William J. Litchy

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population‐based cohort: The Rochester Diabetic Neuropathy Study

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%; and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently–6% of IDDM and 1% of NIDDM patients. Overall, two thirds of diabetic patients have objective evidence for some variety of neuropathy, but only about 20% have symptoms, and only 6% of IDDM and only 1% of NIDDM patients have sufficiently severe polyneuropathy to be graded stage 2b, and none were graded stage 3. Approximately one quarter of patients had subclinical carpal tunnel syndrome, but only 7.7% had symptomatic carpal tunnel syndrome. Thus, diabetic peripheral neuropathy is frequent but less severe than generally thought. As generally believed, however, neuropathy, retinopathy, and nephropathy are significantly associated.

The Rochester Diabetic Neuropathy Study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests

A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester, MN- The Rochester Diabetic Neuropathy Study (RDNS)-is population-based and uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy. Nondiabetic persons, drawn from the same population, serve as controls. For patients 10 to 70 years old, the RDNS cohort is representative of diabetics living in Rochester, MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (r1) as a measure of test reproducibility, we found high r1 (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observors for NDS and the W-NDS.

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470–1472TCC>ATA (p.Asp490Glu–Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.

Variables influencing neuropathic endpoints: The Rochester Diabetic Neuropathy Study of Healthy Subjects

Article abstract—We determined the normal limits for various neuropathic tests in healthy subjects. The study, the Rochester Diabetic Neuropathy Study (RDNS), is noteworthy because of its size (more than 400 subjects), random selection of subjects, and selection of at least 15 men and 15 women without neuropathy, neurologic disease, or diseases predisposing to neuropathy from each hemidecade between 18 and 74 years of age from the population of a defined region (Rochester, MN). Subjects were classified into those with (nonhealthy subjects, RDNS-NS) and without (healthy subjects, RDNS-HS) neuropathy, neurologic or psychiatric disease, or diseases known to predispose to neuropathy. The study provides normal limits for tests used in the RDNS but it has broader uses as well. We found that (1) less than 10% of subjects in the third decade, approximately 20% in the fourth decade, and approximately 30% in the fifth or older decades were placed into the RDNS-NS category; (2) healthy subjects (RDNS-HS) retain their ability to walk on toes and heels regardless of age, excessive weight, or lack of physical fitness, but not their ability to arise from a kneeled position—lost in more than 5% of persons 60 years and older; (3) the frequency of decreased or absent ankle reflexes exceeds 5% in healthy subjects older than 50 years—limiting their value as a sign of diabetic polyneuropathy and necessitating a grading change with age in the neuropathy impairment score. We also found that (1) physical variables other than age influence neuropathic endpoints; (2) the variables are different among neuropathic endpoints; and (3) it is now possible to compute specific percentile values automatically for neuropathic endpoints for a given patient. We found that the improved estimates of normal limits sometimes provide a different estimate of normality from the one that was available from age consideration only. We suggest that the percentile approach considering physical variables influencing neuropathic endpoints might be adopted by clinical EMG, sensory, and autonomic laboratories. Continued use of normal limits tables, which are corrected only for age, provides quite inadequate reference values, especially for some attributes of nerve conduction and for the extremes of height and weight.

Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial

IMPORTANCE Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294671.

The Rochester Diabetic Neuropathy Study Reassessment of tests and criteria for diagnosis and staged severity

We evaluated the initial assessments of the 380 diabetic patients with and without polyneuropathy in the Rochester Diabetic Neuropathy Study for (1) associations among neuropathy test results, (2) usefulness of different tests for diagnosing and staging polyneuropathy, (3) appropriateness of different minimal criteria for the diagnosis of polyneuropathy, and (4) significant differences in test results with increasing stage of polyneuropathy. Nerve conduction ([NC]; abnormality in two or more nerves) and quantitative autonomic examination ([QAE]; decreased heartbeat response to deep breathing [DB] or the Valsalva maneuver [VAL]) were the most sensitive and objective and were especially suitable for detection of subclinical neuropathy. We propose the following minimal criteria for the diagnosis of diabetic polyneuropathy: ⩾ abnormal evaluations (from among neuropathic symptoms, neuropathic deficits, NC, quantitative sensory examination [QSE], and QAE) with one of the two being abnormality of NC or QAE (DB or VAL). Neuropathy Symptom Score, Neuropathy Disability Score, QSE (vibratory or cooling detection threshold), and summated compound muscle action potential of ulnar, peroneal, and tibial nerves were best for judging severity. Inability to walk on heels provided a discrete separation of diabetic patients into those with mild and those with more severe neuropathy—a separation helpful in staging.

Vibratory and Cooling Detection Thresholds Compared With Other Tests in Diagnosing and Staging Diabetic Neuropathy

Increasingly more tests are being used to detect and characterize diabetic polyneuropathy, but their value in setting minimal criteria for the diagnosis of neuropathy and for staging severity remains inadequately studied. In 180 diabetics, we compared the percentage of patients with test abnormalities and associations among test results, evaluating neuropathic symptoms [neuropathy symptom score (NSS) and neuropathy scale of neuropathy symptom profile (NNSP)], deficits [neurologic disability score (NDS) and vibratory (VDT) and cooling (CDT) detection thresholds], or nerve dysfunction [nerve conduction (NC)]. The percentage of patients that were abnormal varied considerably depending on criteria for abnormality and the tests used. Abnormality (≥ 3 SD of 1 or more parameters) of NC of one or more of four nerves occurred in 80%, of two or more in 69%, of three or more in 46%, and of four in 21%. Similarly, for other tests, the rate of abnormality decreased with use of increasingly stringent criteria. Setting the criteria for abnormal NC at abnormality of two or more nerves, NSS at ≥ 1, NDS at > 6, NNSP at ≥ 97.5th percentile, and at ≥ 95th percentile for the other tests, NC was abnormal in 69%, NSS in 54%, NDS in 48%, NNSP in 47%, VDT in 44%, and CDT in 35%. Abnormality of any two or more of the six tests evaluated occurred in 64% of patients. We estimated that at least 16% of patients without abnormal NC (<2 abnormal nerves) had other findings indicative of neuropathy. By regression analysis, results of one test were in almost all cases associated with those of another test, but the association was not close enough to be predictive. Therefore, although NC provides objective and repeatable results, symptoms and deficits must be measured independently. Assuming no differences between groups of patients, the standardized and validated test (NNSP, VDT, or CDT) should provide the same results at different medical centers. By contrast, the results of NSS or NDS tests, with less standardized approaches and based on the judgment of physicians, might not provide the same results at different medical centers. Tests such as the ones described here may be used to define minimal criteria for the diagnosis of polyneuropathy and for staging its severity.

Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid Over 4 Years in Diabetic Polyneuropathy: The NATHAN 1 Trial

OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

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

Physiological prediction of muscle forces—I. Theoretical formulation

A physiological model for predicting muscle forces is described. Rigid-body mechanics and musculoskeletal physiology are used to describe the dynamics of the segment model and muscle model. Unknown muscle and joint contact forces outnumber the equilibrium equations resulting in an indeterminate problem. Mathematical optimization is utilized to resolve the indeterminacy. The modeling procedure relies entirely on established physiological principles. Data describing the muscle anatomy and body structures are included. A model defining the force-length-velocity-activation relationship of a muscle is adopted. The force a muscle produces is assumed to be proportional to its maximum stress, physiological cross-sectional area, activation, and its functional configurations including the muscle architecture, muscle length, contracting velocity, and passive tension. These factors are incorporated into inequality equations which limit the force for each muscle. Minimal muscular activation is forwarded as the optimization criterion for muscle force determination.