Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications.

AIMS: The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments: a 15-item self-administered questionnaire and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes. The purpose of this study was to evaluate the performance of the MNSI in detecting distal symmetrical peripheral neuropathy in patients with Type 1 diabetes and to develop new scoring algorithms. METHODS: The MNSI was performed by trained personnel at each of the 28 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications clinical sites. Neurologic examinations and nerve conduction studies were performed during the same year. Confirmed clinical neuropathy was defined by symptoms and signs of distal symmetrical peripheral neuropathy based on the examination of a neurologist and abnormal nerve conduction findings in ≥ 2 anatomically distinct nerves among the sural, peroneal and median nerves. RESULTS: We studied 1184 subjects with Type 1 diabetes. Mean age was 47 years and duration of diabetes was 26 years. Thirty per cent of participants had confirmed clinical neuropathy, 18% had ≥ 4 and 5% had ≥ 7 abnormal responses on the MNSI questionnaire, and 33% had abnormal scores (≥ 2.5) on the MNSI examination. New scoring algorithms were developed and cut points defined to improve the performance of the MNSI questionnaire, examination and the combination of the two. CONCLUSIONS: Altering the cut point to define an abnormal test from ≥ 7 abnormal to ≥ 4 abnormal items improves the performance of the MNSI questionnaire. The MNSI is a simple, non-invasive and valid measure of distal symmetrical peripheral neuropathy in Type 1 diabetes.

Chlorpyrifos exposure and biological monitoring among manufacturing workers.

AIM: To use biological monitoring data to evaluate the soundness of job based exposure classifications. METHODS: The authors studied 52 chlorpyrifos manufacturing workers and 60 referent workers to compare chlorpyrifos exposure estimations from job titles and work areas to urinary excretion of 3,5,6 trichloro-2-pyridinol (TCP), a metabolite of chlorpyrifos. Work history records and industrial hygiene monitoring data were used to establish cumulative interim exposure. Chlorpyrifos exposure during the study year was assessed biologically by urinary excretion of TCP. RESULTS: Exposure as measured by three urinary TCP samples was significantly higher among the chlorpyrifos workers (188 microg/l) than it was for the referent subjects (7 microg/l). Urinary TCP also correlated well with specific exposure categories of negligible (0.73-1.98 mg/m3 days), low (1.99-4.91 mg/m3 days), and moderate (4.92-15.36 mg/m3 days). The weighted Kappa coefficient was 0.80 (95% CI 0.72 to 0.87) for the mean TCP over the study period. CONCLUSIONS: The estimates of chlorpyrifos exposure based on job classifications and industrial hygiene measurements were significantly related to urinary TCP excretion, indicating that the ambient estimates are useful for providing exposure estimates among chlorpyrifos manufacturing workers.

The effects of occupational exposure to chlorpyrifos on the peripheral nervous system: a prospective cohort study.

AIMS: To determine whether chronic occupational exposure to chlorpyrifos at levels associated with various aspects of manufacturing produced a clinically evident or subclinical peripheral neuropathy. METHODS: Clinical and quantitative nerve conduction study (NCS) examinations were performed on two occasions on chlorpyrifos manufacturing workers who had measurable chlorpyrifos exposure and a referent group. Baseline evaluations were performed on 53 of 66 eligible chlorpyrifos subjects and on 60 of 74 eligible referent subjects; one-year evaluations were completed on 111 of the 113 subjects evaluated at baseline. RESULTS: Chlorpyrifos and referent groups differed significantly in measures of 3,5,6 trichloro-2-pyridinol excretion and plasma butyrylcholinesterase (BuChE) activity, indicating substantially higher exposures among chlorpyrifos subjects. Few subjects had clinically important neurological symptoms or signs. NCS results were comparable to control values, and there were no significant group differences in NCS results at baseline, one year, or change over one year. No chlorpyrifos subject fulfilled conventional criteria for confirmed peripheral neuropathy at baseline or one-year examinations. The odds ratios for developing any diagnosable level of peripheral neuropathy among the chlorpyrifos subjects was not increased at baseline or at one year compared to referents at baseline. Mixed regression models used to evaluate subclinical group-by-time interactions showed numerous significant NCS differences attributable to near-nerve temperature differences among all subjects between the baseline and one-year examinations, but only a few disparate effects related to group. CONCLUSIONS: Chronic chlorpyrifos exposure during the manufacturing process sufficient to produce biological effects on BuChE activity was not associated with clinically evident or subclinical peripheral neuropathy at baseline or with measurable deterioration among chlorpyrifos subjects compared to referents after one year of additional exposure.

Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand.

We studied whether exposure to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War is related to peripheral neuropathy. The index subjects were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. We report peripheral nerve function assessed in 1982, 1985, 1987, 1992 and 1997, nerve conduction velocities measured in 1982, and vibrotactile thresholds of the great toes measured in 1992 and 1997. We assigned each Ranch Hand veteran to one of three exposure categories named "background", "low" and "high", based on his serum dioxin level. Other than the bilateral vibrotactile abnormalities, we consistently found a statistically significant increased risk of all indices of peripheral neuropathy among Ranch Hand veterans in the high exposure category in 1997, and a statistically significant increased risk of diagnosed peripheral neuropathy, incorporating bilateral vibrotactile abnormalities of the great toes, in the high category in 1992. Restricting to the enlisted veterans did not alter these results. Cautious interpretation of these results is appropriate until the relationship between pre-clinical diabetes mellitus and peripheral neuropathy is further evaluated in future examinations.

Evaluation of blink reflex results obtained from workers previously diagnosed with solvent-induced toxic encephalopathy.

We reviewed blink reflexes recorded from 51 railroad workers with long-term occupational exposure to solvents who were diagnosed by others with solvent-induced toxic encephalopathy. No worker fulfilled conventional clinical criteria for dementia or trigeminal mononeuropathy. All workers had normal R1 and R2 blink reflex latencies. R1 latencies correlated significantly with several nerve conduction measures, including F wave latencies, suggesting that some intersubject variability reflected intrinsic conduction properties, not isolated brain-stem function. Although normal, the workers' R1 latencies were significantly prolonged compared with historical control groups, including gender-matched control subjects of similar mean age (11.2 ms vs 9.9 ms; P < 0.0001). Stepwise multiple regression models demonstrated significant associations of R1 latency with age and use of CNS-active prescription medications (P = 0.003), but duration of occupational solvent exposure did not enter into the models. Paradoxically, workers using CNS-active medications had significantly shorter R1 latencies compared with workers not using such medications (10.9 vs 11.7 ms; P = 0.01). Job title, another potential surrogate measure of exposure, was not significantly related to reflex latencies. The geographical site of predominant solvent exposure did influence R1 latency, and workers from one site had longer exposure duration and longer R1 latencies than remaining workers. However, an interaction between age and exposure duration (r = 0.39; P = 0.003) confounded interpretation of this observation. Disability or work status, mental status findings, or classification of encephalopathy did not influence blink reflex latencies. The overall results do not support, but do not entirely exclude, a possible relationship between subclinical blink reflex abnormalities and occupational exposure to solvents. Nevertheless, it is clear from these results that the small group differences in R1 latency between exposed workers and control subjects are of no diagnostic importance and of uncertain physiologic importance, and they may reflect unrecognized confounders and technical factors.

Diabetic neuropathies.

Diabetes mellitus is a systemic disorder with a significant impact on the peripheral nervous system. Over half of the 15 million patients with diabetes mellitus in the United States have some form of diabetic neuropathy. Individuals with diabetes may develop acute or subacute painful polyneuropathy, proximal motor neuropathy, autonomic neuropathy, compression neuropathy, focal neuropathy, and chronic polyneuropathy. Studies have shown that optimizing diabetic control provides the greatest likelihood of either preventing or slowing the development of diabetic neuropathy.

Controversies in neurotoxicology: current status.

Several controversial neurotoxic syndromes have received notoriety in the past several decades. For each, the controversy involves the most fundamental question about the existence of the disorder as a clinically diagnosable entity. Interestingly, the most controversial of these syndromes share several features, including argument about the existence of each syndrome in the courtroom. The authors focus their discussion on three problems (painter's encephalopathy, silicone breast implant neurotoxicity, and the Gulf War syndrome) for which no scientific consensus has been reached that would establish them as diagnosable disorders. These syndromes do not meet traditional disease criteria, and until a clear set of symptoms and objective signs can be defined, a definite course and clear cause demonstrated, and specific tests and treatments identified, these syndromes are likely to remain highly controversial.

Neurologic evaluation of workers previously diagnosed with solvent-induced toxic encephalopathy.

We examined 52 railroad workers with long-term occupational solvent exposures (average 22 years duration) who had been previously diagnosed by others as having solvent-induced toxic encephalopathy. All described episodes of transient intoxication associated with occupational solvent exposure. Persistent symptoms developed, an average, 16 years after exposure onset and included impaired memory (38), altered mood (21), imbalance (18), and headache (17). Thirteen workers had mild mental status abnormalities, but none fulfilled conventional clinical criteria for encephalopathy or dementia. None had abnormal blink reflex (51) or abnormal electroencephalographic (39) studies. Eight of 47 magnetic resonance imaging studies showed evidence of scattered ischemic lesions among workers with known diabetes mellitus (2), elevated blood pressure (4), or peripheral vascular disease (2). One magnetic resonance imaging scan showed mild cortical atrophy. In stepwise multiple linear and logistic regression models, no statistically significant (P < 0.05) dose-response relationships were found between exposure duration and symptoms or signs that were suggestive of encephalopathy. However, the number of symptoms (P < 0.001) and the number of signs (P = 0.05) were associated with current use of central nervous system-active medications. Further, lower Mini-Mental Status Examination scores were associated with a history of alcohol abuse (P = 0.01) and lower educational level (P = 0.03). The number of chief symptoms involving memory, mood, balance, or headache differed significantly among workers in different geographic sites (F(3.48) = 2.94, P = 0.04), a finding that was not explained by job title or exposure duration. There also was a significant (P = 0.0001) inverse relationship between initial exposure year (r2 = 0.60) or total years of exposure through 1987 (r2 = 0.56) and interval to major neurologic symptom onset, suggesting that factors other than solvent exposure account in part for worker complaints. We found no objective neurologic evidence supportive of toxic encephalopathy or any other uniform syndrome among these individuals, and most complaints were explained by neuropsychological factors or conditions unrelated to occupational solvent exposure.

Analysis of chlorpyrifos exposure and human health: expert panel report.

This report summarizes the deliberations of an eight-member panel of scientists convened by Dow AgroSciences in cooperation with the U.S. Environmental Protection Agency (EPA). The panel was charged with evaluating the scientific literature on the health effects potentially associated with exposure to the insecticide chlorpyrifos. Specifically, the panel was asked to (1) evaluate human experience data available and address the adequacy of the available current literature; (2) develop a list of recommendations for epidemiology studies, including appropriate endpoints and study populations, and strengths and weaknesses of each approach; and (3) draft a report to summarize its recommendations. The panel assessed the quality of the existing epidemiologic literature on chlorpyrifos and specific outcomes such as neuropathy (including organophosphate induced delayed neurotoxicity), behavior (cognition and affect), immunologic, and multiple complaints (also referred to as multiple chemical sensitivities). The majority of panel members (five members) agreed that the literature reviewed provided little or no scientific evidence that chlorpyrifos exposure causes harm to human health other than its known cholinergic effects associated with acute poisoning. Those panel members voting in the minority (three members) agreed that the studies reviewed provided inadequate evidence to preclude the possibility of adverse effects to human health from chlorpyrifos exposure at levels associated with its manufacture or professional application. Those voting in the minority suggested further investigation of cohort(s) of workers engaged in either the manufacture or the professional application of chlorpyrifos, or both. Compared to the general population, these groups have relatively high levels of exposure to chlorpyrifos. The primary health outcomes recommended for study were cognitive and affective disorders, with consideration of the assessment of peripheral neuropathy also suggested for at least a subset of the cohort.

Reliability of nerve conduction studies among active workers.

Nerve conduction studies play an important role in clinical practice and research. Given their widespread use, reliability of tests merits careful attention. We assessed interexaminer and intraexaminer reliability of median and ulnar sensory nerve measures of amplitude, onset latency, and peak latency. In a two-phase cross-sectional study, two examiners tested 158 workers. Reliability was assessed with intraclass correlations (ICC) and kappa statistics. Median nerve measures were more reliable (ICC range, 0.76 to 0.92) than ulnar measures (ICC range, 0.22 to 0.85). Ulnar-onset latencies had the worst reliability. The median-ulnar peak latency difference was a particularly stable measure (ICC range, 0.79 to 0.92). The median-ulnar peak latency difference had high interexaminer reliability (kappa range, 0.71 to 0.79) for normal tests defined by cut points of 0.8 ms and 0.5 ms. Intraexaminer reliability was higher with the 0.8-ms cut point (kappa = 0.90 and kappa = 0.85 for examiners 1 and 2, respectively). Rather than absolute cut points to describe normality, a more rational interpretation of results can be made with ordered categories or continuous measures.

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.

Absence of polyneuropathy among workers previously diagnosed with solvent-induced toxic encephalopathy.

An association between polyneuropathy and occupational exposure to trichloroethylene, trichloroethane, perchloroethylene, or similar solvents alone or in combination is controversial. We sought to determine whether workers previously diagnosed with solvent-induced toxic encephalopathy had objective evidence of polyneuropathy. Thirty railroad workers previously diagnosed with toxic encephalopathy were examined in the context of litigation against their employers. All described long-term occupational solvent exposure averaging 20 years in duration (range, 10 to 29 years) and producing acute intoxication on a regular basis. The diagnosis of subclinical or clinical polyneuropathy was established using a combination of symptoms, signs, and nerve conduction study (NCS) measures, consistent with standard clinical practice. Potential confounders were identified. NCS results were compared with historical controls, including unexposed workers matched by gender, age, and body mass index. Dose-response relationships were evaluated using simple linear and stepwise regression models. Three workers fulfilled clinical polyneuropathy criteria. The only worker fulfilling NCS criteria for confirmed clinical polyneuropathy had diabetes mellitus. Mean NCS values for most measures were similar to control values, and existing differences in sensory amplitudes disappeared when compared with the matched control group. NCS measures were not significantly influenced by exposure duration or job title. Separation into groups on the basis of the presence or absence of polyneuropathy symptoms, previous diagnosis of polyneuropathy, disability status, and severity or type of encephalopathy did not demonstrate significant NCS differences. The complaints of these workers claiming neurotoxic injury from occupational solvent exposure are not explained by peripheral nervous system dysfunction.

Agreement between symptom surveys, physical examination procedures and electrodiagnostic findings for the carpal tunnel syndrome.

OBJECTIVES: The goal of this study was to evaluate the concordance between various clinical screening procedures for carpal tunnel syndrome. METHODS: The subject population consisted of 824 workers from 6 facilities. The evaluated procedures included bilateral sensory nerve conduction testing, physical examinations, and symptom surveys, including hand diagrams. The agreement between the outcomes of various combinations of these procedures was assessed by determining the kappa coefficient. RESULTS: There was relatively poor overlap between the reported symptoms, the physical examination findings, and the electrodiagnostic results consistent with carpal tunnel syndrome. Overall, only 23 out of 449 subjects (5%) with at least 1 positive finding met all 3 criteria (symptoms, physical examination findings, and electrophysiological results consistent with carpal tunnel syndrome) for the dominant hand. The screening procedures showed poor or no agreement with kappa values ranging between 0.00 and 0.18 for all the case definitions evaluated for carpal tunnel syndrome. CONCLUSIONS: The poor overlap between the various screening procedures warns against the use of electrodiagnostic findings alone without the symptom presentation being considered. The results of this study also point to a need for the further development and evaluation of methods for detecting carpal tunnel syndrome.

Median and ulnar nerve conduction studies among workers: normative values.

To determine normative values for nerve conduction studies among workers, we selected a subset of 326 workers from 955 subjects who participated in medical surveys in the workplace. The reference cohort was composed exclusively of active workers, in contrast to the typical convenience samples. Nerve conduction measures included bilateral median and ulnar sensory amplitude and latency (onset and peak). Workers with upper extremity symptoms, medical conditions that could adversely affect peripheral nerve function, low hand temperature, or highly repetitive jobs were excluded from the "normal" cohort. Linear regression models explained between 21% and 51% of the variance in nerve function, with covariates of age, sex, hand temperature, and anthropometric factors. The most robust models were fitted for sensory amplitudes in the median and ulnar nerves for dominant and nondominant hands. The median-ulnar difference was least sensitive to adjustment, indicating it is the best measure to use if corrections are not made to account for relevant covariates. A key point was that the magnitude of variance increased with age and anthropometric factors. These findings provide strong evidence that to improve diagnostic accuracy, electrodiagnostic testing should control for relevant covariates, particularly age, sex, hand temperature, and anthropometric factors.

Median mononeuropathy among active workers: are there differences between symptomatic and asymptomatic workers?

The objective was to determine whether symptomatic workers with an abnormal sensory nerve conduction study consistent with carpal tunnel syndrome differed, in terms of electrophysiologic measures, psychosocial, demographic, anthropometric, or ergonomic variables, from workers with an asymptomatic median mononeuropathy. This was a cross-sectional study of active workers at six different work sites. Cases were defined as workers with electrodiagnostic findings of a median mononeuropathy in either hand, based on a 0.5-msec prolongation of the median sensory evoked peak latency compared to the ulnar latency. This group was stratified on the basis of symptoms of numbness, tingling, burning or pain in the hand. The two groups were compared in terms of demographic, anthropomorphic, psychosocial, electrophysiologic, and ergonomic risk factors. Active workers from six different sites were tested; five sites involved manufacturing workers, and one site represented clerical workers. One hundred eighty-four active workers with a median mononeuropathy were documented on nerve conduction studies. These workers represented a subset of more than 700 workers screened at six different locations. The main outcome measure was the patient's report of symptoms of pain, numbness, tingling or burning in the hand or fingers that lasted more than 1 week or occurred three or more times at the initial screening. Workers with a median mononeuropathy who complained of hand symptoms were more likely to be female, to have jobs with higher hand repetition levels, to have higher ratings of job security, not to have a history of diabetes, to use more force in their job with more abnormal postures of their wrist and fingers, and to have a trend toward a more prolonged median sensory distal latency. Most logistic regression models explained less than 15% of the variance (pseudo R2). Women with jobs that have higher ergonomic risks and no history of diabetes were more likely to have reported symptoms associated with carpal tunnel syndrome compared to other workers with a documented median mononeuropathy. Psychosocial variables were not particularly discriminatory. None of the models allows enough precision to predict on an individual basis.

Chronic inflammatory demyelinating polyradiculoneuropathy in children: II. Long-term follow-up, with comparison to adults.

We previously reviewed the presentation, initial clinical course, and electrodiagnostic features of children with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now report the long-term follow-up of 12 children with idiopathic CIDP, and compare these to 62 adults with idiopathic CIDP. Children often had more rapidly fluctuating courses than adults. A relapsing course was significantly more common in children than in adults. The recovery of children from each episode of deterioration was usually excellent, and better, on average, than in adults. Ventilatory support was never required for children with slowly evolving illness; only 2 children with a precipitous onset clinically resembling Guillain-Barré syndrome required ventilatory support. Prednisone, plasma exchange, and intravenous immunoglobulin (IVIg) usually were effective in children. Multiple courses of IVIg could be given with continued efficacy. Treatment often could be discontinued in children with relapsing courses. The prognosis for children was excellent. Adults demonstrated a good, but more variable, outcome.

n-Hexane neuropathy due to rubber cement sniffing.

n-Hexane neuropathy has been described after glue sniffing and industrial exposure. Onset may be subacute and reminiscent of Guillain-Barré syndrome. Although the primary pathology is axonal, electrophysiologic evaluation is frequently most remarkable for conduction slowing. We describe a patient with a severe subacute neuropathy following n-hexane exposure via glue sniffing. Although symptoms worsened after termination of exposure ("coasting"), strength gradually improved to near normal. Sources of toxic exposure should be sought in all patients with subacute demyelinating neuropathies.

Randomized trial of azathioprine or prednisone for initial immunosuppressive treatment of myasthenia gravis.

Ten patients with myasthenia gravis were randomized to azathioprine or prednisone as the initial immunomodulating drug and followed for over one year. Of five patients randomized to azathioprine, two had idiosyncratic reactions and were immediately crossed over to prednisone. Two patients completed one year on azathioprine with little or no change in level of function and were crossed over to prednisone and showed greater improvement. The fifth patient on azathioprine had a satisfactory improvement and continued on it during the second year. All patients initially randomized to prednisone improved, but the degree varied among patients. The side effects of azathioprine were idiosyncratic reactions. The side effects of prednisone were manageable.

Collet-Sicard syndrome mimicking neuralgic amyotrophy.

A man with shoulder pain, wasting, and weakness had ipsilateral cranial nerve abnormalities. Electrodiagnostic studies supported a diagnosis of neuralgic amyotrophy, but we later demonstrated a spinal accessory mononeuropathy with ipsilateral hypoglossal weakness (Collet-Sicard syndrome). Magnetic resonance imaging demonstrated an inaccessible occipital condyle mass, and disseminated adenocarcinoma was subsequently diagnosed. Although cranial mononeuropathies can occur in neuralgic amyotrophy, this case illustrates the importance of identifying a focal lesion, and highlights the localizing value of electrodiagnosis.