 50-59 years; group 4, 60-69 years; group 5, 70-79 years). METHODS: Each person's falls risk (using the Physiological Profile Assessment), simple reaction time, leg strength, walking ability, and standing balance were assessed before and after a period of incline walking on an automated treadmill. The walking task consisted of three 5-minute trials at a faster than preferred pace. Fatigue during walking was elicited by increasing the treadmill incline in increments of 2° (from level) every minute to a maximum of 8°. RESULTS: As predicted, significant age-related differences were observed before the walking activity. In general, increasing age was associated with declines in gait speed, lower limb strength, slower reaction times, and increases in overall falls risk. Following the treadmill task, older adults exhibited increased sway (path length 60-69 years; 10.2 ± 0.7 to 12.1 ± 0.7 cm: 70-79 years; 12.8 ± 1.1 to 15.1 ± 0.8 cm), slower reaction times (70-79 years; 256 ± 6 to 287 ± 8 ms), and declines in lower limb strength (60-69 years; 36 ± 2 to 31 ± 1 kg: 70-79 years; 32.3 ± 2 to 27 ± 1 kg). However, a significant increase in overall falls risk (pre; 0.51 ± 0.17: post; 1.01 ± 0.18) was only seen in the oldest group (70-79 years). For all other persons (30-69 years), changes resulting from the treadmill-walking task did not lead to a significant increase in falls risk. CONCLUSIONS: As most falls occur when an individual is moving and/or fatigued, assessing functional properties related to balance, gait, strength, and falls risk in older adults both at rest and following activity may provide additional insight.

Detection of undisclosed neuropathy and assessment of its impact on quality of life: a survey in 25,000 Romanian patients with diabetes.

AIMS: The objective of this cross-sectional survey was to capture undiagnosed neuropathy in Romanian patients with self-reported diabetes using Norfolk QoL-DN as a screening tool and to assess its impact on quality of life (QoL). METHODS: 25,000 Romanian-translated, validated Norfolk QoL-DN questionnaires were distributed between June and December 2012. 21,261 patients who self-reported diabetes and answered questions related to neuropathy, ulceration, gangrene and amputation were included in the analysis. RESULTS: 52% of diabetic patients (n = 6615) who answered "no" to the question "Do you have neuropathy?" had total QoL scores above the cut-off, suggesting the presence of diabetic neuropathy. 13,854 (65.2%) patients answered "yes" to the question "Do you have neuropathy?" and 3,150 (14.8%) reported at least one episode of ulceration, gangrene or amputation. Total QoL score was 3-fold higher (worse) for patients who answered "yes" to the question "Do you have neuropathy?" than for those who answered "no" (38.39 vs. 13.71; p < 0.001) and 1.4-fold worse for patients who reported ulceration, gangrene or amputation than for those who did not report any of these (50.38 vs. 34.87; p < 0.001). CONCLUSIONS: We found a high prevalence of undisclosed diabetic neuropathy in this population and showed that neuropathy severity has an increasing impact on total QoL and its domains.

Falls risk in older adults with type 2 diabetes.

Falls are a major health issue for older adults, especially for those who develop type 2 diabetes who must contend with age-related declines in balance, muscle strength, and walking ability. They must also contend with health-related issues specific to the disease process. Given the general association between these variables and falls, being able to identify which measures negatively impact on balance in older diabetic persons is a critical step. Moreover, designing specific interventions to target these physiologic functions underlying balance and gait control will produce the greatest benefit for reducing falls in older persons with diabetes.

Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy.

The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP.

German-translated Norfolk quality of life (QOL-DN) identifies the same factors as the English version of the tool and discriminates different levels of neuropathy severity.

BACKGROUND: The development and validation of Norfolk QOL-DN, a fiber-specific, quality-of-life tool for diabetic neuropathy, was published previously (Part 1). This study (Part 2) defines the psychometric properties of the German-translated Norfolk QOL-DN in a large multicenter (96 sites) population with neuropathy ranging from minimal to severe, comparing them with those in the original English/American version in a 30-center European/North American population with mild neuropathy; determines the power of the German-translated version in a five-staged diabetic peripheral neuropathy (DPN) German population to discriminate different levels of neuropathy severity; and establishes factors having the greatest impact on QOL. METHODS: One hundred eighty-six German patients were assessed: asymptomatic of DPN (n = 40), symptomatic (n = 46), DN with foot-ulcer history (n = 32), DN with amputations (n = 22), and DN amputation history (n = 46). German-translated Norfolk QOL-DN was administered to 177 patients with staged DN complications. German-translated Norfolk QOL-DN data were compared with QOL-DN data from the European/American study of 379 mild neuropathy patients. Exploratory factor analysis assessed factor structure consistency in the translated instrument. Ordinal regression analysis (polytomous universal model) was used to evaluate the association between factor scores and complication stages. RESULTS: The German translation identified the same five factors in more advanced neuropathy as in the English mild neuropathy population. Total QOL scores differed among each of the five neuropathy severity groups [analysis of variance p < 0.001, Tukey-Kramer post hoc, alpha = 0.05]. Two factors emerged as predictors of impaired QOL and disease severity: physical function/large fiber (Wald chi(2) = 6.188, p = 0.013) and activities of daily living (ADL)(Wald chi(2) = 9.098, p = 0.003). CONCLUSIONS: Norfolk QOL-DN discriminates levels of neuropathy within and between populations. Physical functioning and ADL are the most important determinants of QOL. Early occurrence of orthostasis suggests a redefinition of autonomic neuropathy to be more symptom inclusive.

The development and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic neuropathy.

BACKGROUND: This study was designed to develop and validate a patient-reported outcomes measure, sensitive to the different features of diabetic neuropathy (DN)-small fiber, large fiber, and autonomic nerve function. METHODS: The review of 1,000 structured patient interviews guided the development of 28 items pertaining specifically to the symptoms and impact of large fiber, small fiber, and autonomic nerve function. These items, in addition to 14 generic health status items and five general information items formed the 47-item Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QOL-DN). Items were grouped according to small fiber, large fiber, and autonomic nerve function, symptoms, and activities of daily living (ADL). Scores in individual domains were aggregated to provide a total score. Item groupings were tested for their ability to distinguish between the effects of specific nerve fiber deficits in 262 subjects-81 healthy controls (C), 86 controls with diabetes (DC), and 95 patients with DN-using one-way analysis of variance (ANOVA). Internal consistency was estimated using Cronbach's alpha coefficient. Test-retest reliability over a 4-6-week period was estimated by intra-class correlation coefficients and ANOVA on data of a subset of patients and controls. RESULTS: Differences between DN subjects and both DC and C subjects were significant (P < 0.05) for all item groupings. Total quality of life (QOL) scores correlated with total neuropathy scores. The ADL, total QOL, and autonomic scores were greater in DC than C subjects (P < 0.05). Intra-class correlation coefficients were > 0.9 for most domains. Internal consistency of the fiberspecific domains using Cronbach's alpha was > 0.6 and up to 0.8. CONCLUSIONS: The fiber-specific domains of the QOL-DN demonstrated acceptable reliability and ability to discriminate between subjects with and without neuropathy. Not surprisingly, the DN group scored significantly (P < 0.05) higher than either of the two control groups (i.e., greater impairment). The positive scores for the DC group in the ADL and autonomic domains suggest that diabetes per se impacts these aspects of QOL.