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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 15  |  Issue : 1  |  Page : 52-58

Peripheral neuropathy in stable chronic obstructive pulmonary disease: Is the phrenic nerve more affected compared with other peripheral nerves?


1 Department of Chest Disease, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
2 Department of Neurology, Faculty of Medicine, Al-Azhar University, Damietta, Egypt

Date of Submission08-Jan-2017
Date of Acceptance28-Mar-2017
Date of Web Publication23-Aug-2017

Correspondence Address:
Atef W El-Rifai
Mansoura, 35511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_5_17

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  Abstract 


Background
Chronic obstructive pulmonary disease (COPD) is a multicomponent disease with extrapulmonary manifestation. Peripheral nerve affection may be one of the results or mechanism of COPD.
Objective
The aim of this study was to evaluate peripheral neuropathy in patients with stable COPD and whether these changes are more or less marked in the phrenic nerve when compared with other peripheral nerves.
Patients and methods
Eighty patients with COPD and 60 healthy individuals as a control group were included. All were subjected to the following: (i) full history taking; (ii) clinical and neurological examination; (iii) chest radiography; (iv) high-resol ution computed tomography scanning of the chest; (v) arterial blood gases analysis at room air; and (vi) spirometric tests.
Results
There was a statistically significant increase in smoking packs/year, respiratory rate, hemoglobin, and white blood cells in the COPD group. There was a significant decrease in oxygen saturation, pH, arterial oxygen tension, forced expiratory volume in 1 s, forced expiratory volume in 1 s/forced vital capacity, and forced vital capacity% in the study group when compared with the control group, whereas there was a significant increase in CO2 tension in the COPD group. There was a significant increase in the distal latency of all nerves and a significant decrease in the amplitude and conduction velocity of all nerves, except the amplitude of the phrenic nerve in the COPD group. The difference for phrenic nerve amplitude was statistically nonsignificant. In the COPD group, abnormal motor activity in the median, ulnar, common peroneal, and phrenic nerves of 30, 22.5, 35, and 22.5%, respectively, was reported, whereas abnormal sensory activity in the median, ulnar, and sural nerves of 30.0, 27.5, and 42.5%, respectively, was reported. Finally, we found a statistically significant increase in nerve abnormalities with increased severity of the disease.
Conclusion
COPD had a significant affection on peripheral nerves, either motor or sensory. In addition, COPD had a significant affection on the phrenic nerve and muscle of the diaphragm. However, this affection of the phrenic nerve was confined to grades III and IV and was the least affection of studied nerves.

Keywords: chronic obstructive pulmonary disease, common peroneal nerve, diaphragm, median nerve, neuropathy, peripheral nerve, phrenic nerve, respiratory muscles, sural nerve


How to cite this article:
El-Rifai AW, El-Shazli SM. Peripheral neuropathy in stable chronic obstructive pulmonary disease: Is the phrenic nerve more affected compared with other peripheral nerves?. Al-Azhar Assiut Med J 2017;15:52-8

How to cite this URL:
El-Rifai AW, El-Shazli SM. Peripheral neuropathy in stable chronic obstructive pulmonary disease: Is the phrenic nerve more affected compared with other peripheral nerves?. Al-Azhar Assiut Med J [serial online] 2017 [cited 2019 Sep 23];15:52-8. Available from: http://www.azmj.eg.net/text.asp?2017/15/1/52/213589




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is a heterogeneous and multicomponent disease, with patients differing in terms of clinical presentation and rate of disease progression. Some patients can live their lives untouched by the disease, whereas others are completely handicapped. A major goal in the management of this disease is to ensure that its burden is minimized. Traditionally, the severity of the disease was equated with airflow limitation, as measured by means of impairment in forced expiratory volume in 1 s (FEV1), and management of COPD was also largely based on spirometric assessment [1]. However, because COPD is a multicomponent disorder, structural and functional changes take place in other organs, as well as in the lungs. Therefore, airflow limitation alone does not reflect the full burden of COPD and it is perhaps not surprising that FEV1 correlates poorly with patient outcomes, such as dyspnea, exercise intolerance, and impairment of health-related quality of life [2]. There is growing awareness about the cardiovascular, neurological, psychiatric, and endocrinological comorbidities associated with COPD [3].

As pulmonary function deteriorates, the risk for alveolar hypoxia and consequent hypoxemia increases in COPD patients. It now seems clear that tissue hypoxia has a key role in many of the maladaptive processes and extrapulmonary comorbidities in COPD [4]. Various electrophysiological studies of patients with COPD have demonstrated that it affects both the central and peripheral nervous systems, either sequentially or simultaneously [3].

COPD and chronic hypoxia were shown to cause polyneuropathy by Appenzeller et al. [5]. Following this first report on neurological manifestations of COPD, numerous studies have confirmed that polyneuropathy is common among patients with COPD, with an incidence of 28–95%, and that neuropathy increases with hypoxia [6].


  Aim Top


The aim of this study was to evaluate peripheral neuropathy in patients with stable COPD and whether these changes are more or less marked in the phrenic nerve when compared with other peripheral nerves.


  Patients and methods Top


This study was designed as a case–control study conducted on 80 patients with COPD and 60 (age and sex matched) nonsmoker, healthy individuals as a control group at both neurology and chest departments, Al-Azhar University Hospital (New Damietta). Diagnosis of COPD was made on the basis of the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) criteria [7]. The study protocol was approved by local ethics committee of Al-Azhar University (New Damietta). Patient consent for participation was obtained after full explanation of the study protocol. confidentiality and right for withdrawal at any time were warranted.

Exclusion criteria

Patients fulfilling one or more of the following criteria were excluded from the study: neurological complaints or findings suggestive of neuromuscular disorder due to causes other than COPD (such as diabetes mellitus, chronic liver disease, chronic renal failure, and chronic alcoholism).

All included participants were subjected to the following: (i) full history taking with special attention to main complaint, age, sex, smoking habits, duration of disease, risk factors (occupation, pollution, resident area, etc.), history of other systemic diseases; (ii) clinical and neurological examination; (iii) chest radiography (posteroanterior and lateral views); (iv) electrocardiogram; (v) high-resolution computed tomography scanning of the chest; (vi) arterial blood gases: pH, partial arterial oxygen tension, partial arterial carbon dioxide tension, and oxygen saturation were measured in arterial blood sample at room air; and (vii) spirometric tests − all patients underwent spirometry, and forced vital capacity (FVC), FEV1, and FEV1/FVC ratio were measured.

Spirometric studies were carried out on all patients. It was conducted in accordance with American Thoracic Society as follows: (i) the procedure was explained to the patient carefully; (ii) it was ensured that the patient was standing or sitting erect with his or her feet firm on the floor; (iii) a nasal clip was applied to the patient’s nose; (iv) the patient was instructed to breathe in fully; (v) the lips of the patient were sealed around the mouth piece; (vi) the patient was instructed to exhale maximally until the lungs were completely empty; (vii) the patient was instructed to breathe again as forcibly and fully as possible; and (viii) at least three technically accepted maneuvers were performed. Activities that should preferably be avoided before lung function testing include the following: (i) smoking within at least 1 h of testing; (ii) consuming alcohol within 4 h of testing; (iii) performing vigorous exercise within 30 min of testing; (iv) wearing clothing that substantially restricts full chest and abdominal expansion; (v) eating a large meal within 2 h of testing; and (vi) patient should hold bronchodilator few hours before the test studies of pulmonary function were performed using Zan Mebgeraee GmbH (Kölner Str. 226F, 40227 Düsseldorf - Oberbilk; Nordrhein-Westfalen; Germany) [8].

Neurophysiological assessment included nerve conduction studies. Motor nerve conduction study for the median, ulnar, common peroneal and phrenic nerves were carried out for distal latencies, amplitudes, and motor conduction velocities. Sensory nerve conduction study for the median, ulnar, and sural nerves was carried out for sensory distal latencies, amplitudes, and conduction velocities. Studies of nerve conduction were performed using Nihon Kohden machine [Model UT-0800 J. Box Board (2CH) for JB-942BK; Nihon Kohden, Tokyo, Japan].

Motor nerve conduction

Motor nerve conduction studies are performed by means of electrical stimulation of a peripheral nerve and recording from a muscle supplied by this nerve. The time it takes for the electrical impulse to travel from the stimulation to the recording site is measured. This value is called the latency and is measured in milliseconds. The size of the response − called the amplitude (measured from peak to baseline) − is also measured. Motor amplitudes are measured in millvolts. By stimulating in two or more different locations along the same nerve, the Nerve conduction velocity (NCV) across different segments can be determined. Calculations are performed using the distance between the different stimulating electrodes and the difference in latencies.

Sensory nerve conduction

Sensory nerve conduction studies are performed by means of electrical stimulation of a peripheral nerve and recording from a purely sensory portion of the nerve, such as on a finger. Similar to the motor studies, sensory latencies are measured in milliseconds. Sensory amplitudes (measured from peak to baseline) are much smaller compared with the motor amplitudes, usually in the microvolt range. The sensory NCV is calculated on the basis of the latency and the distance between the stimulating and recording electrodes.

Statistical analysis

The collected data were coded and statistically analyzed using SPSS program for windows (version 16; SPSS Inc., USA; 233 S. Wacker Drive, 11th floorÜhicago, IL 60606-6307). Parametric numerical data were expressed as mean and SD, whereas qualitative data were expressed as relative frequency (n) and percent distribution. Independent samples Student’s t-test was used for comparison between two means for parametric variables and the Mann–Whitney U-test for nonparametric numerical variables. In addition, qualitative data were compared using the χ2-test. A P-value less than or equal to 0.05 was considered significant for interpretation of results.


  Results Top


In the present study, there was a statistically nonsignificant difference between the COPD and control groups as regards age (63.80±2.13 vs. 64.13±1.94, respectively) and sex (male represented 85.0 vs. 70.0% of the COPD and control groups, respectively). However, there was a statistically significant increase in smoking packs/year and respiratory rate in the COPD group when compared with the control group (23.62±14.50 and 17.50±3.01 vs. 0.0±0.0, and 11.70±0.59, respectively). However, there was no significant difference between the COPD group and the control group as regards blood pressure, platelets, and serum blood sugar. However, there was a significant increase in hemoglobin and white blood cells in the COPD group when compared with the control group (16.57±1.10 and 11.66±7.19 vs. 15.76±0.89 and 4.73±1.41, respectively) ([Table 1]).
Table 1 Patient characteristics, hemodynamics, and laboratory data in studied populations

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As regards radiological examination, chest radiography revealed that hyperinflated chest was reported in 60% of participants in the COPD group and there was chronic bronchitis in 40% of patients in the same group. However, no participants reported any chest radiography changes in the control group. In addition, there was a significant decrease in oxygen saturation, pH, arterial oxygen tension, FEV1, FEV1/FVC, and FVC% in the study group when compared with the control group, whereas there was a significant increase in CO2 tension in the COPD group when compared with the control group ([Table 2]). Electrophysiological examination of peripheral nerves showed that there was a significant increase in the distal latency of all nerves and a significant decrease in the amplitude and conduction velocity of all nerves except the amplitude of the phrenic nerve in the COPD group when compared with the control group. The difference for phrenic nerve amplitude was statistically nonsignificant ([Table 3]).
Table 2 Radiological examination, arterial blood gases, and pulmonary function test in studied participants

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Table 3 Motor and sensory assessment of studied nerves

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As regards abnormal changes in studied nerves in the COPD group, abnormal motor median nerve was reported in 30% of participants, abnormal ulnar motor nerve was reported in 22.5%, abnormal common peroneal nerve in 35%, abnormal phrenic nerve in 22.5%, abnormal median sensory nerve in 30.0%, abnormal ulnar sensory nerve in 27.5%, and abnormal sural nerve in 42.5%. Thus, phrenic and ulnar motor were the least affected nerves ([Table 4]). On studying the relation between COPD severity and abnormalities in studied nerves, we found a statistically significant increase in nerve abnormalities with increased severity of the disease. All patients in grade IV COPD had abnormal median motor and sensory activity, abnormal common peroneal, phrenic nerve, abnormal ulnar sensory, and abnormal sural nerve. It is worthy of mention that all patients in grade III had abnormal common peroneal and abnormal sural nerve. In addition, phrenic nerve abnormalities were confined to grades III and IV, whereas all other nerve abnormalities were reported in grades II, III, and IV. Only grade I had no peripheral nerve changes ([Table 5]).
Table 4 Frequency of abnormal changes in studied nerves in the chronic obstructive pulmonary disease group

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Table 5 Relation between chronic obstructive pulmonary disease severity and abnormal changes

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  Discussion Top


It is well known that COPD is associated with significant systemic abnormalities [9]. Multisystem involvement with extrapulmonary manifestations has been seen in COPD patients [10]. Hypoxemia, hypercapnia, systemic inflammation, and neuron-hormonal activation are the main mechanisms of the pathophysiology in systemic involvement [11].

As regards patient characteristics, the mean age in the COPD group was 63.80±2.13 years, whereas the mean age in the control group was 64.13±1.94 years. Male sex represented 85% of the COPD group and 70% of the control group, and there was no significant difference between the two groups as regards age and sex distribution. However, smoking packs/year was significantly higher in the COPD group when compared with the control group (23.62±14.50 vs. 0.00±0.00, respectively). These results are in accordance with those of Atis et al. [12], who studied 16 men and five women in the patient group. Their mean age was 64±6.5 years (range: 46–72 years). Fourteen men and seven women were included in the control group with a mean age of 53.1±7.88 years (range: 40–67 years; P>0.05). In the patient group, 15 (71%) participants had a history of cigarette smoking. The mean cigarette consumption was 24.59±21.21 packs/years. Moreover, in agreement with the present study, Sezer et al. [13] conducted their study only in older patients (with the mean age of 64.0±6.5, 61.5±8.8, 59.4±9.4, and 62.1±9.9, respectively). However, Karthikkeyan et al. [14] reported that the mean age of COPD patients observed in the study was 45.57 years and ranged from 36 to 55 years. Considering these younger ages of COPD patients in this study, it could be confirmed that COPD affects the middle age group and the evidence of central neuropathy noticed in the patients are disease-driven rather than age related.

In the present work, results of arterial blood gases and pulmonary function tests revealed a significant decrease in SO2, pH, PaO2, FEV1, FEV1/FVC, and FVC% in the COPD group when compared with the control group. However, there was a significant increase in PCO2 in the COPD group when compared with the control group (59.85±6.46 vs. 41.40±2.11, respectively). These results are consistent with those reported by Calik-Kutukcu et al. [15], who reported that FVC, FEV1, FEV1/FVC, forced expiratory flow at 25–75%, and peak expiratory flow values of patients were significantly lower than those of healthy individuals (P=0.001). In addition, these results are in agreement with those of Hamed et al. [16], who reported a significant decrease in SO2, pH, PaO2, FEV1, FEV1/FVC, and FVC% and a significant increase in PaCO2 in the COPD group. Furthermore, Agrawal et al. [17] reported that the difference between healthy volunteers and COPD patients with respect to FVC, FEV1, peak expiratory flow rate, FEV1/FVC%, and oxygen saturation (SaO2) was significant statistically (P<0.001) as was expected.

Results of the present study revealed that there was a significant increase in peripheral nerve motor and sensory changes in the study group when compared with the control group. In addition, there was a significant correlation between nerve abnormalities and grade of COPD. This means that in patients with COPD there is peripheral neuropathy and that with increased COPD severity the peripheral nerve affection was increased. These results are comparable to those reported by Ilik et al. [18], who conducted their study on 43 patients (27 male and 16 female). The mean age of the patients was 68.8±12.28 years.

Regardless of nerve affection, the percentage of affected individuals, and the type of peripheral neuropathy, the results of the present study are comparable to those reported by Kazi et al. [19], who reported that, according to the NCV test, of 50 patients, 48 were found to have neuropathy. Therefore, 96% of the patients were having neuropathy, mainly subclinical, as most of the patients did not have any signs and symptoms of neuropathy. Neuropathy involved sensory nerves, mainly the sural nerve. They added that there is a significant association and correlation between stages of COPD with sural NCV and amplitude. Therefore, as chronicity of disease increases there are chances of sural nerve neuropathy. There is a strong and positive correlation of ulnar sensory nerve amplitude with FEV1%, and hence FEV1% decreases. In addition, Jann et al. [20] reported the presence of polyneuropathy in 19 of 30 COPD patients.

In the present work, there was a significant increase in the distal latency of the phrenic nerve. However, there was a nonsignificant increase in the amplitude in the COPD group. These results are in agreement with those of Podnar and Harlander [21], who reported that phrenic nerve compound motor action potential latencies were significantly longer, and amplitudes were bilaterally higher in COPD patients compared with controls. The higher amplitude observed in their study and our work can be attributed to the flattening of the diaphragm, which is easily seen on chest radiography and abdominal ultrasound. Flattening of the diaphragm is caused by lung overexpansion. This leads to shortening and thickening of the muscle fibers, which lead to higher amplitude [22]. An alternative explanation for the higher phrenic nerve amplitude in COPD patients is the larger diaphragm muscle mass in this patient population. In COPD patients, lower respiratory airway obstruction is characteristic. However, due to dynamic airway compression, the expiration phase is mainly affected [23].

As regards sural nerve sensory changes, there was a significant increase in distal latency and a significant decrease in amplitude and conduction velocity in the COPD group when compared with the control group in the right and left nerves. These results are in agreement with those of Agrawal et al. [17], who reported that both the amplitude and the conduction velocity of the sural sensory nerve in the COPD group were decreased. These findings were statistically highly significant. The latency of the sural sensory nerve in the COPD group was significantly higher when compared with the healthy volunteers. These changes in peripheral nerves may affect the muscles of respiration, especially the diaphragm. It had been reported that the diaphragm is the main inspiratory muscle agonist. There are several pieces of evidence that the diaphragm and other respiratory muscles are able to express adaptive changes early in the disease course in response to pulmonary hyperinflation [24]. However, an imbalance between respiratory muscle overload and adaptation may occur in response to persistent hyperinflation, increase in disease severity, increments in mechanical or metabolic loads, poor energy supply, and recurrent infection and exacerbations [25]. The imbalance between inspiratory muscle load and capacity places the muscles at mechanical disadvantage, resulting in diaphragmatic fatigue or weakness [26], shortness of breath, exertion intolerance, and hypoventilation [27]. This myogenic phenomenon was commonly accepted as a mechanism of hypercapnic respiratory failure in COPD. However, the discrepancy between in-vivo and in-vitro results makes this myogenic assumption with COPD less likely as a sole mechanism and the exact pathophysiology of diaphragm dysfunction is still unclear [28]. It has been suggested that the contractile function of diaphragm fibers may be impaired in early stages of COPD [29]. This is supported by the following findings: many patients develop respiratory failure and require hospital admission even if the cause of the exacerbation is less dramatic as in the presence of bronchial infection, pain of any nature, etc., which means that loss of balance between respiratory muscle overload and adaptation is not always associated with extreme situations [30]. This can be attributed to the fact that the diaphragm contractile performance in vivo is also determined by many factors, which include the following: the corticospinal neural drive, phrenic nerve function, neuromuscular transmission, contractile function of a single fiber, muscle fiber recruitment, calcium homeostasis, etc [31]. Hence, although all studied nerves were affected to variable degrees, the affection of the phrenic nerve (as a sole nerve supply to the diaphragm) may be responsible for hypoventilation in the patients with COPD.

In short, results of the present study revealed that COPD had significant affection on peripheral nerves, either motor or sensory. In addition, COPD had significant affection on the phrenic nerve and muscle of the diaphragm. However, this affection of phrenic nerve was confined to grades III and IV and was the least affection of studied nerves.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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