Chronic symmetric symptomatic polyneuropathy in the elderly

Received May 18, 1994. Accepted in final form February 26, 1995.

Address correspondence and reprint requests to Dr. Ettore Beghi, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea, 62, 20157 Milan, Italy.

The prevalence and the comparative distribution of the risk factors for chronic symmetric polyneuropathy in the community are largely unknown. Previous reports dealt with hospital series ^[1] or selected populations at risk, such as individuals exposed to industrial agents ^[2,3] or herbicides, ^[4] or patients with diabetes mellitus. ^[5] Hospital patients may be at a higher risk of polyneuropathy than nonhospital subjects, and the frequency of the disease among people exposed to neurotoxic agents or having disorders causing peripheral neuropathy may not accurately reflect the distribution of polyneuropathy in the general population. In addition, in these studies, the data from unexposed individuals serving as controls are extremely variable depending on the diagnostic criteria for polyneuropathy and the quality of case ascertainment. The elderly are a population at higher risk of polyneuropathy because there is a correlation between age and impairment of the peripheral nervous system ^[6-8] and because the number of agents that impair peripheral nerves, including chronic systemic disorders and neurotoxic drugs, increases with age.

For these reasons, we started a field investigation in Italy in two separate geographic areas with the following aims: (1) to assess the prevalence and general characteristics of chronic symmetric polyneuropathy in two well-defined elderly populations; (2) to establish the risk of the disease in patients with different degrees of exposure to risk factors; (3) to establish the influence of two different environments and cultural settings on the risk of polyneuropathy.

The present paper deals only with aim 1. We will assess the risk of polyneuropathy in patients exposed to possible causes of peripheral neuropathy, as compared with unexposed individuals from the same population, in a separate publication.

Methods.

This research design has been implemented through the Organization of General Practice in Italy, which serves as a permanent epidemiologic observatory, easily activated whenever a specific problem is recognized as interesting and important by individual doctors. Each general practitioner (GP) receives from the health authorities a regularly updated file with all the main demographic data of the patients assigned to his or her care. If he or she decides that a more detailed assessment on a specific project is worthwhile, participation in the research does not involve any extra specific incentives, with the exception of support for travel expenses to coordination meetings.

Two sample populations (Varese in northern Italy, and San Giovanni Rotondo in southern Italy) were selected among the patients of two groups of GPs. Details of the background and the study methods are given elsewhere ^[9] and will only be summarized here. In Italy, medical assistance through the GP is largely free of charge, and the elderly are most likely to seek medical consultation for diagnostic and therapeutic purposes. At the start of the study there were 25 participating GPs in Varese and 10 in San Giovanni Rotondo. Of these, 20 (Varese) and 7 (San Giovanni Rotondo) completed the study. Their patients numbered 23,461 (Varese) and 8,224 (San Giovanni Rotondo). The age and sex distributions of the two study populations were similar and matched those of the 1990 Italian population Figure 1.

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Figure 1. Main demographic characteristics of the two study populations in Varese, northern Italy, and San Giovanni Rotondo, southern Italy.

Patients seen in office consultations by the 27 GPs were the target population. Eligible patients (ie, those aged 55 years or older) were randomly interviewed by the GP with a pretested questionnaire including the principal demographic variables, the main conditions thought to be associated with peripheral neuropathy, current drug treatments, and a list of common symptoms of polyneuropathy (muscle cramps, restless legs syndrome, burning feet, muscle pain, problems with object handling, impairment of standing and gait, and distal paresthesia). To improve the quality of case ascertainment and the homogeneity of the screening techniques among GPs, an experienced neurologist gave an explanatory lecture on the significance of each individual symptom, how the questions should be posed, and the weight of the answers. Previous validation of the questionnaire ^[9] showed two or more symptoms giving the best sensitivity (78%) and specificity (82%) measures and satisfactory agreement among participating GPs (kappa statistic 0.6) and neurologists (kappa statistic 0.8) from both study areas. The GP administered the questionnaire directly to the patient in approximately 10 to 15 minutes and explained any terms (eg, muscle cramps) that might have been misunderstood. Before interviewing a new individual, each GP consulted the computer list of his or her affiliates to check for (and exclude) duplicate patients from the screening procedure.

Subjects giving two or more affirmative answers to the screening questions were then invited to undergo a formal clinical examination by a board-certified neurologist. The diagnosis of polyneuropathy was based on clinical judgment in the presence of bilateral impairment of selected nerve functions (strength, sensation, deep tendon reflexes) in the upper or lower extremities with fairly symmetrical and distal distribution. Impairment of tendon reflexes included diffuse hyporeflexia or bilateral segmental areflexia. Impairment of only one modality confirmed a diagnosis of possible polyneuropathy. Probable polyneuropathy was diagnosed when two or three modalities were concurrently impaired.

Crude (overall and age- and sex-specific) and standardized prevalence rates were calculated for the two areas separately. Adjustment for age and sex was made by using the 1990 Italian population as reference. Heterogeneity and trends of sex- and age-specific prevalence rates of polyneuropathy were assessed by the Mantel-Haenszel (M-H) chisquare test and the chisquare test for linear trend.

Results.

Starting from November 8, 1990, and ending on March 23, 1993, GPs screened 3,027 individuals in Varese and 1,164 in San Giovanni Rotondo Table 1. Fifty-one percent of subjects aged 55 years and older were submitted to screening in both study areas. The percentage of patients screened varied for GPs in both areas as follows: less than 25% of patients screened, 3 GPs; 26 to 50%, 11; 51 to 75%, 9; more than 75%, 4. Of these, 533 in Varese (18%) and 355 in San Giovanni Rotondo (30%) complained of two or more symptoms of polyneuropathy. The proportion of symptomatic patients was similar among the case lists of GPs, regardless of the proportions of individuals screened. Eighty-four percent of patients were submitted to neurologic examination in Varese, and 81% in San Giovanni Rotondo. Refusal (104 patients) was the most common explanation for patients who were not examined.

Patients with and without neurologic assessment were fairly similar with respect to the main demographic and clinical characteristics Table 2. In both areas, diabetes was most common among subjects who underwent the neurologic examination. There was a slight difference regarding the age distribution of the samples in the absence of detectable trends. In Varese, 213 patients (7.0%) had possible polyneuropathy and 111 patients (3.7%) had probable polyneuropathy. The corresponding numbers for San Giovanni Rotondo were 94 (8.1%) and 40 (3.4%). The median percentage of patients with probable polyneuropathy was 4.9% among GPs screening less than 25% of their affiliates; the corresponding values for GPs screening 26 to 50%, 51 to 75%, and more than 75% of patients were 2.2, 2.4, and 3.2%.

The prevalence rates of probable polyneuropathy, overall and age- and sex-specific, are given in Table 3 for the two areas separately. The age- and sex-adjusted prevalence rates of probable polyneuropathy were 3.6 per 100 in Varese and 3.3 per 100 in San Giovanni Rotondo. The disease was most common in women in Varese (M-H chi-square, adjusted for age equals 7.82; p equals 0.005) and prevailed slightly in men in San Giovanni Rotondo. A correlation was detected between age and risk of polyneuropathy that was statistically significant only in Varese (chi-square test for linear trend, adjusted for sex equals 4.15; p equals 0.042). In both areas, diabetes was the most common clinical condition associated with probable polyneuropathy Table 4. Muscle cramps and distal paresthesia were the most frequent complaints. In general, polyneuropathy was mild to moderate, loss of deep tendon reflexes and impairment of sensation being the most common clinical findings. With some exceptions, reduced muscle tone and trophism and impaired autonomic function were infrequent. The most common combination of impaired neurologic functions included deep tendon reflexes and sensation (84 patients) Table 5. The impairment of all three modalities ranked second (47 patients), followed by the concurrent impairment of muscle strength and sensation (13 patients) and that of muscle strength and deep tendon reflexes (seven patients). Positive sensory symptoms (distal paresthesia or burning feet) were present in 116 patients (77%). The distribution of the different sets of modalities was fairly similar in patients with paresthesia or burning feet and in patients with other symptom combinations Table 5. The neurologic signs were distal or predominantly distal in all patients. Seventy-seven patients (51%) had signs primarily in the lower extremities and 72 (48%) in the upper and lower extremities. There were only two patients with motor signs in the upper extremities. Sensation and deep tendon reflexes were diffusely involved in one patient, whereas the other had sensory findings and symptoms involving the upper and lower extremities.

Discussion.

To our knowledge, this is the first extensive community study of the prevalence of chronic symmetric polyneuropathy in an unselected elderly population. Previous prevalence studies of peripheral neuropathy were mostly in younger populations. In an observational study dealing with a multidimensional assessment of the physical health status of Vietnam veterans, ^[4] the control population included 1,972 subjects with a mean age of 37.4 years; the prevalence of symptomatic neuropathy (ie, symptoms and signs) in this population was 0.8%. In an older group of 244 individuals (mean age, 56 years) serving as controls to workers previously exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzo-pdioxin, ^[3] symptoms of neuropathy were reported in 2.0% (weakness) to 18.5% (cramping), and abnormal peripheral nerve functions were present in 7% (position sense) to 62% (tendon reflexes). Franklin et al ^[5] reported crude prevalence rates of 3.6% for distal symmetric sensory neuropathy among community controls aged 45 to 64 and 7.1% for those aged 65 to 74 years. Although there seems to be a slight correlation between prevalence of polyneuropathy and age, the use of different study methods prevents meaningful comparisons of these reports and between them and our investigation.

Several items of evidence can be provided in support of the validity and accuracy of our estimates. First, the rates of probable polyneuropathy were strikingly similar in the two study areas. Second, patients submitted to screening were a significant proportion of the eligible patients of most GPs, and the prevalence of the disease was generally unrelated to the percentage of individuals interviewed by the same GP. Third, the general characteristics of the patients not subjected to neurologic examination were similar to those of the individuals completing this assessment. Accordingly, applying the same prevalence rates of probable polyneuropathy to the unexamined symptomatic subjects would have led to the ascertainment of three additional cases in Varese and two in San Giovanni Rotondo, raising the crude prevalence rates to 3.8 and 3.6 cases per 100. Fourth, although a number of subjects with no symptoms of peripheral nerve involvement might have escaped, the assessment of asymptomatic clinical polyneuropathy was beyond the scope of this study.

A series of potential limitations and weaknesses of the study must be emphasized. First, the diagnostic criteria used may be criticized as being electrophysiologically or pathologically unconfirmed, and because the boundaries between physiologic degradation and pathologic findings in the elderly are ill-defined. ^[10] The involvement of two or more modalities with diffuse peripheral distribution was required here to make a diagnosis of probable polyneuropathy. Although these criteria are even more stringent than others, ^[11] the use of a purely clinical diagnosis of polyneuropathy may be debated. However, electrophysiologic tests also make a limited diagnostic contribution ^[12] and morphologic studies, based on nerve biopsy, are invasive and inappropriate for epidemiologic investigations.

Some of our patients might have had symptoms of radiculopathy, but the bilateral, fairly symmetrical neurologic signs in all patients, the characteristics of the sensory findings, and the predominantly distal involvement of the extremities argue against radiculopathy.

Second, patients seen in office consultations were the target population. This may be a biased sample of the elderly population because those seeking medical advice may be at a different risk of polyneuropathy than healthy individuals or handicapped patients. An unselected sample of 93 subjects were interviewed at home by the GPs in Varese and visited by the neurologists if they reported two or more symptoms of polyneuropathy. The percentage of patients with probable polyneuropathy in this subgroup was 4.3%. Even with the limitations of the sampling conditions (healthy subjects are less likely to be found at home), our rates probably only moderately underestimate the prevalence of polyneuropathy in the aged.

The increasing prevalence of chronic symmetric symptomatic polyneuropathy with age in both areas is concordant with the common belief that polyneuropathy is age-related and that changes in peripheral nerves with aging may not be a disease but simply age-related changes in otherwise healthy individuals. The increasing occurrence of diabetes and other risk factors with age could partly explain our findings. Although a similar explanation might be offered for the different sex distribution of the condition in the two areas (there were 37 diabetic women with polyneuropathy in Varese), this would require confirmation by a more detailed investigation of our data.

Appendix.

The Italian General Practitioner Study Group. Principal investigators: E. Beghi and M.L. Monticelli. Members: L. Amoruso, F. Apollo, M.L. Delodovici, G. Grampa, M. Perini, D. Porazzi, P. Simone, P. Tonali, M. Zarrelli (neurologists); D. Bombelli, M.G. Bombelli, F. Canistro, M. Capuano, D. Castiglioni, A. Ciani, M. Cursio, M. Danza, V. Ferrari, S. Galli, T. Gandini, D. Giussani, R. Luoni, A. Melchionda, G. Molenda, E. Motta, M. Passamonti, R. Pericoli, R. Picotti, M. Pigni, D. Ponti, M. Puricelli, A. Sessa, D. Sinapi, G. Taramelli, M.G. Venosta, R. Zuccoli (general practitioners). Participating institutions: Istituto di Ricerche Farmacologiche "Mario Negri," Milan; Clinica Neurologica, Ospedale "S. Gerardo," Monza; Divisione Neurologica, Ospedale "Casa Sollievo," San Giovanni Rotondo; Divisione Neurologica, Ospedale di Circolo, Varese; Divisione Neurologica, Ospedale "San Antonio Abate," Gallarate; Divisione Neurologica, Ospedale Generale Provinciale, Busto Arsizio; Clinica Neurologica, Universita Cattolica, Rome.

Acknowledgments

We are grateful to Ms. Judy Baggott for editorial revision and to Ms. Susanna Franceschi for typing the manuscript.