Impact of Yoga and Naturopathy in a Patient with Chronic Idiopathic Axonal Polyneuropathy Associated with Metabolic Syndrome and Rheumatoid Arthritis: A Case Report.

Chronic idiopathic axonal polyneuropathy (CIAP), a common neurological condition, is considered to be a benign neurological condition with a small risk of disability. However, many studies have shown a reduced quality of life and a nonnegligible affection of daily activities in patients with CIAP. Here we summarize recent data about CIAP. We discuss some of the latest articles regarding risk factors, comorbidities, and possible pathogenic factors regarding CIAP. Patients with chronic polyneuropathy have impaired walking capacity, disturbed balance, and an increased risk of falls. Idiopathic polyneuropathy has a negative impact on activities of daily living. Patients with CIAP may develop plantar ulcers and neuropathic arthropathy. Small fiber involvement may occur, and two recent studies indicate that neuropathic pain is present in about two thirds of the CIAP group. Furthermore, patients with CIAP with neuropathic pain have increased fatigue and poorer emotional well being. Despite the relatively mild motor impairment seen in most patients with CIAP, the condition causes limitations in life with decreased mobility, pain, and affection of basal daily activities. Because the pathogenesis of CIAP in unclear, there is no disease modifying treatment. Further studies regarding pathogenesis, and randomized controlled clinical trials regarding possible treatment options are needed.

OBJECTIVEThis study aims to investigate the association between chronic idiopathic axonal polyneuropathy (CIAP) and the metabolic syndrome or its individual components.RESEARCH DESIGN AND METHODSA total of 249 patients with CIAP and 709 controls underwent fasting laboratory studies, and blood pressure and waist circumference were measured. The metabolic syndrome was diagnosed if three or more of the following Adult Treatment Panel III criteria were present: impaired fasting glucose, hypertension, abdominal obesity, reduced HDL cholesterol, and hypertriglyceridemia. Subgroup analysis was performed for patients with a painful predominantly sensory CIAP, because this phenotype is most similar to diabetic polyneuropathy. Statistical analysis was performed with adjustment for age and gender.RESULTSFifty-five percent of all patients fulfilled the metabolic syndrome criteria compared with 34% of controls (odds ratio 2.2 [95% CI 1.7–3.0]). Multivariate analysis shows hypertension (2.9 [1.7–4.9]) and abdominal obesity (3.3 [2.4–4.6]) to be significantly more prevalent in patients than in controls. Of the patients classified as having a painful predominantly sensory CIAP, 62% fulfilled the metabolic syndrome criteria (3.1 [2.0–4.8]). In this subgroup, hypertension and abdominal obesity also were significantly more prevalent compared with controls.CONCLUSIONSAbdominal obesity and hypertension seem to be the most consistent contributing components of the metabolic syndrome in patients with CIAP. Evaluation and appropriate treatment of these risk factors in patients with CIAP would be advocated.

AimChronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive, predominantly sensory, axonal polyneuropathy, with no aetiology being identified despite extensive investigations. We studied the potential role of the metabolic syndrome, neurotoxic 1-deoxysphingolipids (1-deoxySLs), microangiopathy and inflammation in sural nerve biopsies.MethodsWe included 30 CIAP-patients, 28 with diabetic distal symmetrical polyneuropathy (DSPN) and 31 healthy controls. We assessed standardised scales, tested for the metabolic syndrome, measured 1-deoxySLs in plasma, performed electroneurography and studied 17 sural nerve biopsies (10 CIAP; 7 DSPN).ResultsOne third of the CIAP-patients had a metabolic syndrome, significantly less frequent than DSPN-patients (89%). Although the metabolic syndrome was not significantly more prevalent in CIAP compared to healthy controls, hypercholesterolemia did occur significantly more frequent. 1-deoxySLs were significantly and equally elevated in both patient groups compared to healthy controls. Mean basal lamina thickness of small endoneurial vessels and the number of CD68- or CD8-positive cells in biopsies of CIAP- and DSPN-patients did not differ significantly. However, the number of leucocyte-common-antigen positive cells was significantly increased in CIAP.ConclusionsA non-significant trend towards a higher occurrence of the metabolic syndrome in CIAP-patients compared to healthy controls was found. 1-deoxySLs were significantly increased in plasma of CIAP-patients. Microangiopathy and an inflammatory component were present in CIAP-biopsies.

Impaired glucose tolerance and metabolic syndrome in idiopathic polyneuropathy: The role of pain and depression

Chronic idiopathic axonal polyneuropathy (CIAP) is a frequent neurologic disorder in elderly persons. In view of the aging population, it is important to know the long-term prognosis of CIAP. To determine if CIAP is influenced by the superposition of the effects of aging and to evaluate the severity of CIAP according to the disease duration. Controlled cohort study. Outpatient clinic for neuromuscular diseases at the University Medical Center Utrecht, Utrecht, the Netherlands. One hundred twenty-seven patients with CIAP and 108 age-matched control subjects were included. We defined CIAP on the basis of symmetrical distal sensory or sensorimotor symptoms and signs with evolution over at least 6 months, exclusion of causes by history taking, results of clinical and laboratory investigations, and electrophysiologic findings that agreed with the diagnosis of axonal polyneuropathy. No important neurologic or electrophysiologic differences were found between patients with early-onset (before the age of 65 years) and late-onset (at or after the age of 65 years) CIAP, but patients with early-onset CIAP who had a short disease duration (<10 years) experienced more disability than patients with late-onset CIAP who had a similar disease duration. Old controls (age of 65 years or older) more often had symptoms, sensory signs in the legs, absent ankle jerks, and lower mean distal amplitudes of compound muscle action potentials and sensory nerve action potentials than young controls (aged <65 years). Absence of the sural nerve sensory nerve action potentials or presence of spontaneous muscle fiber activity in the anterior tibial muscle was common in patients with CIAP (51% and 60%, respectively), but exceptional (both 2%) in controls. Neither aging of the peripheral nervous system nor disease duration affects CIAP to a considerable degree, but CIAP has a greater influence on the daily life of nonretired patients with early-onset CIAP. The diagnosis of axonal polyneuropathy is probably supported best by either the absence of the sural nerve sensory nerve action potentials or the presence of spontaneous muscle fiber activity in the anterior tibial muscle.

Twenty-five percent of polyneuropathies are idiopathic. Microangiopathy has been suggested to be a possible pathogenic cause of chronic idiopathic axonal polyneuropathy (CIAP). Dysfunction of the autophagy pathway has been implicated as a marker of neurodegeneration in the central nervous system, but the autophagy process is not explored in the peripheral nervous system. In the current study, we examined the presence of microangiopathy and autophagy-related structures in sural nerve biopsies of 10 patients with CIAP, 11 controls with inflammatory neuropathy and 10 controls without sensory polyneuropathy. We did not find any significant difference in endoneurial microangiopathic markers in patients with CIAP compared to normal controls, though we did find a correlation between basal lamina area thickness and age. Unexpectedly, we found a significantly larger basal lamina area thickness in patients with vasculitic neuropathy. Furthermore, we found a significantly higher density of endoneurial autophagy-related structures, particularly in patients with CIAP but also in patients with inflammatory neuropathy, compared to normal controls. It is unclear if the alteration in the autophagy pathway is a consequence or a cause of the neuropathy. Our results do not support the hypothesis that CIAP is primarily caused by a microangiopathic process in endoneurial blood vessels in peripheral nerves. The significantly higher density of autophagy structures in sural nerves obtained from patients with CIAP and inflammatory neuropathy vs. controls indicates the involvement of this pathway in neuropathy, particularly in CIAP, since the increase in density of autophagy-related structures was more pronounced in patients with CIAP than those with inflammatory neuropathy. To our knowledge this is the first report investigating signs of autophagy process in peripheral nerves in patients with CIAP and inflammatory neuropathy.

An underlying cause is found in only 7% to 30% of patients with chronic idiopathic axonal polyneuropathy (CIAP). Diabetes mellitus, inherited disorders, toxin exposure, and primary amyloidosis are the most common identified causes of sensory neuropathies affecting both large and small myelinated fibers. Undiagnosed impaired fasting glucose metabolism has been associated with CIAP at a higher frequency rate than in the general population. This increased prevalence rate was identified using the 2-hour oral glucose tolerance test (2h-OGTT) and a previous version of the American Diabetes Association (ADA) guidelines. To determine the prevalence of abnormal fasting glucose metabolism in patients with CIAP and to compare the value of determining fasting plasma glucose levels using revised (2003) ADA criteria with the 2h-OGTT for predicting abnormal fasting glucose metabolism. In this 24-month retrospective study, 100 consecutive patients were identified with no known cause for CIAP, including diabetes mellitus, between January 2003 and January 2005. All had both a fasting plasma glucose test and a 2h-OGTT in addition to a complete neurological examination. Neurophysiological studies, computer-assisted sensory examination, and quantitative sudomotor axonal reflex testing were used to classify CIAP into subtypes according to nerve fiber involvement. The prevalence of undiagnosed abnormal fasting glucose metabolism was found to be nearly 2-fold higher (62%) in patients with CIAP than in similar age-matched general population groups (33%). Using the 2003 revised ADA criteria, 39 patients (39%) had abnormal fasting plasma glucose metabolism (36 with impaired fasting glucose, 3 with diabetes mellitus), while the 2h-OGTT provided an even higher diagnostic rate of 62% (62 patients; P<.001) of impaired fasting glucose metabolism (38 with impaired glucose tolerance, 24 with diabetes mellitus). The abnormal glucose metabolism rates were found to be similar across the 3 subtypes (sensorimotor, pure sensory, and small-fiber neuropathy) of CIAP (P = .60, .72, and .61). This study adds to emerging evidence that abnormal glucose metabolism may be a risk factor for CIAP. Even with revised (2003) ADA criteria, the 2h-OGTT provides additional diagnostic information to the health care professional in the evaluation of CIAP. Subtypes of CIAP are equally likely to have abnormal glucose metabolism.

For chronic idiopathic axonal polyneuropathy (CIAP), even after extensive evaluation, no cause has yet been found. Considering the age and sex distribution of patients with this disease, it is possible that vascular disease plays a role in the development of this polyneuropathy. As endoneurial vessel abnormalities can be related to ischemia, we investigated endoneurial vessels in sural nerve biopsies of 18 patients with CIAP. As controls we used sural nerves of 4 patients with diabetes mellitus, 6 patients with hereditary motor and sensory neuropathy type II (HMSN type III) and 10 autopsy cases. Basal lamina area thickness, endothelial cell area, lumen area, and the number of basal laminae, endothelial cells and periendothelial cell nuclei were investigated. Basal lamina area thickness, endoneurial cell area and number of endothelial cell nuclei in CIAP were increased in comparison with HMSN type III, whereas the basal lamina area thickness of patients with CIAP and diabetes mellitus were in the same range. The structure of the basal lamina area in CIAP differed from diabetes mellitus; in diabetes mellitus there was a larger number of lamellae, whereas in CIAP there was an increase in collagen. There was no correlation between basal lamina area thickness and age. In CIAP patients with peripheral vascular disease of the legs, basal lamina area thickness was increased. The relation between basal lamina area thickening and peripheral vascular disease of the legs in CIAP may indicate a role for ischemia in the development of this polyneuropathy.

The objective of the study was to determine the diagnostic value of features of demyelination and inflammation in sural nerve biopsy specimens of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The features of (i) demyelination, (ii) axonal de- and regeneration and (iii) inflammation were investigated by measuring the number of onion bulbs, g ratio (axon diameter/total nerve fibre diameter), myelinated nerve fibre density, number of clusters and endoneurial area in 21 patients with CIDP, as well as in 13 patients with chronic idiopathic axonal polyneuropathy (CIAP) and six autopsy controls. In addition, teased fibres were classified and lengths of internodes measured. We found no difference in demyelinating features between patients with CIDP and CIAP, as the percentage of fibres with segmental de- and remyelination and the number of onion bulbs were similar in both polyneuropathy groups. The g ratio, expected to be higher in a demyelinating disease due to thinner myelin sheaths, was significantly lower in CIDP than CIAP. Evidence for axonal degeneration was found in both CIDP and CIAP, as both showed a decrease in myelinated nerve fibre density. There was no evidence of endoneurial oedema in CIDP, as the endoneurial area did not differ between CIDP, CIAP and the autopsy controls. Although significant differences of features of demyelination, axonal degeneration and inflammation were found in sural nerve biopsy specimens, there was a considerable overlap between abnormalities in CIDP and CIAP patients. In the majority of patients, quantitative analysis of light microscopical abnormalities in sural nerves was similar in CIDP and CIAP. Therefore, a sural nerve biopsy is of limited diagnostic value in CIDP.

Chronic idiopathic axonal polyneuropathy is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, it reduces quality of life. To assess whether drug therapy for chronic idiopathic axonal polyneuropathy reduces disability, ameliorates neurological symptoms and associated impairments, and whether treatment is safe. We searched Cochrane Library (Cochrane Neuromuscular Disease Review Group Register, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Reviews of Effectiveness, and the Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, ISI, and ACP Journal Club's Best Evidence, from 1981 until December 2002. We also hand searched the reference lists of relevant articles, reviews and textbooks identified electronically, and contacted authors and other experts in the field to identify additional studies. We sought all randomised or quasi-randomised (alternate or other systematic treatment allocation), unconfounded trials that examined the effects of any drug therapy in patients with chronic idiopathic axonal polyneuropathy at least one year after the onset of treatment. Patients with chronic idiopathic axonal polyneuropathy had to fulfil the following criteria: age 40 years or older, distal sensory or sensorimotor polyneuropathy, absence of systemic or other neurological disease, chronic clinical course not reaching a nadir in less than two months, exclusion of any recognised cause of the polyneuropathy by medical history taking, clinical or laboratory investigations, electrophysiological studies in agreement with axonal polyneuropathy without evidence of demyelinating features. The primary outcome was the proportion of patients with a significant improvement in disability. Secondary outcomes were change in the mean disability score, change in the proportion of patients who make use of walking aids, change in the mean Medical Research Council sum score, degree of pain relief and/or reduction of other positive sensory symptoms, change in the proportion of patients with pain or other positive sensory symptoms, and frequency of adverse effects. Two reviewers independently reviewed and extracted details of trial methodology and outcome data of all potentially relevant trials. Eighteen studies were identified and assessed for possible inclusion in the review, but all were excluded because of insufficient quality or lack of relevance. Even though chronic idiopathic axonal polyneuropathy has been clearly described and delineated, no adequate randomised or quasi-randomised controlled clinical treatment trials have been performed. In their absence there is no proven efficacious drug therapy.

Chronic idiopathic axonal polyneuropathy (CIAP) is a disorder with insidious onset and slow progression, where no etiology is identified despite appropriate investigations. We aimed to investigate the role of oxidative stress as a risk factor for the pathogenesis of CIAP. Sera of patients with CIAP were tested for protein carbonyl (PC) and 8-hydroxydeoxyguanosine (8H). As a control group, we recruited patients with gluten neuropathy. Twenty-one patients with CIAP and 21 controls were recruited. The two groups did not differ significantly regarding demographics or clinical characteristics (i.e., neuropathy type or disease severity). After adjusting for gender, having CIAP was positively correlated with both the 8H titer (standardized beta coefficient 0.349, p = 0.013) and the PC titer (standardized beta coefficient 0.469, p = 0.001). Oxidative stress appears to be increased in CIAP and might have a role in the pathogenesis of the disease.

Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.

Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, CIAP reduces quality of life. CIAP is diagnosed in 10% to 25% of people referred for evaluation of polyneuropathy. There is a need to gather and review emerging evidence on treatments, as the number of people affected is likely to increase in ageing populations. This is an update of a review first published in 2004 and previously updated in 2006, 2008, 2011 and 2013. To assess the effects of drug therapy for chronic idiopathic axonal polyneuropathy for reducing disability and ameliorating neurological symptoms and associated impairments, and to assess any adverse effects of treatment. In July 2016, we searched Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews in the Cochrane Library, MEDLINE, Embase, and the Web of Science. We searched two trials registries for ongoing trials. We also handsearched the reference lists of relevant articles, reviews and textbooks identified electronically, and we would have contacted authors and other experts in the field to identify additional studies if this seemed useful. We sought all randomised or quasi-randomised (alternate or other systematic treatment allocation) trials that examined the effects of any drug therapy in people with CIAP at least one year after the onset of treatment. People with CIAP had to fulfil the following criteria: age 40 years or older, distal sensory or sensorimotor polyneuropathy, absence of systemic or other neurological disease, chronic clinical course not reaching a nadir in less than two months, exclusion of any recognised cause of the polyneuropathy by medical history taking, clinical or laboratory investigations, and electrophysiological studies in agreement with axonal polyneuropathy, without evidence of demyelinating features. The primary outcome was the proportion of participants with a significant improvement in disability. Secondary outcomes were change in the mean disability score, change in the proportion of participants who make use of walking aids, change in the mean Medical Research Council sum score, degree of pain relief and/or reduction of other positive sensory symptoms, change in the proportion of participants with pain or other positive sensory symptoms, and frequency of adverse effects. Two review authors independently reviewed the results of the literature search and extracted details of trial methodology and outcome data of all potentially relevant trials. We identified 39 studies and assessed them for possible inclusion in the review, but we excluded all of them because of insufficient quality or lack of relevance. We summarised evidence from non-randomised studies in the Discussion. Even though CIAP has been clearly described and delineated, no adequate randomised or quasi-randomised controlled clinical treatment trials have been performed. In their absence there is no proven efficacious drug therapy.

Studying the comorbidities of chronic idiopathic axonal polyneuropathy (CIAP) might help to better understand its etiopathogenesis. We aimed to assess the associations of mitochondrial disease (MD), Alzheimer's disease (AD) and vascular dementia (VD) with CIAP. In this nested case-control study we included 2659 patients with CIAP identified from the Swedish Patient Register and 13 295 age- and sex-matched controls to assess the associations of MD, AD and VD with the subsequent risk of CIAP. We also conducted a follow-up study of the cases and controls to assess the risk of MD, AD or VD among patients with CIAP in comparison to individuals without CIAP. Individuals with MD had an increased risk of subsequent CIAP [odds ratio (OR), 4.17; 95% confidence intervals (CI), 1.27-13.65], whereas individuals with AD and VD had a decreased risk (OR, 0.18; 95% CI, 0.06-0.59 and OR, 0.17; 95% CI, 0.04-0.69). Patients with CIAP had a ninefold increased risk of subsequent MD [hazard ratio (HR), 9.37; 95% CI, 4.00-21.93], twofold increased risk of VD (HR, 1.97; 95% CI, 1.23-3.16), but no increased risk of AD (HR, 1.33; 95% CI, 0.89-1.98) compared with individuals without CIAP. We found a higher risk of MD among patients with CIAP, both before and after the diagnosis of CIAP. We found a higher risk of VD, but not AD, after the diagnosis of CIAP. The lower risks of AD and VD before CIAP might be due to a reduced surveillance of CIAP symptoms among patients with dementia.

BackgroundEarly diagnosis of hereditary ATTR polyneuropathy (ATTRv-PN) is important since treatment options have become available, which are most effective early in the disease course. ATTRv-PN is likely underdiagnosed as patients might be misdiagnosed with idiopathic polyneuropathy. It is uncertain if it is useful to test for TTR gene mutations in patients with a typical presentation for chronic idiopathic axonal polyneuropathy (CIAP) and which are the distinguishing clinical features.MethodsWe carried out a retrospective cohort study to assess the yield of TTR gene sequencing in patients with polyneuropathy and assessed if the identified patients with ATTRv-PN had a clinical presentation typical of CIAP. Additionally, we assessed which clinical features, including previously defined red flag symptoms, can differentiate between patients with CIAP and ATTRv-PN and assessed the performance of the TTR suspicion index.ResultsOut of 338 patients with polyneuropathy, 10 patients had a pathogenic TTR gene mutation (all p.Val50Met) and none had a clinical presentation typical of CIAP. Patients with ATTRv-PN more often had bilateral CTS, motor involvement of arms, cardiac involvement, family history suggestive of hATTRv, and autonomic symptoms than patients with CIAP. All patients with ATTRv-PN as well as 70% of patients with CIAP fulfilled the suspicion index.ConclusionRoutine TTR gene sequencing in patients with a typical presentation for CIAP is not useful. However, red flag symptoms can differentiate patients with ATTRv-PN from patients with CIAP. We propose an adjusted version of the TTR suspicion index to increase diagnostic yield.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10072-023-06859-w.