Abstract
Introduction/Aims:
Recently, our group found an association between diabetes mellitus (DM) and lumbosacral radiculoplexus neuropathy (LRPN) in Olmsted County, Minnesota; we found a higher risk (OR: 7.91) for developing LRPN in diabetic compared to non-diabetic patients. However, the influence of other comorbidities and anthropomorphic variables was not studied.
Methods:
Demographic and clinical data from 59 LRPN patients and 177 age-sex matched controls were extracted using the Rochester LRPN epidemiological study. Differences between groups were compared by Chi-square/Fisher’s exact test or Wilcox sum rank. Univariate and multivariate logistic regression analysis were performed.
Results:
Factors predictive of LRPN on univariate analysis were DM (OR 7.91; CI 4.11-15.21), dementia (OR 6.36; CI 1.13-35.67), stroke (OR 3.81; CI 1.32-11.01), dyslipidemia (OR 2.844; CI 1.53-5.27), comorbid autoimmune disorders (OR 2.72; CI 1.07-6.93), hypertension (OR 2.25; CI 1.2-4.13), obesity (OR 2.05; CI 1.11-3.8), BMI (OR 1.1; CI 1.04-1.15), and weight (OR 1.02; CI 1.009-1.037). On multivariate logistic regression analysis only DM (OR 8.03; CI 3.86-16.7), comorbid autoimmune disorders (OR 4.58; CI 1.45-14.7), stroke (OR 4.13; CI 1.2-14.25) and BMI (OR 1.07; CI 1.01-1.13) were risk factors for LRPN.
Discussion:
DM is the strongest risk factor for the development of LRPN, followed by comorbid auto-immune disorders, stroke and higher BMI. Altered metabolism and immune dysfunction seem to be the most influential factors in the development of LRPN.
Keywords: vasculitis, lumbosacral radiculoplexus neuropathy, lumbosacral plexopathy, diabetes mellitus
Introduction
Lumbosacral radiculoplexus neuropathy (LRPN) is an immune-mediated neuropathy characterized by unilateral or asymmetrical lower limb weakness, pain, prickling, and sensory loss.1 Initially, it was thought to occur only in people with diabetes mellitus (DM) (DLRPN), but a similar disorder can also affect people without DM, known as non-diabetic LRPN (NDLRPN).2,3 Recently, we found a significantly higher occurrence of DM in LRPN patients compared to age-sex matched controls (66.1% vs. 19.8%) from Olmsted County, Minnesota, USA.4 Within the same population, we found that people with DM have an odds ratio of 7.91 for developing LRPN compared to non-diabetics4 and that the survival is reduced compared to controls (mostly secondary to DM).5
The pathophysiology of LRPN is still not fully elucidated. Several pathological studies have shown evidence of ischemic injury and microvasculitis of nerve and up-regulation of inflammatory mediators in nerves of patients with LRPN,6,2,7-9 which makes LRPN a variant of non-systemic vasculitic neuropathy.10 DM is a definite risk factor, but how DM triggers an auto-immune attack to roots, plexus and nerves is still largely unknown. In addition, the influence of anthropomorphic variables or other comorbidities on LRPN has not yet been studied.
Herein we investigate the risk factors for LRPN in a population-based setting from Olmsted County, Minnesota.
Methods
Demographic, anthropomorphic, laboratory and clinical data from LRPN patients and controls were extracted from the Olmsted County LRPN epidemiological study, in which the incidence of LRPN was recently determined.4 The study design, LRPN inclusion and exclusion criteria and controls identification can be found in supplementary table 1.4 Each case of LRPN was matched with three non-LRPN patients by age and sex. In people with LRPN, data were extracted from the time of diagnosis. In the control group, data were extracted from the closest medical visit or laboratory study within one year of the matched-LRPN diagnosis date. This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center.
Anthropomorphic variables
The metrics used were standard international. Overweight and obesity were defined by body mass index (BMI) > 25 and > 30 kg/m2 respectively.
Medical Comorbidities
Diabetes Mellitus
The diagnosis of DM was according to American Diabetes Association criteria.11 Duration of DM, presence of microvascular complications, and amputation were extracted from medical records.
Other comorbidities
History of hypertension, dyslipidemia, heart failure, coronary artery disease, stroke, non-skin-cancer, chronic kidney disease (CKD), dementia, peripheral artery disease, and comorbid autoimmune disorders was extracted from problem list diagnostic index or medical notes.
Statistical Analysis
Categorical variables were summarized using frequencies and percentages and groups were compared using χ2 and Fisher's exact tests as appropriate. Continuous variables are presented as median and range, and groups were compared using Wilcoxon rank sum test. Association between LRPN and risk factors were accessed using univariate and multivariate logistic regression with odds ratios (OR) reported. A two-tailed a priori alpha level of <0.05 was considered significant. Statistical analysis were performed using SAS® (version 9.4, SAS Institute, Cary, NC) and JMP (pro version 15.0, SAS Institute, Cary, NC).
Results
LRPN versus controls
Fifty nine LRPN patients and 177 age-sex matched controls were identified. Compared to controls, LRPN patients more frequently had: hypertension, DM,4, obesity, dyslipidemia, stroke, dementia, and comorbid autoimmune disorder (table 1). Patients with LRPN had a higher BMI and a higher weight compared to the control group (table 1). In the LRPN group, 9 patients had 11 comorbid autoimmune disorders (2 patients had 2 comorbid autoimmune disorders): autoimmune thyroiditis (n=4), inflammatory bowel disease (n=2), type 1 DM (n=2), myasthenia gravis (n=1), multiple sclerosis (n=1), and psoriasis (n=1).
Table 1-.
Comparison of comorbidities and anthropomorphic variables between patients with LRPN and controls
| Variables | LRPN n=59 |
Controls n=177 |
p | ||
|---|---|---|---|---|---|
| Yes, N | % | Yes, N | % | ||
| Hypertension | 38 | 64 | 79 | 45 | 0.009 |
| Diabetes Mellitus | 39 | 66 | 35 | 20 | <0.001 |
| Obesity | 30 | 51 | 59 | 33 | 0.021 |
| Dyslipidemia | 39 | 66 | 72 | 41 | <0.001 |
| CKD | 9 | 15 | 18 | 11 | 0.288 |
| Stroke | 8 | 14 | 7 | 4 | 0.009 |
| Heart failure | 5 | 8 | 14 | 8 | 0.890 |
| CAD | 18 | 31 | 34 | 19 | 0.07 |
| PAD | 1 | 2 | 6 | 3 | 0.506 |
| Dementia | 4 | 7 | 2 | 1 | 0.017 |
| Comorbid autoimmune disorder | 9 | 15 | 11 | 6 | 0.031 |
| Cancer | 15 | 25 | 35 | 20 | 0.356 |
| Median | range | Median | range | ||
| BMI, kg/m2 | 31.4 | 18.4-57.5 | 28 | 16.1-47.7 | <0.001 |
| Weight, kgs | 90.3 | 53-172 | 79.6 | 37.8-181 | <0.001 |
| Height, cms | 171 | 135-188 | 168 | 98.9-196 | 0.36 |
LRPN- lumbosacral radiculoplexus neuropathy; CKD- chronic kidney disease; CAD- coronary artery disease; PAD- peripheral artery disease; BMI- body mass index; kgs- kilograms; cms- centimeters
DLRPN versus diabetic controls
In patients with DM, DM duration, fasting glucose, BMI, weight, microvascular DM complications, or frequency of any other comorbidity were similar between DLRPN and diabetic controls (table 2).
Table 2-.
Comparison of comorbidities and laboratory and anthropomorphic variables in diabetic (LRPN vs controls) and non-diabetic (LRPN vs controls) patients
| Variables | Diabetic LRPN n=39 |
Diabetic Controls n=35 |
p | ||
|---|---|---|---|---|---|
| Yes, N | % | Yes, N | % | ||
| Diabetic microvascular complications | 18 | 46 | 16 | 46 | 0.887 |
| Amputation | 2 | 5 | 1 | 3 | 0.621 |
| Hypertension | 28 | 72 | 26 | 74 | 0.81 |
| Dyslipidemia | 27 | 69 | 24 | 69 | 0.951 |
| Stroke | 4 | 10 | 3 | 9 | 0.805 |
| Obesity | 24 | 62 | 17 | 49 | 0.276 |
| Dementia | 3 | 8 | 1 | 3 | 0.358 |
| Comorbid auto disorder | 6 | 15 | 2 | 6 | 0.181 |
| Median | range | Median | range | ||
| DM duration, years | 8.5 | 0-41 | 10 | 1-50 | 0.753 |
| Fasting glucose, mg/dl | 163 | 41-430 | 143 | 99-291 | 0.409 |
| HbA1c, % | 7.6 | 5.2-12.5 | 6.6 | 5.4-10.7 | 0.074 |
| BMI, kg/m2 | 33.3 | 18.4-57.5 | 31.2 | 16.1-47.7 | 0.132 |
| Weight, kgs | 98 | 53-172 | 85 | 42-152 | 0.072 |
| Variables | Non-diabetic LRPN n=20 |
Non-diabetic Controls n=142 |
p | ||
| Yes, N | % | Yes, N | % | ||
| Hypertension | 10 | 50 | 53 | 37 | 0.323 |
| Pre-diabetes | 10 | 50 | 55 | 38.7 | 0.336 |
| Dyslipidemia | 12 | 60 | 48 | 34 | 0.028 |
| Stroke | 4 | 20 | 4 | 2.8 | 0.009 |
| Obesity | 7 | 35 | 47 | 33 | 0.965 |
| Dementia | 1 | 5 | 1 | 1 | 0.232 |
| Comorbid auto disorder | 3 | 15 | 9 | 6 | 0.171 |
| Median | range | Median | range | ||
| BMI, kg/m2 | 29.4 | 21.0-52.1 | 27.4 | 16.1-46.2 | 0.345 |
| Weight, kgs | 87 | 53-140 | 79 | 38-181 | 0.35 |
LRPN- lumbosacral radiculoplexus neuropathy; DM- diabetes mellitus; Comorbid auto disorder- comorbid autoimmune disorder; BMI- body mass index; kgs- kilograms.
NDLRPN versus non-diabetic controls
In non-diabetic patients, the frequency of stroke and dyslipidemia were higher in the LRPN group (table 2) versus non-diabetic controls. No other comorbidity or anthropomorphic variable was different between groups.
Risk factor analysis
On univariate logistic regression analysis, DM,4 dementia stroke, dyslipidemia, comorbid auto-immune disorders, hypertension, obesity, BMI, and weight, were predictive factors for the development of LRPN (table 3). On multivariate logistic regression analysis, only DM, comorbid autoimmune disorders, stroke and BMI remained as risk factors for LRPN (table 3).
Table 3-.
Risk factors for Lumbosacral Radiculoplexus Neuropathy
| UNIVARIATE LOGISTIC REGRESSION | |||
|---|---|---|---|
| Variables | OR | 95% CI of OR | |
| Sex | 1.122 | 0.619 | 2.035 |
| Age | 1.002 | 0.982 | 1.023 |
| BMI | 1.095 | 1.044 | 1.148 |
| Weight | 1.023 | 1.009 | 1.037 |
| Height | 1.012 | 0.985 | 1.04 |
| Overweight | 1.935 | 0.845 | 4.434 |
| Obesity | 2.053 | 1.111 | 3.796 |
| Chronic Kidney Dysfunction | 1.59 | 0.672 | 3.762 |
| Hypertension | 2.245 | 1.22 | 4.13 |
| Diabetes | 7.911 | 4.114 | 15.211 |
| Pre-diabetes | 1.006 | 1.004 | 1.012 |
| Coronary artery disease | 1.846 | 0.946 | 3.603 |
| Heart failure | 1.078 | 0.371 | 3.132 |
| Amputation | 6.173 | 0.55 | 69.346 |
| Stroke | 3.81 | 1.318 | 11.013 |
| Dementia | 6.362 | 1.134 | 35.673 |
| Peripheral artery disease | 0.491 | 0.058 | 4.167 |
| Dyslipidemia | 2.844 | 1.535 | 5.27 |
| Cancer | 1.383 | 0.692 | 2.766 |
| Comorbid Autoimmune disorder | 2.716 | 1.065 | 6.926 |
| MULTIVARIATE LOGISTIC REGRESSION | |||
| Variables | OR | 95% CI of OR | |
| BMI | 1.068 | 1.011 | 1.129 |
| Diabetes | 8.029 | 3.86 | 16.7 |
| Stroke | 4.128 | 1.195 | 14.257 |
| Comorbid autoimmune disorder | 4.61 | 1.446 | 14.696 |
LRPN- lumbosacral radiculoplexus neuropathy; OR- odds ratio; CI- confidence interval; BMI- body mass index. p<0.05 are shown en bold.
Discussion
In this study, we demonstrate that hypertension, stroke, obesity, dementia, dyslipidemia, and comorbid autoimmune disorders are more frequent in patients with LRPN than age-sex matched controls. Many of these variables are part of the metabolic syndrome. This adds to our previous study within the same population,4 which showed that DM frequency is higher in the LRPN population4 and that survival is reduced.5 In people with DM, the odds for developing LRPN are increased approximately 8-fold. On multivariate analysis, we now show that DM is the strongest risk factor for the development of LRPN, followed by a history of comorbid autoimmune disorders, stroke, and higher BMI. This suggests that there were no unmeasured confounding factors in our previous study and that DM is the most important risk factor for developing LRPN.
The pathogenic processes that trigger LRPN are not known. DM (chronic hyperglycemia) may induce neuronal damage by several mechanisms, including the formation of advanced glycation end-products, increased oxidative stress, mitochondrial dysfunction, and activation of the polyol and hexosamine pathways.12 Rapid glycemic changes may lead to neuronal apoptosis due to glucose deprivation and microvascular neuronal damage due to recurrent hypoglycemia.13 Hyperlipidemia induces excessive fatty acid oxidation, which generates reactive species of oxygen and systemic and local inflammation via macrophage activation with subsequent cytokine and chemokine production; this may injure the peripheral nervous system, especially the Schwan cells.14 Several studies have found positive associations between serum markers of inflammation, lipid metabolism, and onset and progression of complications in individuals with type 1 and type 2 DM.15 Metabolic syndrome and DM are associated with the accumulation of neurotoxic deoxysphingolipids that may induce neuronal apoptosis.16 Although none of the these mechanisms seem to directly cause LRPN, we postulate that metabolic-mediated peripheral nerve injury may trigger an inflammatory response against roots, plexus and nerves, manifesting as LRPN. This may relate to rapid glycemic change as can occur in DLRPN and as has been shown to occur in treatment-induced diabetic neuropathy.17
We found that comorbid autoimmune disorders are risk factors for the development of LRPN. The comorbid autoimmune conditions most commonly encountered were autoimmune thyroiditis, inflammatory bowel disease, and type 1 DM. It is unclear if type 1 DM is a risk factor because of the diabetic state or because of its autoimmune pathogenesis. Genetic predisposition is likely to play a role in autoimmunity, which may explain autoimmune disorders co-occurring within individuals and families.18 HLA is the most reported genetic factor associated with several autoimmune diseases, being the most associated with type 1 DM, rheumatoid arthritis, celiac disease, ankylosing spondylitis, and multiple sclerosis.19 History of stroke and obesity (increased BMI) are also risk factors for LRPN after multivariate analysis. We think these findings strengthen our hypothesis that metabolic factors and the metabolic syndrome play a role because people with stroke frequently have hypertension, DM, obesity, poor diet, sedentarism, and dyslipidemia.20 Patients with LRPN may share a particular genetic predisposition for developing this neuropathy when challenged by these metabolic factors. The higher median BMI(31.8 vs 25.76 and 25.12 kg/m2) and less frequent weight loss (>10 lbs)(32.2% vs 77.8%) in the community LRPN cohort compared to referral-LRPN cohorts likely reflectsdifferences among these cohorts, with more severe disease occurring in the referral-cohorts.5
There was no significant difference among anthropomorphic variables, comorbidities, DM complications, DM duration, or laboratory findings between DLRPN patients and controls with DM. Compared to a DLRPN referral-based cohort,6 the median duration of DM was longer in our community-based LRPN cohort (8.5 vs. 4.1 years), but the median HbA1c was essentially the same (7.6% vs. 7.5%). Even though our study sheds some light on possible risk factors for LRPN, it is still unclear what particular characteristics a person with DM may have that causes them to develop LRPN.
Our study has some limitations. The major limitation is its retrospective nature (case-control design) that did not allow us to investigate if rapid glycemic change, surgery, weight loss, change in exercise routine, dietary habits or infections are risk factors for LRPN. Also, most of the comorbidities were extracted from clinical notes or problem list diagnostic indices rather than directly from laboratory or other clinical data and so the results may have been less accurate.
Conclusion
We find that DM is the largest risk factor for the development of LRPN, followed by comorbid autoimmune disorders, stroke, and higher BMI. Altered metabolism and immune dysfunction seem to be the most influential factors in the development of this immune-mediated neuropathy.
Supplementary Material
Study funding:
This study used the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations
- BMI
body mass index
- CI
confidence interval
- DLRPN
diabetic lumbosacral radiculoplexus neuropathy
- DM
diabetes mellitus
- LRPN
lumbosacral radiculoplexus neuropathy
- NDLRPN
nondiabetic lumbosacral radiculoplexus neuropathy
- REP
Rochester Epidemiology Project
Footnotes
Financial Disclosures: Drs. Pinto, Ng, Laughlin, Aragon Pinto, Shelly, Shouman and PJB Dyck and Mr. Thapa report no disclosures. Dr. Peter J. Dyck previously received honoraria for his services as an associate editor of Diabetes. He has and continues to receive honoraria for the teaching of the neurological examination and neurophysiological tests in pharmaceutical industry trials from Alnylam, Inc., Ionis, Inc., and Eidos, Inc. None of these trials are related to the present report.
Ethical Statement: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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