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Year : 2006  |  Volume : 23  |  Issue : 1  |  Page : 25-33 Table of Contents   

Chronic obstructive pulmonary disease and peripheral neuropathy

1 Department of Tuberculosis & Respiratory Medicine, Postgraduate Institute of Medical Sciences, Rohtak., India
2 Department of Physiology, Postgraduate Institute of Medical Sciences, Rohtak., India

Correspondence Address:
Prem Prakash Gupta
9J/17, Medical Enclave, PGIMS, Rohtak-124 001.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-2113.44427

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death world-wide and a further increase in the prevalence as well as mortality of the disease is predicted for coming decades. There is now an increased appreciation for the need to build awareness regarding COPD and to help the thousands of people who suffer from this disease and die prematurely from COPD or its associated complication(s). Peripheral neuropathy in COPD has received scanty attention despite the fact that very often clinicians come across COPD patients having clinical features suggestive of peripheral neuropathy. Electrophysiological tests like nerve conduction studies are required to distinguish between axonal and demyelinating type of disorder that cannot be analyzed by clinical examination alone. However, various studies addressing peripheral neuropathy in COPD carried out so far have included patients with COPD having markedly varying baseline characteristics like severe hypoxemia, elderly patients, those with long duration of illness, etc. that are not uniform across the studies and make it difficult to interpret the results to a consistent conclusion. Almost one-third of COPD patients have clinical evidence of peripheral neuropathy and two-thirds have electrophysiological abnormalities. Some patients with no clinical indication of peripheral neuropathy do have electrophysiological deficit suggestive of peripheral neuropathy. The more frequent presentation consists of a polyneuropathy that is subclinical or with predominantly sensory signs, and the neurophysiological and pathological features of predominantly axonal neuropathy. The presumed etiopathogenic factors are multiple: chronic hypoxia, tobacco smoke, alcoholism, malnutrition and adverse effects of certain drugs.

Keywords: COPD, Peripheral neuropathy, Electrophysiological studies, Nerve conduction studies, Axonal degeneration

How to cite this article:
Gupta PP, Agarwal D. Chronic obstructive pulmonary disease and peripheral neuropathy. Lung India 2006;23:25-33

How to cite this URL:
Gupta PP, Agarwal D. Chronic obstructive pulmonary disease and peripheral neuropathy. Lung India [serial online] 2006 [cited 2021 Jun 14];23:25-33. Available from: https://www.lungindia.com/text.asp?2006/23/1/25/44427

   Introduction Top

Chronic obstructive pulmonary disease (COPD) has been a major public health problem worldwide. It is the fourth leading cause of chronic morbidity and mortality in the United States [1] , is the fourth leading cause of death in the world [2] , and further increase in the prevalence and mortality of the disease is predicted for coming decades. There is now an increased recognition for the need to create awareness regarding COPD and to help the thousands of people who suffer from this disease and die prematurely from COPD or its associated complication(s). As a result, a committed group of scientists encouraged the US National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [3] . The initial step in the GOLD program was to prepare a Consensus Workshop Report, Global Strategy for the Diagnosis, Management, and Prevention of COPD.

   Definition Top

COPD is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases [3] . Poorly reversible airflow limitation commonly observed in bronchiectasis, cystic fibrosis, tuberculosis, or asthma is not included except in so far as these conditions overlap with COPD.

   Pathogenesis Top

COPD is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. Macrophages, T lymphocytes (predominantly CD8+), and neutrophils are increased in various parts of the lung. Activated inflammatory cells release a variety of mediators - including leukotriene B4 (LTB4) [4] , interleukin 8 (IL-8) [5],[6],[7] , tumor necrosis factor alpha (TNF-alpha) [5],[8] and others - capable of damaging lung structures and/or supporting neutrophilic inflammation. In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and antiproteinases in the lung, and the oxidative stress. Inflammation of the lungs is caused by exposure to inhaled noxious particles and gases. Cigarette smoke can induce inflammation and directly damage the lungs [9],[10],[11],[12],[13],[14] . Although not much of data is available, it is likely that other COPD risk factors can initiate a similar inflammatory process. It is assumed that this inflammation can then lead to COPD.

   Pathophysiology Top

Pathological changes in the lungs lead to corresponding physiological changes characteristic of the disease, including mucus hypersecretion, ciliary dysfunction, airflow limitation, pulmonary hyperinflation, gas exchange abnormalities, pulmonary hypertension, and cor pulmonale. They usually develop in this order over the course of the disease. Mucus hypersecretion and ciliary dysfunction generally lead to chronic cough and sputum production. These symptoms can be present for many years before other symptoms or physiological abnormalities develop.

Expiratory airflow limitation is the hallmark physiological change of COPD [2] and the key to diagnosis of the disease. It is primarily due to fixed airways obstruction and the consequent increase in airways resistance. Destruction of alveolar attachments, which inhibits the ability of the small airways to maintain patency, plays a smaller role. In advanced COPD, peripheral airways obstruction, parenchymal destruction, and pulmonary vascular abnormalities reduce the lung capacity for gas exchange, producing hypoxemia and, later on, hypercapnia. Pulmonary hypertension, which develops late in the course of COPD, is the major cardiovascular complication of COPD. It is associated with the development of cor pulmonale and a poor prognosis [20] .

   Epidemiology Top

COPD is primarily a disease of the adult. Its prevalence reported in different population-based studies from India is highly variable [21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32] . A regional difference in prevalence has also been reported. The prevalence rates in male subjects of 2.12% to 9.4% in studies reported from North India are generally higher than 1.4% to 4.08% reported from South India. The respective ranges for female subjects vary from 1.33% to 4.9% from North and from 2.55% to 2.7% from South India. For epidemiological consideration, the rounded-off median prevalence rates were estimated as 5% for male and 2.7% for female subjects having an age of 30 years or more. The disease is particularly more common in males. The male to female ratio had varied from 1.32:1 to 2.6:1 in different studies with a median ratio of 1.6:1.

The various presently known etiological risk factors are briefly described below:

Smoking: Tobacco smoke, a mixture of more than 4000 chemical constituents, is the most significant recognized cause. Amongst males, tobacco smoking is responsible in more than 80% of patients [21],[33] . Both cigarette and bidi smoking are equally responsible for the development of COPD [33] . Pipe and hookah smoking are also important. There is no reliable information on smoking associated COPD in women in whom the overall prevalence of smoking is low. Besides active tobacco smoking, passive smoking better termed as environmental tobacco smoke (ETS) exposure, may also play a noteworthy contributory role especially in non-smoker individuals including women [34],[35] .

Smoke from Solid Fuel Combustion: The smoke from combustion of solid fuels such as wood, dried dung, and crop residue used for cooking and heating, is a significant cause of indoor air pollution. It is accountable for a large number of COPD in the rural inhabitants in general and women, in particular [36],[37],[38],[39] .

Outdoor Air Pollution: Exhausts from vehicles and industrial units; dusts, fumes and smoke from burning of crop residues in the fields constitute important sources of air pollution. Chronic exposure to polluted air has been identified as a vital cause of COPD [40],[41] .

   Host Factors Top

Genes: Many genetic factors are believed to increase (or decrease) a person's risk of developing COPD. A genetic risk factor that is well studied is hereditary deficiency of alpha-1 antitrypsin [42],[43],[44] . The severe deficiency of alpha-1 antitrypsin is associated with a premature and accelerated development of panlobular emphysema and decline in lung function in many smokers and nonsmokers, although smoking increases the risk substantially.

Airway Hyperresponsiveness: Asthma and airway hyperresponsiveness, recognized as risk factors that add to the development of COPD [45] , are related to a number of genetic and environmental factors. Airway hyperresponsiveness may also develop after exposure to tobacco smoke or other environmental insults and thus may be a result of smoking- related airways disease.

Lung Growth: Lung growth is related to processes occurring during gestation, birth eight, and exposures during childhood [46],[47] . Reduced maximal attained lung function may identify individuals who are at increased risk for the development of COPD.

   Diagnosis Top

A diagnosis of COPD is considered in any patient who has cough, sputum production, or dyspnoea, and/ or a history of exposure to known risk factors. The diagnosis is confirmed by an objective measure of airflow limitation (spirometry). Chronic cough, usually the first symptom 48 of COPD to develop, may be intermittent in the beginning, but later is present every day, often throughout the day. Small quantities of tenacious sputum are usually raised by COPD patients after coughing bouts. Dyspnoea is the basis why most patients usually seek medical attention. As lung functions worsen, breathlessness becomes more disturbing. Wheezing and chest tightness are relatively nonspecific symptoms. Physical signs of airflow limitation are rarely present until significant impairment of lung function has occurred [49],[50] , and their detection has a relatively low sensitivity and specificity.

Measurement of Airflow Limitation: Spirometry is indicated to diagnose COPD. Spirometry should measure forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1 ); and the ratio of these two measurements (FEV 1 /FVC) is then calculated. Patients with COPD classically show a decrease in both FEV 1 and FVC. The presence of a post-bronchodilator FEV 1 < 80% of the predicted value in combination with an FEV 1 /FVC < 70% confirms the presence of airflow limitation that is not fully reversible. Bronchodilator reversibility testing is useful to rule out a diagnosis of asthma, to establish a patient's best attainable lung function, to determine a patient's prognosis, and to guide treatment decisions.

   Peripheral Neuropathy Top

Peripheral neuropathy [51] is a general term indicating peripheral nerve disorder due to any etiology; the manifestation of such a disorder is often baffling and complex. Clinical history may provide invaluable clues to the diagnosis of specific entity-viral illness, institution of new medications, exposure to solvents/ pesticides/ heavy metals and concomitant other systemic symptoms. The occurrence of similar symptoms in family members or co-workers; habits of alcohol intake and a presence of a known pre-existing medical disorder are very significant in diagnostic workup. The appearance and clinical course of illness may provide crucial clues.

For patients [52] with polyneuropathy standard tests should include a complete blood count, measurements of erythrocyte sedimentation rate (ESR), urinalysis, chest X-ray, blood sugar, and serum protein levels. Further tests are dictated by the combined results of clinical examination and electrodiagnostic examination.

Electrophysiological Diagnosis: Electrodiagnostic examination [52] is a key procedure in all patients with suspected neuropathy. It is an ideal test to distinguish between axonal and demyelinating type of disorder that cannot be analyzed by clinical examination alone

Nerve Biopsy: Nerve biopsy is an invasive procedure and there are few indications for it. Diagnostic considerations include vasculitis, multifocal demyelinating neuropathy, amyloidosis, leprosy, and sarcoidosis. Some genetically determined childhood disorders also require nerve biopsy. In distal symmetrical polyneuropathies of acute or chronic nature, nerve biopsy is not recommended as the diagnostic yield is low.

   Electrophysiological Diagnosis Top

Electrophysiological methods are very significant in revealing the pathophysiology of peripheral nerve disorders [53] . Traumatic lesions of the nerve usually lead to structural changes in the axon with or without separation of its supporting connective tissue sheath [54] . Nontraumatic disorders of the peripheral nerve may affect the cell body, axon, Schwann cell, connective tissue, or vascular supply, singly or in combination. Histologic and electrophysiologic characteristics indicate the presence of three relatively distinct categories [55],[56],[57],[58] of peripheral nerve disorders [Table 1]:

  1.  Wallerian degeneration More Details after focal interruption of axons as in vasculitis
  2. Axonal degeneration with centripetal or dying back degeneration from metabolic derangement of the neuron; and
  3. Segmental demyelination with slowed nerve conduction.

   Axonal Degeneration Top

Axons may degenerate in neuropathies due to mechanical compression of the nerve, exposure to vibration [60] , application of toxic substances, or death of the cell body. Nerve ischemia also leads to axonal degeneration, affecting large myelinated fibers first, followed by smaller myelinated fibers and unmyelinated axons [61],[62] .

In mild cases, axonal degeneration affects nerve conduction only minimally, especially if the disease primarily involves the small fibers [63] . More commonly, selective loss of the large fast-conducting fibers results in reduced amplitude and slowing of conduction below the normal range especially when recorded from distal as opposed to proximal muscles [64] . In milder cases with the amplitude of the recorded response greater than 80 percent of the expected value, conduction velocity should remain above 80 percent of the lower limits (80% rule) [65],[66] . A greater loss of fast conducting fibers would result in further conduction slowing but not beyond 70 percent of the lower limits of the normal value. Thus, physiologic criteria hardly ever misclassify a neuropathy with predominant axon loss on biopsy as demyelinating [67] .

Axonal, Motor More Than Sensory Polyneuropathy : The nerve conduction studies reveal reduced compound muscle action potential (CMAP) amplitude, whereas the conduction velocity remains normal until substantial reduction in CMAP amplitude has occurred [68] . Sensory nerve action potential amplitudes are also reduced.

Sensory Axonal Polyneuropathy: In COPD, usually sensory axonal polyneuropathy is found. Nerve conduction generally reveals decreased or absent sensory nerve action potential (SNAP) amplitude along with a normal motor nerve condution velocity [68] .

Axonal Type of Mixed Sensory Motor Polyneuropathy: Nerve conduction studies reveal absent/ reduced SNAP although motor nerve conduction is normal in the early stages of the disease. The CMAP amplitude becomes smaller and motor conduction velocity may decrease slightly in the late stage. Distal latency may be prolonged before the CMAP amplitude decreases.

Mixed Axonal Loss and Demyelinating Neuropathy: The major pathologic abnormalities in these group neuropathies are segmental demyelination and remyelination in addition to axonal degeneration. The nerve conduction studies reveal reduced or unrecordable CMAP, SNAP or both moderate to severe slowing of nerve conduction velocities with temporal dispersion of CMAP on proximal stimulation and a conduction block.

   Peripheral Neuropathy in COPD: An Overview of Existing Clinical Studies Top

The work over presence of peripheral neuropathies in patients with COPD has been much less considering the fact that COPD is one of the leading causes of morbidity and mortality. Narayan and Ferranti [71] studied 16 patients with chronic respiratory insufficiency and severe hypoxemia. When matched with a control group, a statistically significant slowing of nerve conduction was noted in the motor median, ulnar, peroneal and tibial nerves and also in the sensory median nerve.

In a different study [72] , 20 out of 23 COPD patients showed electrophysiologic evidence of peripheral nerve dysfunction. Abnormalities of sensory nerve conduction were most common, affecting the sural nerve (20 subjects), ulnar nerve (11), radial nerve (8), and median nerve (7). Six subjects had impairment of both sensory and motor nerve function; the common peroneal was the most frequently affected motor nerve. Clinical signs of neuropathy were found in four patients. COPD­related neuropathy was established to be correlated with cigarette consumption.

Nineteen patients with chronic respiratory insufficiency with no conditions known to cause polyneuropathies (PNP) were investigated in a study [73] . The motor and sensory conduction studies showed only reduced mean amplitude of the ulnar nerve SNAP and of the compound muscle action potential of the abductor pollices brevis muscle. The EMG was abnormal in 94.7% of the cases. The data from this study support the hypothesis of an involvement of motor neurons in COPD.

A study [74] investigated 43 patients with COPD. PNP was found in 74% patients, it was mild in 39%, and severe in 35%. The authors concluded that neuropathies were mixed but predominantly of the axonal type. Axonal degeneration and demyelination were confirmed by nerve biopsy; muscles presented neurogenic atrophy. Statistical analysis showed that the duration of hypoxemia was related to neuropathy.

In a prospective study [75] , 43 COPD patients having no known risk factor causing PNP were included. Electrophysiological recordings showed slight or significant signs of PNP in 17 and 15 patients respectively, thus indicating that the condition was frequent. Clinically, it was often silent or manifested only by sensory disorders predominant in the lower limbs. Electrophysiology suggested axonal degeneration associated with some degree of demyelinization, and these lesions were found at histology to be present in sensory nerves. Age, alcoholism and the other respiratory function values did not correlate with lesions of the peripheral nervous system, though the duration of hypoxia correlated with polyneuropathy.

Almitrine bismesylate had been earlier thought to provoke PNP in patients with COPD. Lerebours et al [76] examined 22 patients with COPD with no other cause of PNP, before and after 6 and 12 months of treatment with almitrine. Seventy-eight similar patients, who did not take almitrine, were also studied (controls), 64% of controls and 55% of almitrine patients initially had at least one neurophysiological abnormality. They found no change in the studied parameters after 6 months and one year's treatment with almitrine.

In a multicentric study [77] , 43 of 151 patients with COPD showed a clinically manifested PNP, whereas in a comparative group comprising of 32 asthmatics there were only 2 clinical PNP cases. Patients with known risk factors for PNP were not included in this study. The PNP observed was usually mild, mainly sensorial, distal and leg-accentuated. Out of 52 COPD patients with a PaO 2 up to 55 Torr, polyneuropathy was seen in 21 (40%); and of 59 COPD patients with a PaO 2 above 60 Torr, 10 (17%) had polyneuropathy.

The prevalence of clinical and electrophysiological signs of PNP was evaluated in 151 COPD patients with no concomitant disorders affecting the peripheral nervous system [78] . Thirty patients had clinical signs of a mild sensorimotor and distal neuropathy and 13 additional patients had only electrophysiological abnormalities. The rate and the severity of the neuropathy correlated with the severity of chronic hypoxaemia. Three out of 20 patients with mild hypoxaemia (PaO 2 less than 15 mm Hg below normal) had polyneuropathy as compared with 15 out of 36 with severe hypoxaemia (PaO 2 more than 30 mm Hg below normal (rates different at the 10% level)). PaO 2 and age were the only variables discriminating between patients with and without peripheral neuropathy.

To investigate the prevalence and type neuropathies PNP in patients with COPD, Nowak et al [79] studied lung function and blood gases, clinical signs of PNP, and neurophysiological function in 151 patients with COPD without known risk factors for PNP. Mean age was 65 years, mean arterial PO 2 was 59 mmHg, and mean FEV 1 / VC was 42%. Thirty patients (20%) had clinically detectable and 6 (4%) had subclinical PNP of mild degree. Fourteen (9%) of the patients with clinically detectable PNP had symptoms due to PNP. They also observed that prevalence of PNP increased with severity of hypoxemia and was more pronounced in the lower than in the upper limbs. Age and the degree of hypoxemia were predictors for PNP.

In another study [80] including 89 COPD patients, abnormal nerve conduction studies were found in 44%. Electrophysiological signs of PNP were found in 5-18%, depending on diagnostic criteria. Lesions which were thought to be due to compression or other forms of trauma were present in a further 24%. In the patients with peripheral neuropathy, the changes were distally predominant, affected mainly sensory fibres, and were consistent with an axonal type of neuropathy. There was a significant correlation between age and the incidence of PNP. Electrophysiological evidence of neuropathy was three times as common as clinical evidence.

A prospective study [81] enrolled 30 COPD patients (28 men and 2 women) with no known causes of PNP. Six patients reported slight paresthesiae. Clinical examination revealed signs that clearly suggested PNP in 8 patients (27%) whereas signs were nonspecific in 14. The neurophysiological study was abnormal in 26 patients (87%), suggesting axonal polyneuropathy that was predominantly sensory. The presence of PNP was related to age, duration of disease and smoking, but not with sex or pO 2 or pCO 2 on the date of examination.

Jann et al [82] reported the presence of PNP in 19 out of 30 COPD patients: 7 patients had clinical signs of a symmetric motor and sensory polyneuropathy, 12 patients had only subclinical evidence of peripheral nervous system involvement. Neurophysiological studies showed low amplitude CMAP and SNAP with only slight reduction of nerve conduction velocity in affected patients: these data confirm an axonal polyneuropathy. The severity of PNP in COPD patients correlated with hypercapnia, the degree of disability and thus with the severity of COPD. Hypoxia, age and duration of the disease were not related with the presence of PNP. Improvement of respiratory function produced slight but progressive improvement of neurological symptoms.

Ozge and co-workers [83] studied 49 patients with COPD in whom other causes of PNP had been excluded. COPD patients were divided into two groups: 21 hypoxemic and 28 normoxemic. Twenty one nonsmoker healthy subjects were included as the control group. They investigated the results of clinical (neurological symptom score-NSS, neurological disability score-NDS and vibration perception thresholds-VPT) and neurophysiological evaluations in COPD patients and the control group. NSS results were pathologic in 34% of COPD patients, NDS in 42% and VPT in 94%. Carpal tunnel syndrome was found in 24% of the patients, neuropathy in 55%, and polyneuropathy in 44.8%. The rate of axonal neuropathy was significantly higher in the hypoxemic group and the severity of neuropathy was correlated with the degree of hypoxemia.

A study [84] enrolled 32 patients (30 M, 2 F) with COPD. The subjects were divided into two groups: Group I, n: 19, PaO 2 < 55 mmHg and Group II, n: 13, PaO 2 > 55 mmHg. All subjects were evaluated with motor and sensory nerve conduction studies electromyography, visual and brainstem evoked potentials. The authors detected PNP in 93.8% of the study subjects. Distal latency of sural nerve correlated significantly with cigarette consumption and reduction in PEFR. Sensory nerve conduction velocity of median nerve was reduced as PaCO 2 was elevated and pH was lowered.

   Conclusions Top

The evidence so far from these studies carried out has suggested the existence of impaired peripheral nerve functions in patients with COPD. Nearly one-third of COPD patients have clinical evidence of peripheral neuropathy and two-thirds have electrophysiological abnormalities. Some patients with no clinical evidence of peripheral neuropathy do have electrophysiological deficit suggestive of peripheral neuropathy. The appearance consists of a polyneuropathy often subclinical or with primarily sensory signs, which has the neurophysiological and pathological features of mainly axonal neuropathy. The presumed etiopathogenic factors are multiple: chronic hypoxia, tobacco smoke, alcoholism, malnutrition and adverse effects of certain drugs. Hypoxia probably plays the foremost part, either by direct action on nerves fibres or by enhancing the effects of other neurotoxic factors or deficiencies. However, these studies have included patients with COPD having markedly varying baseline characteristics like severe hypoxemia, elderly patients, those with long duration of illness, etc. that are not uniform in all studies and make it problematical to interpret the results to a consistent conclusion. As observed in general clinical practice, majority of patients are those who are having stable COPD and it would be of great practical importance to study the prevalence of peripheral neuropathy in stable COPD patients.[85]

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