James W. Albers

Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments

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 treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Cross-sectional study of the relationship between repetitive work and the prevalence of upper limb musculoskeletal disorders

BACKGROUND This study examined the relationship of repetitive work and other physical stressors to prevalence of upper limb discomfort, tendinitis, and carpal tunnel syndrome. METHODS Three hundred fifty-two workers from three companies participated. Job exposure levels for repetition and other physical stressors were quantified using an observational rating technique. Ergonomic exposures were rated on a 10-point scale, where 0 corresponded to no stress and 10 corresponded to maximum stress. Job selection was based on repetition (three categories: high, medium, and low) to ensure a wide range of exposures. Physical evaluations on all participating workers were performed by medical professionals and included a self-administered questionnaire, physical exam, and limited electrodiagnostic testing. RESULTS Repetitiveness of work was found to be significantly associated with prevalence of reported discomfort in the wrist, hand, or fingers (odds ratio (OR) = 1.17 per unit of repetition; OR = 2.45 for high vs. low repetition), tendinitis in the distal upper extremity (OR = 1.23 per unit of repetition; OR = 3.23 for high vs. low repetition), and symptoms consistent with carpal tunnel syndrome (OR = 1.16 per unit of repetition; OR = 2.32 for high vs. low repetition). An association was also found between repetitiveness of work and carpal tunnel syndrome, indicated by the combination of positive electrodiagnostic results and symptoms consistent with carpal tunnel syndrome (OR = 1. 22 per unit of repetition; OR = 3.11 for high vs. low repetition). CONCLUSIONS These findings indicate that repetitive work is related to upper limb discomfort, tendinitis, and carpal tunnel syndrome in workers. Further research with a wider range of exposures is needed to evaluate the effects of other physical stresses alone and in combination.

Gangliosides GM1 and GD1b are antigens for IgM M-protein in a patient with motor neuron disease

We studied a patient with an IgM M-protein and lower motor neuron disease to identify the antigens to which the M-protein bound. Gangliosides from peripheral nerve and spinal cord were separated by high-performance thin-layer chromatography and immunostained with the patients serum. The serum IgM immunostained two gangliosides identified as GM1 and GD1b, and immunostaining was specific for the M- protein light chain type. IgM-binding to the two gangliosides was detectable by ELISA at serum dilutions of greater than 1:10,000, and the M-protein was selectively immunoabsorbed by liposomes containing GM1 or GD1b. The IgM M-protein also bound to asialo-GM1, indicating reactivity to the galactosyl(beta 1-3)N-acetylgalactosaminyl moiety shared by GM1, GD1b, and asialo-GM1.

Effect Of Prior Intensive Insulin Treatment During The Diabetes Control And Complications Trial (DCCT) On Peripheral Neuropathy In Type 1 Diabetes During The Epidemiology Of Diabetes Interventions, And Complications (EDIC) Study

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Effects of Prior Intensive Insulin Therapy on Cardiac Autonomic Nervous System Function in Type 1 Diabetes Mellitus The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC)

Background— The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes mellitus. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive and conventional therapy subjects 13 to 14 years after DCCT closeout. Methods and Results— DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjustment for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in the former intensive group versus the former conventional group (28.9% versus 35.2%; P=0.018). Adjusted R-R variation was significantly greater in the former DCCT intensive versus the former conventional group (29.9 versus 25.9; P<0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% (odds ratio, 0.69; 95% confidence interval, 0.51 to 0.93) and of incident abnormal R-R variation by 30% (odds ratio, 0.70; 95% confidence interval, 0.51 to 0.96) in EDIC year 13/14. Conclusions— Although CAN prevalence increased in both groups, the incidence was significantly lower in the former intensive group compared with the former conventional group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.

Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease

The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A-->G that disrupted an interspecies conserved residue (M1012V) in NTEs catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G-->A mutation, which disrupts an interspecies conserved residue in NTEs catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTEs importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.

Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity

Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13‐18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long‐standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease—but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small‐fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre‐specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject‐ and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN. Copyright

Neuropathy and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

OBJECTIVE To describe the development and progression of neuropathy and related findings among patients with type 1 diabetes who participated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS The main diabetic peripheral neuropathy (DPN) outcome was assessed using clinical symptoms, signs, and nerve conduction study results during DCCT and repeated in EDIC year 13/14. Cardiovascular autonomic neuropathy (CAN) was assessed by R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing during DCCT and in EDIC years 13/14 and 16/17. Additionally, symptoms reflecting neuropathic pain and autonomic function (including hypoglycemia awareness) were collected yearly in EDIC using standardized questionnaires; peripheral neuropathy was also assessed annually using the Michigan Neuropathy Screening Instrument. Assessments of genitourinary function were collected at EDIC year 10. RESULTS Intensive therapy during the DCCT significantly reduced the risk of DPN and CAN at DCCT closeout (64% and 45%, respectively, P < 0.01). The prevalence and incidence of DPN and CAN remained significantly lower in the DCCT intensive therapy group compared with the DCCT conventional therapy group through EDIC year 13/14. CONCLUSIONS The persistent effects of prior intensive therapy on neuropathy measures through 14 years of EDIC largely mirror those observed for other diabetes complications. DCCT/EDIC provides important information on the influence of glycemic control, and the clinical course of diabetic neuropathy, and, most important, on how to prevent neuropathy in type 1 diabetes.

Presentation and initial clinical course in patients with chronic inflammatory demyelinating polyradiculoneuropathy Comparison of patients without and with monoclonal gammopathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may occur in association with a monoclonal gammopathy of undetermined significance (MGUS) or a variety of other systemic illnesses. It is not known if the clinical features of CIDP are altered by the presence of an MGUS. We compared demographic features, clinical presentation, improvement and outcome after initial treatment, and electrodiagnostic features of a group of 77 patients with idiopathic CIDP (CIDP-I, no associated systemic illness) with 26 patients with CIDP in whom an MGUS was found during evaluation of the neuropathy (CIDP-MGUS). Patients with CIDP-MGUS had, on average, a more indolent course and less severe weakness than patients with CIDP-I, despite similar motor conduction studies. CIDP-MGUS patients also demonstrated less functional impairment, more frequent sensory loss, and more abnormal sensory conduction studies than patients with CIDP-I. Because of the greater improvement of CIDP-I patients with treatment, both groups had similar outcomes from their initial episodes of weakness. Subgroup analysis of CIDP-MGUS patients did not demonstrate differences between groups with IgM and IgG or IgA gammopathies.

Acute sensory neuropathy-neuronopathy from pyridoxine overdose

We report two patients who developed an acute, profound, and permanent sensory deficit after treatment with massive doses of parenteral pyridoxine. Aside from rapid onset, their clinical picture resembles that described in chronic pyridoxine neurotoxicity. It also is consonant with experimental models of acute pyridoxine intoxication and is probably secondary to a sensory ganglion neuronopathy. These patients also had transient autonomic dysfunction, mild weakness, nystagmus, lethargy, and respiratory depression. These previously undocumented features may be attributable to either the preservative used in the parenteral pyridoxine preparation or to the exceptionally high doses of pyridoxine these patients received.