Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. METHODS: This study was performed within the population-based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6-78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome-wide association studies. RESULTS: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]diabetes, p < 1.0  = 1.21, 95% confidence interval [CI] = 1.05-1.39 and ORBMI, p < 1.0  = 1.21, 95% CI = 1.04-1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR vitamin B12, p < 5e-6  = 0.79, 95% CI = 0.68-0.92 and ORalcohol, p < 5e-8  = 1.17, 95% CI = 1.02-1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGSp < 5e-8 and polyneuropathy. CONCLUSIONS: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well-known clinical risk factors and polyneuropathy.

Cardiovascular health and chronic axonal polyneuropathy: A population-based study.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common, usually multifactorial, disease for which there is no treatment yet available. We investigated the association between cardiovascular health, defined by the health score of the American Heart Association, and chronic axonal polyneuropathy. METHODS: Between June 2013 and January 2017, we investigated participants of the Rotterdam Study, a population-based cohort study. Participants were screened for polyneuropathy and categorized as having no, possible, probable or definite polyneuropathy. The cardiovascular health score (range 0-14; higher score reflecting better health) consisted of four health behaviours (diet, physical activity, smoking and body mass index) and three health factors (blood pressure, serum cholesterol and fasting glucose level). RESULTS: We included 1919 participants, of whom 120 (6.3%) had definite polyneuropathy. The median (interquartile range [IQR]) age was 69.0 (58.6-73.7) years and 53.4% were women. A higher cardiovascular health score was associated with a lower prevalence of definite polyneuropathy (per point increase: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84-0.96). Optimal cardiovascular health (score≥10) was strongly associated with a lower prevalence of definite polyneuropathy (OR 0.55, 95% CI 0.32-0.90). An increase in health factors and health behaviour scores separately was associated with a lower prevalence of polyneuropathy (per point increase: OR 0.82, 95% CI 0.71-0.95 and OR 0.86, 95% CI 0.78-0.96, respectively). The association between a lower cardiovascular health score and lower sural nerve amplitude was not significant after correction for covariates (difference 0.07µV, 95% CI -0.02-0.17). CONCLUSIONS: Better cardiovascular health, consisting of both modifiable health behaviours and health factors, is associated with a lower prevalence of chronic axonal polyneuropathy.

Diagnostic value of symptoms in chronic polyneuropathy: The Erasmus Polyneuropathy Symptom Score.

In this study, we evaluated the diagnostic value of symptoms of chronic polyneuropathy and to construct and validate a simple questionnaire that can help diagnose chronic polyneuropathy. In a multi-step procedure, we initially compiled a 12-item questionnaire concerning polyneuropathy symptoms. The questionnaire was completed by 117 polyneuropathy patients and 188 controls (headache, transient ischemic attack, multiple sclerosis). First, we calculated sensitivity, specificity and likelihood ratios of each symptom. Next, we used multi-variable logistic regression to create a model that could discriminate patients from controls, using only the most informative symptoms and their frequency of occurrence. Based on the regression coefficients, we developed a simple scoring system (Erasmus Polyneuropathy Symptom Score, E-PSS), which was externally validated in 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without polyneuropathy. We assessed performance with discrimination (area under the curve, AUC) and calibration analyses. Numb and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. Walking on cotton wool and allodynia had the highest specificity. Logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. Based on this analysis, the E-PSS was created, ranging from 0 to 14. The E-PSS had a good performance (AUC = 0.92) in the derivation set and proved to be valid in the external population (AUC = 0.95). In conclusion, the Erasmus Polyneuropathy Symptom Score (E-PSS) is a simple, validated six-item score that takes the presence and frequency of six different symptoms into account and it may be a helpful tool to screen individuals for the presence of chronic polyneuropathy.

Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies.

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.

Bullous Pemphigoid With a Dual Pattern of Glomerular Immune Complex Disease.

A 75-year-old man presented with a blistering skin disease and nephrotic syndrome. Bullous pemphigoid was diagnosed by linear immunoglobulin G (IgG) and C3 staining along the basement membrane zone of a skin biopsy specimen and by the presence of circulating IgG recognizing the 180-kDa bullous pemphigoid antigen (BP180; type XVII collagen). A kidney biopsy specimen showed endocapillary inflammation without crescents. Direct immunofluorescence showed strong IgG and C3 staining in a combined granular and linear pattern along the glomerular basement membrane. Electron microscopy showed subepithelial deposits. In serum, no antibodies against the Goodpasture antigen (type IV collagen) or phospholipase A2 receptor were detected. Indirect immunofluorescence studies using the patient's serum showed a strikingly linear but not granular IgG pattern along the epithelial basement membranes of monkey esophagus and kidney. Although type XVII collagen was recently identified in the glomerulus, the patient's serum did not produce a 180-kDa band on immunoblot of kidney tissue and still stained glomeruli of BP180 knockout mice by indirect immunofluorescence. The patient was treated with prednisone and azathioprine, which resulted in complete remission of skin and kidney manifestations. Although bullous pemphigoid has been reported previously in association with anti-glomerular basement membrane disease or membranous nephropathy, this case demonstrates both elements in 1 patient. This concurrence and the linear pattern on indirect immunofluorescence support the possibility of cross-reactive or parallel autoantibodies to basement membranes with a secondary membranous component.

Age-Related Changes in Neurologic Examination and Sensory Nerve Amplitude in the General Population: Aging of the Peripheral Nervous System.

BACKGROUND AND OBJECTIVES: Chronic axonal polyneuropathy is a common disease of the peripheral nervous system with increasing prevalence with age. Typical neurologic signs are present in patients with polyneuropathy but may also occur in individuals without disease. Owing to limited knowledge on normal aging of the peripheral nervous system, it can be difficult to distinguish peripheral nerve dysfunction due to disease from variations in normal aging. Therefore, we described the changes in neurologic examination and nerve conduction studies that accompany aging in the general population. METHODS: In this cross-sectional population-based study, we screened participants for chronic polyneuropathy in a controlled environment using standardized methods including a symptom questionnaire, neurologic examination, and nerve conduction studies (NCS). Inclusion criteria were 40 years or older and living in a suburb of Rotterdam, the Netherlands. Participants not diagnosed with chronic polyneuropathy, based on the discussion of findings in the screening by an expert team, were included to determine the effect of age (range 41-96 years) on features of neurologic examination and NCS using frequency calculations and quantile regression analysis. RESULTS: In total, 4,179 participants (mean age 64.5 ± 12.7 years, 54.9% female) were included of whom 3,780 (90.5%) did not fulfil the criteria for polyneuropathy. In the population without polyneuropathy, the frequency of normal features at neurologic examination declined with age, most pronounced for vibration sense at the hallux (from 6.6 [SD ± 1.5] in 40-49 years to 3.6 [SD ± 3.1] in 80 years or older) and Achilles tendon reflexes (absent in 9% in 40-49 years up to 33% in 80 years or older). Superficial pain sensation and patellar tendon reflexes remained stable over time. Sural sensory nerve action potential (SNAP) amplitude declined with age from 11.2 µV in 40-49 years to 3.3 µV in 80 years or older. Nonrecordable SNAP amplitudes were found in 25.1% of the participants older than 80 years, more often in men (30.3%) than in women (21.0%). DISCUSSION: This study showed the effect of age on features of neurologic examination and sural nerve amplitude in the general population. These findings are helpful to distinguish features suggesting polyneuropathy from variations of normal aging of the peripheral nervous system.

Prevalence and Risk Factor Profiles for Chronic Axonal Polyneuropathy in the General Population.

BACKGROUND AND OBJECTIVES: Chronic axonal polyneuropathy is a common disease with increasing prevalence with age. It majorly impacts quality of life and leads to difficulties with various activities. Persons with polyneuropathy often not seek medical care and thus the societal burden of disease is likely underreported. Given the aging populations contemporary data on the prevalence as well as risk factor profiles of polyneuropathy in the general population are required. Therefore, we estimated the current and expected prevalence, and investigated the (co-)occurrence of risk factors in participants with chronic axonal polyneuropathy. METHODS: Between June 2013 and January 2020, participants of the population-based Rotterdam Study underwent extensive in-person examination to diagnose polyneuropathy. Age-standardized prevalence's were calculated for populations aged ≥40 years of the Netherlands, Europe, United States and the world population. Putative risk factors were identified using laboratory findings, interviews, questionnaire data and a review of medical records. RESULTS: In total, 4114 participants were included (mean age 64.3 years, 55.2% females) of whom 167 had chronic axonal polyneuropathy. More than half (54.5%) had yet not received the diagnosis through regular care. Age-standardized prevalence's were 3.3% (95% CI 2.8-4.0) for the European, 3.0% (95% CI 2.5-3.5) for the US and 2.3% (95% CI 1.9-2.8) for the world population. Based on the expected age distributions, the prevalence of chronic axonal polyneuropathy will increase with ±25% in the next 20 years. Known risk factors were present in 62.9% (N=105) of the cases with polyneuropathy and most often included diabetes (34.1%) and vitamin deficiencies (15.1%). Importantly, combinations of various risk factors were found in 20.4% (N=34) of cases with polyneuropathy. DISCUSSION: Prevalence of chronic axonal polyneuropathy increases with age and is expected to further rise over time. Combinations of multiple known risk factors are often present, indicating the need for a full diagnostic workup, even when a single risk factor for polyneuropathy is known. These findings suggest that cumulative effects of multiple risk factors are important in the development and course of disease.

Diet quality and chronic axonal polyneuropathy: a population-based study.

OBJECTIVE: To investigate the association between diet quality and chronic axonal polyneuropathy. METHODS: Between June 2013 and January 2017, among 1650 participants of the Rotterdam Study (median age 69.1 years, 54.2% women), diet quality was quantified based on food frequency questionnaires as a sum score of adherence (yes/no) to 14 components of the Dutch dietary guidelines. Presence of polyneuropathy was determined based on a questionnaire, neurological examination of the legs, and nerve conduction studies. We used logistic regression to associate diet quality with the presence of chronic axonal polyneuropathy and linear regression to associate with sural sensory nerve action potential (SNAP) amplitude in participants without polyneuropathy. Results were adjusted for age, sex, time between measurements, body mass index, blood pressure, diabetes mellitus, smoking, kidney function, and education. RESULTS: Overall diet quality was not associated with chronic axonal polyneuropathy (odds ratio [OR] = 0.99, 95% confidence interval [CI] 0.88; 1.12, P = 0.842), nor with sural SNAP amplitude in participants without polyneuropathy (difference = 0.01, 95% CI -0.14; 0.15, P = 0.993). Although not surviving multiple testing, a nominally significant association was found between salt intake ≤6 g/day and presence of chronic axonal polyneuropathy (OR = 0.55, 95% CI 0.35; 0.86, P = 0.008). INTERPRETATION: We did not find an association between diet quality and chronic axonal polyneuropathy.