Content uploaded by James W. Albers
Author content
All content in this area was uploaded by James W. Albers on Oct 17, 2014
Content may be subject to copyright.
A preview of the PDF is not available
"Unequivocally Abnormal" vs "Usual" Signs and Symptoms for Proficient Diagnosis of Diabetic Polyneuropathy Cl vs N Phys Trial
Abstract and Figures
OBJECTIVE To repeat the Clinical vs Neurophysiology (Cl vs N Phys) trial using "unequivocally abnormal" signs and symptoms (Trial 2) compared with the earlier trial (Trial 1), which used "usual" signs and symptoms. DESIGN Standard and referenced nerve conduction abnormalities were used in both Trials 1 and 2 as the standard criterion indicative of diabetic sensorimotor polyneuropathy. Physician proficiency (accuracy among evaluators) was compared between Trials 1 and 2. SETTING Academic medical centers in Canada, Denmark, England, and the United States. PARTICIPANTS Thirteen expert neuromuscular physicians. One expert was replaced in Trial 2. RESULTS The marked overreporting, especially of signs, in Trial 1 was avoided in Trial 2. Reproducibility of diagnosis between days 1 and 2 was significantly (P = .005) better in Trial 2. The correlation of the following clinical scores with composite nerve conduction measures spanning the range of normality and abnormality was improved in Trial 2: pinprick sensation (P = .03), decreased reflexes (P = .06), touch-pressure sensation (P = .06), and the sum of symptoms (P = .06). CONCLUSIONS The simple pretrial decision to use unequivocally abnormal signs and symptoms-taking age, sex, and physical variables into account-in making clinical judgments for the diagnosis of diabetic sensorimotor polyneuropathy (Trial 2) improves physician proficiency compared with use of usual elicitation of signs and symptoms (Trial 1); both compare to confirmed nerve conduction abnormality.
Figures - uploaded by James W. Albers
Author content
All figure content in this area was uploaded by James W. Albers
Content may be subject to copyright.
... Physical examination may reveal abnormalities in sensory or motor function, and deep tendon reflexes [14]. ...
... In those with small fiber dysfunction, clinical exam may reveal diminished temperature or pinprick sensation [14]. Large-fiber involvement may manifest as decreased vibration perception, proprioception, light-touch perception, and reduced ankle reflexes on physical exam [15]. ...
Purpose of Review
Painful diabetic neuropathy (PDN) manifests with pain typically in the distal lower extremities and can be challenging to treat. The authors appraised the literature for evidence on conservative, pharmacological, and neuromodulation treatment options for PDN.
Recent Findings
Intensive glycemic control with insulin in patients with type 1 diabetes may be associated with lower odds of distal symmetric polyneuropathy compared to patients who receive conventional insulin therapy. First-line pharmacologic therapy for PDN includes gabapentinoids (pregabalin and gabapentin) and duloxetine. Additional pharmacologic modalities that are approved by the Food and Drug Administration (FDA) but are considered second-line agents include tapentadol and 8% capsaicin patch, although studies have revealed modest treatment effects from these modalities. There is level I evidence on the use of dorsal column spinal cord stimulation (SCS) for treatment of PDN, delivering either a 10-kHz waveform or tonic waveform.
Summary
In summary, this review provides an overview of treatment options for PDN. Furthermore, it provides updates on the level of evidence for SCS therapy in cases of PDN refractory to conventional medical therapy.
... In this study, in which patients' neuropathic signs were assessed based on individual physicians' usual evaluations, intra-and inter-test variability was high [31]. However, in a repeat study, in which the physicians were asked to grade only unequivocally abnormal neuropathic signs (taking into account variables of age, sex, physical fitness, and physical characteristics), the intra-and inter-test variability was significantly lower [32]. These studies suggest that in clinical trials, NIS should be used only by expert examiners who have preliminary consensus training and surveillance throughout the study. ...
... This detailed disease characterization is valuable in clinical studies but requires extensive training to ensure proficiency and minimize variability between centers and investigators. Experts should be trained to use only clear disease-associated abnormalities rather than more traditional criteria and not grade signs of concomitant diseases; this approach has been shown to reduce variability [31,32]. When measuring NCS, consistency and reproducibility can be enhanced with specialist training, standardized reference values, and evaluation of tracings at a central reading center [41,59]. ...
Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. Measures used to assess polyneuropathy in other diseases have been tested as endpoints in hATTR amyloidosis clinical trials (i.e. Neuropathy Impairment Score [NIS], NIS-lower limb, and NIS + 7), yet the unique nature of the polyneuropathy in this disease has necessitated modifications to these scales. In particular, the heterogeneous impairment and the aggressive disease course have been key drivers in developing scales that better capture the disease burden and progression of polyneuropathy in hATTR amyloidosis.
The modified NIS + 7 (mNIS + 7) scale was specifically designed to assess polyneuropathy impairment in patients with hATTR amyloidosis, and has been the primary endpoint in two recent, phase III studies in this disease. The mNIS + 7 uses highly standardized, quantitative, and referenced assessments to quantify decreased muscle weakness, muscle stretch reflexes, sensory loss, and autonomic impairment. Physicians using this scale in clinical trials should be specifically trained and monitored to minimize variability. This article discusses the different scales that have been/are being used to assess polyneuropathy in patients with hATTR amyloidosis, their correlation with other disease assessments, and reflects on how and why scales have evolved to the latest iteration of mNIS + 7.
... However, it does not encompass the autonomic and cardiac involvement of the disease. Also, even if performed by expert and preliminarily-trained clinicians, NIS and NIS-LL are limited by intra-and inter-rater variability [4,30,31] along with patient's motivation. To better capture the multisystem involvement in ATTRv amyloidosis and reduce its variability [32], novel compound scales, NIS + 7 and mNIS + 7, have been developed [7,[9][10][11]. ...
Background
The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv.
Methods
Calf- and thigh-centered multi-echo T2-weighted spin-echo and gradient-echo sequences were obtained in patients with ATTRv amyloidosis with polyneuropathy ( n = 24) and healthy controls ( n = 12). Water T2 (wT2) and fat fraction (FF) were calculated. Neurological assessment was performed in all ATTRv subjects. Quantitative MRI parameters were correlated with clinical and neurophysiological measures of disease severity.
Results
Quantitative imaging revealed significantly higher FF in lower limb muscles in patients with ATTRv amyloidosis compared to controls. In addition, wT2 was significantly higher in ATTRv patients. There was prominent involvement of the posterior compartment of the thighs. Noticeably, FF and wT2 did not exhibit a length-dependent pattern in ATTRv patients. MRI biomarkers correlated with previously validated clinical outcome measures, Polyneuropathy Disability scoring system, Neuropathy Impairment Score (NIS) and NIS-lower limb, and neurophysiological parameters of axonal damage regardless of age, sex, treatment and TTR mutation.
Conclusions
Muscle qMRI revealed significant difference between ATTRv and healthy controls. MRI biomarkers showed high correlation with clinical and neurophysiological measures of disease severity making qMRI as a promising tool to be further investigated in longitudinal studies to assess its role at monitoring onset, progression, and therapy efficacy for future clinical trials on this treatable condition.
Introduction/aims:
In the Diabetes Control and Complications Trial (DCCT), the minimal nerve conduction (NC) criterion for diabetic sensorimotor polyneuropathy (DSPN) was abnormality of NC in >1 peripheral nerve without specifying the attributes of NCs to be evaluated. In the present study, we assess individual and composite scores of NCs meeting the DCCT criterion and signs for improved diagnosis and assessment of DSPN severity.
Methods:
Evaluated were 13 attributes and 6 composite NC scores and signs and symptoms in 395 healthy subjects (HS) and 388 persons with diabetes (DM).
Results:
Percent abnormality between subjects with DM and HS was remarkably different among individual attributes and the 6 composite NC scores. For diagnosis of DSPN using the DCCT criterion, assessment of conduction velocities (CVs) and distal latencies (DLs) provided sensitive diagnoses of DSPN. NC amplitudes provided stronger measures of severity. In studied cohorts, DSPN was staged: N0, no NC abnormality using NC score #2 (CVs and DLs), 60.0%; N1, NC abnormality only, 18.4%; N2, NC abnormality and signs of feet or legs, 16.3%; and N3, NC abnormality and signs of thighs, 5.3%.
Discussion:
For sensitive and standard diagnosis of DSPN using the DCCT NC criterion, specifically defined composite scores of CVs and DLs, e.g., score #2, is recommended. A composite score of amplitudes, e.g., score #4, provides a stronger measure of neuropathy severity. Also, provided are HS reference values of evaluated attributes of NCs and estimates of staged severity of DSPN of mid North American DM cohorts. This article is protected by copyright. All rights reserved.
Background:
Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN).
Methods:
We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide.
Results:
Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process.
Expert opinion:
The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.
Introduction
Inotersen, an antisense oligonucleotide inhibitor of TTR protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score +7 neurophysiologic tests (mNIS+7) in patients with hereditary transthyretin‐mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the Lower Limb Function (LLF) test.
Methods
Adults with hATTR were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks.
Results
All major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS‐reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate deep breathing did not show significant effects.
Discussion
The results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.
This article is protected by copyright. All rights reserved.
Introduction
Hereditary transthyretin‐mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO‐TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score.
Methods
Stage 1/2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline, 35, and 66 weeks.
Results
At 66 weeks, inotersen‐treated patients experienced symptom stabilization versus worsening in patients receiving placebo in NSC total score; the subdomains of muscle weakness, sensory, pain, and autonomic symptoms; and for various individual items.
Discussion
Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR based on the NSC score, which may be an effective assessment of neuropathy progression and patients' neuropathy experience in clinical practice.
This article is protected by copyright. All rights reserved.
Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae.
Diabetic neuropathy (DN) is one of the most common complications related to diabetes. While any nerve in the body may be affected, the length dependent distal symmetrical sensory predominant neuropathy (DSPN) is the most classical presentation. DSPN develops insidiously and often remains asymptomatic until well established. Important complications of DSPN include the development of neuropathic pain, foot deformities and ulceration all which lead to considerable morbidity and which may put the patient on a pathway to lower extremity amputation. Impairment of autonomic control may lead to various presentations from the organ systems involved such as cardiovascular, gastrointestinal, genitourinary and sudomotor neuropathies. Although hyperglycaemia related neuronal damage has been long considered the key aetiopathogenic trigger, more recently other factors, such as cardiometabolic and vascular risk factors, are increasingly recognised to play a significant role in DN development. Newer putative agents, although have shown promise in experimental diabetic neuropathy, are yet to be proven clinically. Thus, glucose control remains the only proven strategy to delay the development of DN. Treatment of neuropathic pain, an annual foot risk assessment and ulcer prevention strategies along with symptomatic management of autonomic features and optimisation of cardiovascular risk factors are important management considerations. In this review, we discuss the classification, diagnosis and management of the DN with a focus on DSPN.
Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treat merits of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs. Diabetes Care 33:2285-2293, 2010
To evaluate the impact of former intensive versus conventional insulin treatment on neuropathy in Diabetes Control and Complications Trial (DCCT) intensive and conventional treatment subjects with type 1 diabetes 13-14 years after DCCT closeout, during which time the two groups had achieved similar A1C levels.
Clinical and nerve conduction studies (NCSs) performed during the DCCT were repeated during the Epidemiology of Diabetes Interventions and Complications (EDIC) study by examiners masked to treatment status on 603 former intensive and 583 former conventional treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving two or more nerves among the median, peroneal, and sural nerves.
The prevalence of neuropathy increased 13-14 years after DCCT closeout from 9 to 25% in former intensive and from 17 to 35% in former conventional treatment groups, but the difference between groups remained significant (P < 0.001), and the incidence of neuropathy remained lower among former intensive (22%) than former conventional (28%) treatment subjects (P = 0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (odds ratio 1.17 [95% CI 0.84-1.63]). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean A1C and measures of incident and prevalent neuropathy.
The benefits of former intensive insulin treatment persisted for 13-14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.
Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.
In this study we aimed to determine which criteria are valid for nerve conduction (NC) diagnosis of typical diabetic sensorimotor polyneuropathy (DSPN).
Eight criteria were assessed from among diabetes databases, the Rochester Diabetic Neuropathy Study (RDNS, N = 456), and in healthy subjects (RDNS-HS, N = 330).
In the RDNS, the most frequent abnormal attributes (≤2.5th/≥97.5th percentile) are: fibular motor nerve conduction velocity (MNCV; 26.3%); sural sensory nerve conduction velocity (SNAP; 25.4%); tibial MNCV (24.8%); ulnar MNCV (21.3%); fibular F latency (16.9%); and ulnar F latency (16.0%). Normal deviate (from percentiles) composite scores of NC included: representative of neurophysiological abnormalities; sensitive and specific for diagnosis and useful for epidemiological surveys; randomized trials; and medical practice. By contrast, abnormality of one or more attributes in any nerve or abnormally of two most sensitive attributes performed poorly.
Composite sum scores of normal deviates (from percentiles corrected for applicable variables) of sensitive NC attributes and with modifications, RDNS and AAN criteria performed acceptably for diagnosis of DSPN.
The purpose was to test whether physicians can validly and reproducibly diagnose diabetic sensorimotor polyneuropathy (DSPN). Twelve physicians assessed 24 patients with diabetes mellitus (DM) on consecutive days (576 examinations) with physical features and voice disguised. Results were compared to gold standard 75% group diagnosis (dx) and a nerve conduction score (Sigma5 NC nds). Masking of patients was achieved. Reproducibility measured by the kappa coefficient and compared to Sigma5 NC nd varied considerably among physicians: median and ranges: signs 0.8 (0.32-1.0); symptoms 0.79 (0.36-1.0), and diagnoses 0.47 (0.33-0.84), both low and high scores indicating poor performance. There was substantial agreement between 75% group dx and confirmed NC abnormality (abn). As compared to Sigma5 NC, individual physicians' clinical dx was excessively variable and frequently inaccurate. Study physician dx from signs and symptoms were excessively variable, often overestimating DSPN. Specific approaches to improving clinical proficiency should be tested.