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Corresponding author. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, UK.
Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, UKThe North-West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
Department of Medicine, Section of Respiratory Medicine, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, DenmarkDepartment of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Neurology, Colentina Clinical Hospital, Bucharest, RomaniaDepartment of Clinical Neurosciences, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Peripheral neuropathy represents a prevalent comorbidity in COPD.
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Inflammation, advanced age, malnutrition, medications, smoking, hypoxia and hypercapnia predispose to polyneuropathy in COPD.
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Prevalent comorbidities of patients with COPD, such as cardiovascular or metabolic comorbidities, can also precipitate peripheral neuropathy.
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Screening strategies are needed to facilitate early diagnosis and treatment of polyneuropathy among patients with COPD.
Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory syndrome with systemic involvement leading to various cardiovascular, metabolic, and neurological comorbidities. It is well known that conditions associated with oxygen deprivation and metabolic disturbance are associated with polyneuropathy, but current data regarding the relationship between COPD and peripheral nervous system pathology is limited. This review summarizes the available data on the association between COPD and polyneuropathy, including possible pathophysiological mechanisms such as the role of hypoxia, proinflammatory state, and smoking in nerve damage; the role of cardiovascular and metabolic comorbidities, as well as the diagnostic methods and screening tools for identifying polyneuropathy. Furthermore, it outlines the available options for managing and preventing polyneuropathy in COPD patients. Overall, current data suggest that optimal screening strategies to diagnose polyneuropathy early should be implemented in COPD patients due to their relatively common association and the additional burden of polyneuropathy on quality of life.
Chronic obstructive pulmonary disease (COPD) is a condition that was traditionally characterized by irreversible or partially reversible airway obstruction. However, this definition is outdated, and the disease itself is no longer regarded as an isolated disease of the lungs. In fact, the systemic involvement in patients with COPD, and the interactions between COPD and its comorbidities, justify the description of a chronic systemic inflammatory syndrome. Patients with COPD often have a variety of comorbidities, including but not limited to cardiovascular, metabolic, gastrointestinal, pulmonary, and hematological diseases [
]. Many of the comorbidities in COPD have been regarded as the sequelae of the aging process and are related to the high prevalence of cardiovascular and metabolic disease in the elderly or smoking [
]. Recent advances demonstrate that the relationship between COPD and the nervous system is extensive, and patients are at increased risk of stroke, dementia, depression, and other neurological and psychiatric conditions even after controlling for the main confounding risk factors such as age and smoking [
]. It is well-known that systemic conditions associated with metabolic disturbance and oxygen deprivation are associated with polyneuropathy. However, data on the interplay between COPD and peripheral nervous system diseases are limited [
The terms “polyneuropathy” (PNP), “peripheral neuropathy” and “neuropathy” are distinct and should not be used interchangeably. Neuropathy is a general term for central and peripheral nervous systems disorders. Peripheral neuropathy refers to any peripheral nervous system disorder, including radiculopathies and mononeuropathies. In contrast, polyneuropathy implies a homogeneous process affecting peripheral nerves, specifically distal nerves, more severely than proximal ones [
]. PNP is one of the most common peripheral nervous system diseases in adults. Although it is prevalent, its exact etiology is unknown in 20–30% of cases. As a result, most of these patients remain diagnosed with chronic idiopathic axonal neuropathy [
There have been substantial advances in respiratory medicine and neurology and growing interest in neuropulmonology, which underlines the complex interconnection between the nervous and respiratory systems. It is also essential to optimize the management of patients where these pathologies co-exist, especially in the neurocritical care environment [
]. This is partially due to the lack of highly specialized neuropulmonology centers and specialists to assess these patients.
This review aims to summarize available data on the association between COPD and PNP and describe their pathophysiological links.
1.1 Methods
SC, IO, and AC performed the literature review for this narrative review using the terms “COPD” and “peripheral neuropathies” along with the MESH terms. The reference list of the articles was carefully reviewed as a potential source of information. The search was based on Medline, Scopus, and Google Scholar engines. Only studies that regarded the relation between COPD and PNP with available abstract or whole text in English were included. Selected publications were analysed and their synthesis was used to write the review and support the hypothesis of the relationship between COPD and PNP.
2. Results
2.1 Clinical data supporting the link between COPD and PNP
The first mention of a possible link between chronic hypoxia and peripheral neuropathy was made by Appenzeller et al. [
] in 1968, observing symmetrical bilateral neuropathy and muscle wasting. Since then, more observational case-control studies and even multi-center studies have proved that chronic hypoxia is a cause of peripheral neuropathy (Table 1).
Table 1Existing studies related to COPD and peripheral neuropathy.
62 patients with COPD without any neurological signs or symptoms, and 30 healthy volunteers with no known neurological or pulmonary diseases as controls
COPD group: 38 males; Control group: 17 males; Mean ages = 64.88 and 62.7 years, in COPD and control respectively
group D COPD patients
27 participants (44%) in the COPD group had sensory, and 36 (58%) participants had motor polyneuropathy
There was no difference in sensory neuropathy between the groups, but a significant difference was found in terms of motor neuropathy.
There were 21 studies with an available abstract or whole text published during 1981–2021, the majority being case-control studies with a relatively small number of subjects varying between 12 and 89 COPD patients. All studies involved COPD patients with a mean age of 55–65 years, with a significantly higher proportion of males. Most studies excluded patients with other potential causes for peripheral neuropathy such as metabolic conditions, chronic alcoholism, sarcoidosis, malignancy, traumatic lesions, neurotoxic drugs, toxins, and active smoking at the moment of inclusion. In most reports, there were no specific inclusion criteria regarding COPD characteristics involving patients with an extensive range from mild to severe forms. Only a few studies separated the patients into hypoxemic and non-hypoxemic [
The percentage of peripheral neuropathies in COPD patients varied between 15 and 93.8%, the majority being axonal sensory polyneuropathy. Only a reduced proportion had mixed types or additionally carpal tunnel syndrome [
]. Axonal polyneuropathy was confirmed on electrophysiology by low amplitude compound muscle action potentials (CMAP) and slight reduction of nerve conduction velocity in sensory action potentials (SNAP) [
]. Another interesting observation was that electrophysiological evidence of neuropathy was much more frequent than clinical evidence in COPD patients [
]. However, an early case-control study from 1984 presented contradictory data, showing that 94.7% of patients had EMG abnormalities, supporting the hypothesis of motor neuron involvement due to greater susceptibility of the spinal cells to anoxia and relative resistance to peripheral nerves instead of PNP [
]. Apart from sensory and motor dysfunction, autonomic dysfunction was described in one study. It assessed the presence of peripheral autonomic neuropathy in patients with COPD by performing an acetylcholine sweat-spot test. They revealed that patients with significantly worse FEV1 and arterial blood gases had worse autonomic function [
Almost all studies reported that neuropathy was predominantly distal, affecting lower limbs more often than upper limbs. Additionally, in most presented studies, peripheral neuropathy correlated with disease duration and hypoxemia severity; the longer the duration and the more severe hypoxia, the more severe peripheral neuropathy was [
]. Moreover, improvement in respiratory function may lead to progressive and significant improvement in CMAP and SNAP amplitude and motor and sensory conduction velocity or even normal electromyography in some cases, according to one study [
]. In contrast, another study demonstrated that with the pO2 elevation and pH decrease, the sensitive nerve conduction velocity of the median nerve was reduced [
]. Other significant determinants of peripheral neuropathy in COPD patients are base excess and ankle-brachial index, which affect the nerves' micromilieu and thus impact the development and degree of peripheral neuropathy [
Advanced age, malnutrition, COPD medications, in particular, systemic corticosteroids, smoking, and hypercapnia are potential contributing factors for developing polyneuropathy apart from chronic hypoxemia [
](21) (Fig. 1). Besides these, increased levels of circulating cytokines, reduced testosterone and Insulin-like growth factor 1 (IGF-1) levels have been possible mechanisms for the development of peripheral neuropathy and myopathy in COPD patients [
]. However, another study established no correlation between proinflammatory cytokines, C-reactive protein (CRP), and electrophysiological findings, although CRP and tumor necrosis factor α (TNF-α) levels were significantly increased and IGF-1 reduced in COPD patients [
]. Moreover, in a multi-center cohort study, no direct relationship between peripheral neuropathy and inflammation was observed, CRP being linked to physical capacity and not directly to PNP [
](23) revealed that almitrine, a peripharal respiratory stimulant, could have precipitated polyneuropathy in COPD patients. Nevertheless, this finding was not corroborated in other studies, that found no higher prevalence of PNP in COPD patients undergoing treatment with almitrine [
]. Oxidative stress may play a predominant role in hypoxia-related neuropathy because isolated nocturnal hypoxia induces the degradation of adenosine monophosphate and thus the production of adenine nucleotides, involved in the generation of free oxygen radicals during reoxygenation [
The mechanisms involved in inflammatory neuropathies include activation and increased expression of vascular cell adhesion molecules (VCAM-1, ICAM-1) and E-selectins on the endothelial cells, recruitment of inflammatory cells (leukocytes, monocytes, lymphocytes), the release of pro-inflammatory cytokines (TNF-α, IL-6, IL-1, and IL-18). This is accompanied by vascular wall stress, arterial smooth muscle cell proliferation, and lipid oxidation. Prolonged inflammation may also lead to reduced local production of endothelium-derived nitric oxide (NO), increased production of angiotensin II, free fatty acids (FFAs), and advanced glycation end products (AGEs) [
]. Even minor changes in local inflammatory status can lead to nerve dysfunction. For instance, elevated local proinflammatory cytokines can lead to small fiber neuropathy (SFN) - a subtype of sensory neuropathy with normal nerve conduction studies [
Cigarette smoking – frequently encountered in COPD patients, induces several potential neurotoxic actions, like exacerbation of tissue hypoxia by carbon monoxide, stimulative actions of nicotine, and interference of cyanogens with nerve function [
]. Moreover, high doses of nicotine acutely affect sensory and neuromuscular transmission because nicotine receptors are placed on axons and terminals of many sensory and motor nerve fibers [
]. The relationship between cigarette consumption and sensory nerve impairment is especially remarkable in patients with a smoking history exceeding 60 pack-years [
Chiefari E. Prevalence and Determinants of Peripheral Neuropathy Among Type 2 Adult Diabetes Patients Attending Jimma University Medical Center, Southwest Ethiopia, 2019, an Institutional-Based Cross-Sectional Study. J Diabetes Res [Internet,
20209562920https://doi.org/10.1155/2020/9562920
]. Furthermore, chronic smokers are four times more predisposed to have associated alcohol dependence - another known risk factor for developing polyneuropathy [
Therefore, cigarette smokers with COPD might have a higher predisposition to develop PNP than non-smokers.
2.2.4 Age as a factor for peripheral neuropathy
Age is also a significant risk factor and is independently associated with the condition even in patients with diabetes - the most common etiology of PNP [
]. Nonetheless, a high prevalence of non-diabetic PNP among adults ≥ 70 years of age suggests that there may be an unexplained loss of peripheral sensation among older adults (possibly idiopathic) that is underrecognized [
Cluster analysis of COPD patients usually identifies several phenotypes based on the degree of airway obstruction, frequency and type of exacerbations, systemic inflammation patterns, comorbidities, gender, and other characteristics [
]. Since up to 78.6% of patients with COPD have comorbidities, with an overall frequency of 2.6 comorbidities per patient (2.5 in males and 3.0 in females) [
], it is challenging to understand and/or define the comorbidome; cardiovascular comorbidities co-exist with metabolic. Moreover, identical clustering analyses across multiple COPD cohorts show modest reproducibility [
]. There is currently limited evidence on whether COPD phenotypes co-exist with PNP. The existing data indicate that PNP can be present in cardiovascular and metabolic disease patients, chronic inflammation, and hypoxia [
]. The ankle-brachial index is one of the significant determinants of PNP in patients with COPD supporting the idea that nerve damage has a vascular origin [
]. However, an inverse relationship between hypertension and PNP was also reported. History of hypertension specifically, and not other hypertension-related variables, was negatively associated with age-associated peripheral neuropathy after controlling for age and body mass index. However, the study was cross-sectional, so the results require validation in other similar studies [
Further investigation of the negative association between hypertension and peripheral neuropathy in the elderly: an Oklahoma physicians resource/research network (OKPRN) study.
J. Am. Board Fam. Med.2006 May 1; 19 (LP – 250. Available from:): 240
Diabetic neuropathy is a well-recognized condition that causes sensory, autonomic, and motor axon damage, in which axonal degeneration is a primary mechanism. In addition, chronic hyperglycemia affects Schwann cells and causes demyelination [
Sunada Y. Kato T. Small Fiber Neuropathy Associated with Hyperlipidemia: Utility of Cutaneous Silent Periods and Autonomic Tests. 2014579242https://doi.org/10.1155/2014/579242
]. Plasma lipid levels are associated with many peripheral neuropathies, including axonal distal polyneuropathy, vision and hearing loss, motor nervous system lesions, and sympathetic nervous system dysfunction. Cholesterol, triacylglycerols, and lipoprotein affect the pathogenesis of these neuropathies [
Acute exacerbation of COPD is associated with several harmful factors to the nervous and muscular system, including infection, nutrition, hypoxia, hypercapnia, electrolyte derangements, comorbidities, systemic inflammation, glucocorticoids, and invasive ventilation [
]. Polyneuropathy associated with invasive ventilation is not only a consequence of the procedure but is also related to organ dysfunction, the severity of the condition, and mortality [
In order to establish a diagnosis of peripheral neuropathy, more specifically polyneuropathy, the most common type of neuropathy accounted for in COPD patients, a combination of symptoms and signs along with electrodiagnostic studies are required. When signs and electrodiagnostic studies diverge, there is a lower likelihood of polyneuropathy [
Distal symmetric polyneuropathy: a definition for clinical research: report of the American academy of neurology, the American association of electrodiagnostic medicine, and the American academy of physical medicine and rehabilitation.
serum glucose, hemoglobin A1c (Hb1Ac), vitamin B12, serum folate, serum and urine protein electrophoresis, thyroid function, erythrocyte sedimentation rate, HIV serology, heavy metals in urine/blood, porphyrins in urine/blood, rheumatoid factor, Sjögren syndrome antibodies, anti-Hu antibodies, Lyme testing, vitamin B1 level, methylmalonic acid homocysteine levels and screening for hepatitis B and C [
axonal degeneration and demyelination, thickening of the basement membrane, narrowing of the lumen, pericytic mural debris, nerve capillary endothelial-cell hyperplasia, hypertrophy, nerve perineurium thickening [
Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnost.
The typical clinical presentation varies but usually follows the course of chronic axonal polyneuropathies. Therefore, the first symptoms appear distally in the lower extremities, sensory symptoms preceding the motor ones. Patients report a slowly progressive sensory loss and dysesthesias like numbness, burning sensation, and pain, accompanied by mild gait impairment. With disease progression, mild weakness might appear initially in the lower legs, followed by hand symptoms, leading to the classic “glove and stocking” sensory loss distribution, and numbness may ascend proximally [
On neurological examination, a distal loss of pinprick, light touch, vibration, temperature, and proprioception sensation are observed. Deep tendon reflexes are usually diminished or even absent [
3.1.1 Muscle wasting/strength as an indicator of peripheral neuropathy in COPD
It is well known that the strength of skeletal and respiratory muscles is reduced in COPD compared to the average population and generalized muscle weakness suggests systemic muscular involvement [
]. Muscle strength also contributes to symptom intensity as a two-fold increase in muscle strength is associated with a 25–30% decrease in the intensity of both leg effort and dyspnea and a 1.4- to 1.6-fold increase in work capacity [
]. PNP occurrence is correlated with the degree of smoking intoxication, the length of COPD, and the depth of hypoxemia. It can be one factor that leads to muscle wasting as it is also subclinical and under-recognized [
Handgrip strength is a simple, accessible, and inexpensive test to measure hand muscle strength. It can also indicate overall muscle strength and correlates with the strength of other muscles such as upper limb muscles, lower limb muscles, and respiratory muscles in COPD.
In subjects with COPD exacerbation, the handgrip strength is lower than that of stable COPD patients, and this difference was not explained by age, comorbidities, the severity of obstruction, or smoking. Handgrip strength also correlates with the 6-min walking distance (6MWD) test and can be used when the 6MWD cannot be performed [
]. Handgrip muscle strength decreases as the forced vital capacity (FVC) and forced expiratory volume (FEV₁) decrease in patients with COPD. This association can be partially explained by decreased respiratory muscle strength [
The 6MWD test is an objective and inexpensive method to assess submaximal exercise capacity. 6MWD test is used clinically to measure the impact of multiple comorbidities, including cardiovascular disease, lung disease, arthritis, diabetes, cognitive dysfunction, and depression, on exercise capacity and endurance in adults [
Electrodiagnostic testing is performed with electromyography (EMG) and/or nerve conduction studies (NCS). In the majority of patients, axonal polyneuropathy is identified [
]. Axonal neuropathies are defined by a diminished amplitude of evoked compound action potentials with relative nerve conduction velocity preservation [
]. Usually, sensory nerves initially display electrophysiological abnormalities through reduced sensory nerve action potentials (SNAPs), followed by compound muscle action potentials (CMAPs), probably due to their lack of compensatory reinnervation. In contrast, CMAP amplitudes can appear normal until more than 75% of the axons are affected due to collateral sprouting in motor nerves [
]. To distinguish a primarily axonal impairment in cases where demyelinating features overlap or there is secondary demyelination due to prominent axonal loss, Tankisi et al. [
] elaborated a series of criteria for electrophysiological polyneuropathy classification. According to them, there have to be at least two nerves (sensory and/or motor) meeting the criteria for axonal loss, specifically a reduction in SNAP or CMAP amplitude with at least 2.5 standard deviations and a minor reduction in conduction velocity/distal motor latency by up to 2.5 standard deviations along with consistent EMG findings [
To exclude other possible causes for axonal neuropathy, the following laboratory tests should be performed: serum glucose and glycated hemoglobin (Hb1Ac), serum vitamin B12 and folate, serum and urine protein electrophoresis, thyroid function, and erythrocyte sedimentation rate. In case of suggestive history, additional testing should be performed for HIV serology, heavy metals in urine/blood, porphyrins in urine/blood, rheumatoid factor, testing for Sjögren syndrome, anti-Hu antibodies, Lyme testing, vitamin B1 level, methylmalonic acid homocysteine levels and screening for hepatitis B and C [
Nerve biopsy is usually not indicated as a diagnostic tool for peripheral neuropathies in COPD patients. It is generally reserved for differential diagnosis when vasculitis or amyloidosis is suspected and there is no supportive evidence from other paraclinical tests [
]. In a French study, axonal degeneration and demyelination were observed in all cases, and the morphometric analysis revealed fiber density reduction [
]. Regarding the pathological modifications in the endoneurial structure of nerve microvessels detected on histology: thickening of the basement membrane, narrowing of the lumen, and pericytic mural debris were observed in COPD patients [
]. Besides nerve capillary endothelial-cell hyperplasia and hypertrophy, which lead to luminal occlusion, nerve perineurium thickens, thus impeding the transport of oxygen and nutrients [
High-resolution nerve sonography and magnetic resonance imaging (MRI) could be used as diagnostic tools in peripheral neuropathies, as they are non-invasive and well tolerated. However, these are still scarcely used, mainly for immune-mediated neuropathies [
]. Nerve sonography also has the advantage of being relatively affordable, providing access to small fibers and peripheral nerves since they usually display a superficial course and rapidly assess the course of a long nerve [
To determine a potential autonomic dysfunction, which is usually specific for small fiber sensory neuropathy but has also been described in hypoxia-induced neuropathy, the composite autonomic scoring scale (CASS) can be used. It includes the measurement of orthostatic blood pressure, the quantitative sudomotor axon reflex test, heart rate variability with deep breathing and in response to tilt, and changes in blood pressure with the Valsalva maneuver [
Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnost.
Peripheral neuropathy screening should include, in all cases, a careful history along with a simple neurologic examination. Specific screening tests for peripheral neuropathy in COPD patients are lacking; most screening tests are directed at diabetic and chemotherapy-induced neuropathy.
The most commonly used tests for diabetic peripheral neuropathy, which also manifests very often as an axonal sensorimotor polyneuropathy, are the Michigan Neuropathy Screening Instrument (MNSI) [
]. For chemotherapy-induced peripheral neuropathy, several specific questionnaires are used, such as a patient-reported one – FACT-GOG/Ntx-11, a clinician-rated one – Total Neuropathy Score (TNSr), or clinical screening tools – National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) (also clinician-rated), Patient-reported outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Neurotoxicity Questionnaire (PNQ) [
]. Some of these screening tools could also be tested on COPD patients for PNP, but more precise and dedicated tools are needed.
3.8 Health-related quality of life in patients with peripheral neuropathy – a measure of disability
Health-related quality of life (HRQoL) is usually defined as a multi-dimensional concept, namely the subjective individual feeling of the effects of a disease and its treatment on the physical, mental, and social aspects of life [
]. HRQoL is usually evaluated using generic instruments applied for most pathologies. For example, a few generic instruments are used in diabetic neuropathy, such as Short Form surveys - SF-36 [
Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics.
How do changes in pain severity levels correspond to changes in health status and function in patients with painful diabetic peripheral neuropathy? Pain.
]. SF-36 includes the domains of physical functioning (10 items), role functioning-physical (4 items), role functioning-emotional (3 items), social functioning (2 items), body pain (2 items), mental health (5 items), vitality (4 items), general health perception (5 items), plus the change in health [
According to a study that developed a comprehensive measure of HRQoL for peripheral neuropathy, tested on diabetic neuropathy, including a generic core and a neuropathy-targeted supplement, the inclusion of peripheral neuropathy-targeted items to the generic ones leads to improved construct responsiveness and validity [
]. Comparing this scale to SF-36 HRQoL revealed that neuropathy has an additional influence on the HRQoL. Thus such a targeted score could be more helpful for these patients. Other diabetic neuropathy-specific measures like Peripheral Neuropathy Quality of Life instrument (PN-QOL-97), Norfolk QOL-DN, and NeuroQoL have been developed, out of which Norfolk QOL-DN and PN-QOL-97 were evaluated as the strongest ones [
]. On the other hand, another study showed that the SF-36 is a helpful generic instrument to reliably appreciate the HRQoL in patients with chronic inflammatory demyelinating polyneuropathy [
In COPD patients, a targeted measurement for evaluating the HRQoL has not been established yet, applying only generic instruments. Nevertheless, it was observed that life-quality scores were significantly reduced, especially in patients with COPD and PNP, than in COPD alone and even more than in healthy control subjects [
An extensive list of already established drugs are tested for their potential neuroprotective role, and others are developed specifically for this purpose. However, none has demonstrated high efficacy. Among these are hormones, such as progesterone [
Nerve regeneration and pharmacological suppression of the scar reaction at the suture site. An experimental study on the effect of estrogen-progesterone, methylprednisolone-acetate and cis-hydroxyproline in rat sciatic nerve.
However, it was remarked that by axonal transection or exposure to toxic drugs, periaxonal Schwann cells upregulate their erythropoietin expression, the usual injury signal that activates the hypoxia-inducible factor-1 – the erythropoietin key regulator in Schwann cells is nitric oxide [
]. Moreover, administration of exogenous erythropoietin seems to have neuroprotective properties, according to a study performed on patients with chemotherapy-induced neuropathy [
]. Among other agents with a potential neuroprotective role tested in chemotherapy-induced neuropathies are: lithium, which ameliorated the mixed sensorimotor neuropathy induced by vincristine, probably by inhibiting the glycogen synthase kinase-3 (GSK3β) [
]; melatonin – reduced the oxaliplatin-induced pain behavior and neuropathic deficits in rats as well as improved the mitochondrial electron transport chain function and the ATP levels and prevented oxaliplatin-induced neuronal apoptosis by accelerating the autophagy pathway in peripheral nerves and dorsal root ganglion [
Regarding diabetic peripheral neuropathy, several agents have the potential to exert neuroprotection. For example, resveratrol demonstrates a considerable range of biological activities, including antioxidant, anti-inflammatory, and chemoprotective [
]. Folic acid - another potential neuroprotective agent- increases the expression of nerve growth factor, leading to increased CMAP amplitudes and reduced peripheral nerve fibrosis [
Other studies are directed at elaborating more productive ways of drug delivery, such as electrospun composite nanofibers incorporating alpha-lipoic acid and atorvastatin, which are sequentially released [
], was liberated faster to exercise a neuroprotective effect in the early phase of neuronal injury, and afterward, it was followed by the release of atorvastatin – which also seems to exert a neuroprotective action [
Antioxidants are a traditional heterogeneous group of medications that may be useful for prophylaxis of nerve damage. Generally, antioxidants have two primary goals. They reduce the harmful effects of free radicals by decreasing their formation or scavenging and inactivating them. Alternatively, they increase the activity of antioxidant enzymes or other proteins involved in antioxidant pathways [
One of the major antioxidant groups is flavonoids, which have been claimed to affect the peripheral nervous system positively. Flavonoids have a selective affinity for GABAA receptors which helps treat diabetic and chemotherapy-induced PNP [
Dietary antioxidants are vitamins A, C, and E that act as natural detoxifiers of free radicals or interact with recycling processes. Vitamin E is one of the most studied vitamins with antioxidative properties and has been reported to alleviate symptoms of diabetes and diabetes-induced complications by reduction of oxidative stress, a positive effect on neural system development and differentiation [
Some vitamin-like substances such as coenzyme Q10 may also positively affect COPD and PNP. Coenzyme Q10 was found to be effective in restoring and improving nerve conduction, particularly in diabetic PNP [
Alpha-lipoic acid is a well-known medication used in diabetic PNP that delays or reverses nerve damage through its multiple antioxidant properties, primarily by increasing reduced glutathione [
]. A meta-analysis of randomized controlled trials demonstrated that when given intravenously at a 600 mg/day dosage for three weeks, alpha-lipoic acid leads to a significant and clinically relevant reduction in neuropathic pain [
]. Among the aldose reductase inhibitors, the most studied is epalrestat, while others such as tolrestat, zenarestat, and ponalrestat were withdrawn due to inefficacy or safety concerns [
]. Ruboxistaurin, a protein kinase C inhibitor with antioxidant effects, improved nerve conduction velocity and endoneurial blood flow in diabetic rats but failed to demonstrate efficacy in clinical practice. However, it appeared to benefit the subgroup of patients with less severe symptomatic PNP [
Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial.
Current therapy for COPD includes a list of medications that may have positive and negative effects on the peripheral nervous system, such as short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), short-acting muscarinic antagonists (SAMA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), oral steroids and oxygen supplementation.
4.2.1 Beta-agonists
The expression of beta-2-adrenoceptors within the nociceptive nervous system suggests a potential role in pain and nociception. Notably, beta-2-agonists participate in the antiallodynic action of antidepressant drugs and might implicate the endogenous opioid system [
. Beta-2-agonists may have a protective effect on the treatment of chronic neuropathic pain. In a rat model, it was demonstrated that chronic but not acute stimulation of beta-2- adrenoceptors with agonists such as clenbuterol, formoterol, metaproterenol, and procaterol suppressed neuropathic allodynia [
]. Similar results were found with activation of β2-adrenoreceptor with formoterol in paclitaxel-induced neuropathic pain due to induction of mitochondrial biogenesis [
Muscarinic antagonists have several positive effects on the nervous system. In vitro, they promote sensory neurite outgrowth. In vivo, using rodents models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy have been shown to prevent and reverse peripheral neuropathy. Topical delivery of muscarinic antagonists may be a practical therapeutic approach to treating diabetic and other peripheral neuropathies [
Pharmacological blockade of muscarinic 1 receptor using pirenzepine activates AMPK and helps to overcome diabetes-induced mitochondrial dysfunction in vitro and in vivo. This effect prevents PNP and results in depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes [
]. These findings were reinforced by a randomized placebo-controlled, double-blinded study where 40 patients with type 2 diabetes mellitus received topical 3% oxybutynin and were assessed at baseline and after 20 weeks of treatment. Intraepidermal nerve fiber density improved significantly after 20 weeks for the treatment group. Neuropathy scores and quality of life also improved considerably in the treatment group. No improvements were seen in the placebo group [
A systematic review and meta-analysis of 32 articles demonstrated that long-term corticosteroid exposure is associated with hypertension (prevalence >30%); bone fracture (21%–30%); cataract (1%–3%); nausea, vomiting, and other gastrointestinal conditions (1%–5%); and metabolic issues (e.g., weight gain, hyperglycemia, and type 2 diabetes; cases had 4-fold the risk of controls) [
]. Extrapolating from their effect on glucose and vasculature, systemic and inhaled corticosteroids are likely to be risk factors for PNP development in patients with COPD and asthma and their overlap.
4.2.4 Oxygen support and treatment
Hypoxia is a well-known risk factor for nerve damage and dysfunction. Chronic hypoxemia in COPD patients is associated with an accentuation in EMG changes in both low and high-frequency bands for adductor pollicis and diaphragm. Inhalation of oxygen-enriched gas mixture for 15 min significantly increased skeletal muscle's maximal performances in chronic hypoxemic patients [
]. Although this does not directly prove a positive effect on the peripheral nervous system, it is safe to assume that oxygen supplementation benefits the nervous system.
Hyperbaric oxygen therapy demonstrated enhanced healing of ischaemic, non-healing diabetic leg ulcers [
] associated with PNP and atherosclerosis, and therefore hyperbaric oxygen may positively affect the nervous system. Hyperbaric oxygen demonstrated antinociceptive and analgesic effects in animal models of inflammatory, neuropathic, and chronic pain. In human studies, hyperbaric oxygen therapy showed beneficial effects on clinical outcomes such as pain scores, pain-related symptoms, and quality of life [
Simultaneous hyperbaric oxygen therapy during systemic chemotherapy reverses chemotherapy-induced peripheral neuropathy by inhibiting TLR4 and TRPV1 activation in the central and peripheral nervous system.
According to literature, PNP is frequently present in COPD patients with a prevalence ranging between 15 and 93.8%, the majority being axonal sensory polyneuropathy [
], but an association with the severity of COPD has not been established (Table 1). Moreover, the current data do not indicate a relationship between COPD stages, GOLD classification, or degree of obstruction and PNP.
Although the common occurrence of comorbidities that predispose COPD patients to develop PNP, such as diabetes mellitus, cardiovascular ones, and the negative influence of some COPD medication options, a clear relationship between PNP and hypoxia was established, specifically the longer the duration and the more severe hypoxia, the more severe peripheral neuropathy was [
]. As elevated base excess seems to reflect the compensation of intermittent chronic nocturnal hypoxemia in stable COPD patients, it may be a marker of prolonged homeostasis modifications leading to comorbidities such as peripheral neuropathy [
]. Apart from this, other aspects of disability in PNP related to COPD are related to the impairment of sensory and motor functions, responsible to gait impairment as well as an increased level of pain. This leads eventually to impairment of activities of daily living and finally to a reduced HRQoL(32). Therefore, it is crucial to screen all COPD patients for the presence of PNP clinically and with electrodiagnostic studies. As yet, no specific screening tools for COPD-related PNP have been elaborated. Screening questionnaires for diabetic neuropathy or other etiologies could also be tried in COPD patients due to mutual pathophysiological mechanisms of these types of PNP, but more specialized tools are required.
Regarding treatment, necessary to mention is that specialized treatment options for COPD patients with PNP are still lacking. Although, improvement in respiratory function may lead to the reversal of hypoxia-induced peripheral nerve lesions, according to electrophysiological studies [
]. Therefore, correction of chronic hypoxemia in COPD patients could also ameliorate PNP in these patients. Additionally, COPD patients could benefit from beta-agonists, muscarinic agents, antioxidants, and neuroprotectors, traditionally prescribed for various peripheral nerve pathologies. However, systemic corticosteroids are considered risk factors for PNP evolution. Therefore, they should be used judiciously in COPD patients with PNP.
The discrepancies in the observed publications related to PNP in COPD could be related to the reduced number of subjects, lack of a control group in some studies, patient inclusion and exclusion criteria, such as demographic characteristics, COPD definition, and phenotypes, as well as the clinical and electrophysiological criteria used for establishing the diagnosis of PNP.
6. Conclusions
Current data indicate that multiple common risk factors in patients with COPD can contribute to the development of PNP. Therefore, the association between COPD and PNP may be secondary, caused by confounding factors such as smoking, age, and comorbidities. However likely, COPD is also a significant risk factor, especially in patients with hypoxia. Optimal screening strategies should be implemented since PNP can impact cardiovascular and metabolic comorbidities and serves as a risk factor for decreased quality of life. The treatment options of PNP are limited, but there is extensive evidence from studies of PNP in patients with diabetes, which can be implemented in clinical practice as COPD shares multiple pathophysiological mechanisms similar to diabetes.
Declaration of competing interest
The authors report no external funding or conflicts of interest related to this review.
Acknowledgements
AGM is supported by the National Institute for Health Research Manchester Biomedical Research Centre (NIHR Manchester BRC) and by an NIHR Clinical Lectureship.
Abbreviations
AGEs
Advanced glycation end products
AP-1
Activator protein 1
BMI
Body mass index
CASCO
CAchexia SCOre
CASS
Composite autonomic scoring scale
CMAP
Compound muscle action potential
COPD
Chronic Obstructive Pulmonary Disease
CRP
C reactive protein
EMG
Electromyography
EQ-5D
EuroQol five-dimensional
FFAs
Free fatty acids
FEV1
Forced expiratory volume in 1 s
FVC
Forced vital capacity
GSK3β
Glycogen synthase kinase-3
HRQoL
Health-related quality of life
ICAM-1
Intercellular cell adhesion molecule 1
ICS
Inhaled corticosteroids
IGF-1
Insulin-like growth factor 1
IL-6, IL-1, IL-18
Interleukin 6, 1, 18
LABA
Long-acting beta-agonists
LAMA
Long-acting muscarinic antagonists
MNSI
Michigan Neuropathy Screening Instrument
MRI
Magnetic resonance imaging
6-MWD
6-min walking distance
NCI-CTCAE
National Cancer Institute, Common Terminology Criteria for Adverse Events
NCS
Nerve conduction studies
NO
Nitric oxide
NSAIDs
Non-steroidal anti-inflammatory drugs
PNP
Polyneuropathy
PNQ
Patient Neurotoxicity Questionnaire
PN-QOL-97
Peripheral Neuropathy Quality of Life instrument
PRO-CTCAE
Patient-reported outcomes, Common Terminology Criteria for Adverse Events
TNF-α
Tumor necrosis factor α
TNSr
Total Neuropathy Score
SABA
Short-acting beta-agonists
SAMA
Short-acting muscarinic antagonists
SF-36
Short Form survey 36
SFN
Small fiber neuropathy
SGRQ
St. George's Respiratory Questionnaire
SNAPs
Sensory nerve action potentials
UENS
Utah Early Neuropathy Scale
VCAM-1
Vascular cell adhesion molecule 1
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