Evaluation of brain stem auditory evoked potentials in stable patients with chronic obstructive pulmonary disease

Though there are few studies addressing brainstem auditory evoked potentials (BAEP) in patients with chronic obstructive pulmonary disease (COPD), subclinical BAEP abnormalities in stable COPD patients have not been studied. The present study aimed to evaluate the BAEP abnormalities in this study group. MATERIALS AND METHODS: In the present study, 80 male subjects were included: COPD group comprised 40 smokers with stable COPD with no clinical neuropathy; 40 age-matched healthy volunteers served as the control group. Latencies of BAEP waves I, II, III, IV, and V, together with interpeak latencies (IPLs) of I-III, I-V, and III-V, and amplitudes of waves I-Ia and V-Va were studied in both the groups to compare the BAEP abnormalities in COPD group; the latter were correlated with patient characteristics and Mini–Mental Status Examination Questionnaire (MMSEQ) scores to seek any significant correlation. RESULTS: Twenty-six (65%) of the 40 COPD patients had BAEP abnormalities. We observed significantly prolonged latencies of waves I, III, V over left ear and waves III, IV, V over right ear; increased IPLs of I-V, III-V over left ear and of I-III, I-V, III-V over right side. Amplitudes of waves I-Ia and V-Va were decreased bilaterally. Over left ear, the latencies of wave I and III were significantly correlated with FEV1; and amplitude of wave I-Ia, with smoking pack years. A weak positive correlation between amplitude of wave I-Ia and duration of illness; and a weak negative correlation between amplitude of wave V-Va and MMSEQ scores were seen over right side. CONCLUSIONS: We observed significant subclinical BAEP abnormalities on electrophysiological evaluation in studied stable COPD male patients having mild-to-moderate airflow obstruction.

C hronic obstructive pulmonary disease (COPD) is a disease state characterized by airfl ow limitation that is not fully reversible. The airfl ow limitation is usually both progressive and associated with an abnormal infl ammatory response of the lungs to noxious particles or gases. COPD is a major public health problem and, currently, fourth leading cause of death worldwide. [1] A further increase in prevalence of, and mortality due to, the disease is predicted for the coming decades. COPD is presently regarded as a multi-system disorder. The associated peripheral neuropathy is well described in medical literature. [2,3] In addition, motor neuron involvement, encephalopathy, and derangement of cognitive function have been observed in patients with chronic respiratory insufficiency. Brainstem auditory evoked potentials (BAEP) are the potentials recorded from the ear and vertex in response to a brief auditory stimulation to assess the conduction through auditory pathway up to midbrain. BAEP in patients with COPD have been evaluated in previous studies, but the characteristics of included patients and study outcomes have been at great variation. [4][5][6] Kayacan et al. observed that smoking, airways obstruction, and longlasting COPD may not only cause peripheral neuropathy but may also affect the pontomedullary portion of the brain due to hypoxemia, hypercapnia, and respiratory acidosis. [4] Atis and co-workers studied BAEP in patients with severe COPD and concluded that eighth cranial nerve and brainstem functions were impaired in COPD. [5] Barbieri et al. reported that there was no signifi cant difference in BAEP in mild-ormoderate chronic respiratory insuffi ciency, apart from acidosis. [6] It appears the previous studies have included COPD patients having severe airfl ow obstruction or signifi cant hypoxemia/ hypercapnia. The present study is undertaken to fi nd out prevalence of BAEP abnormalities in stable patients with COPD having no clinical auditory dysfunction/impairment; and to analyze for possible correlation of BAEP abnormalities with patient characteristics, including age, duration of illness, quantum of smoking, spirometric indices, and Mini-Mental Status Examination Questionnaire scores.

Materials and Methods
The study was conducted in the departments of Respiratory Medicine and Physiology at Rohtak, India. This was a crosssectional study and was approved by the Institutional Board of Studies and by the ethical committee. All subjects were male and enrolled between November 2006 and October 2007. The COPD patients fulfi lling the criteria of the study, having age at least 40 years, attending the COPD clinic run at the Department of Respiratory Medicine, and who gave consent to complete the required investigations as per study protocol were included in the study. The diagnosis of COPD was based on the modifi ed criteria defi ned in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. [7] All the included COPD patients were smokers and had irreversible/partially reversible obstruction of airfl ow. The patients were included only if they had a stable course of their disease with regular follow-up during the preceding 1 year and no hospitalization for COPDrelated illness during the preceding 6 months. Patients with clinical evidence of any neurological defi cit/neuropathy or those having concomitant diabetes mellitus, chronic alcoholism, uremia, cystic fi brosis, sarcoidosis, leprosy, malignancy, any hereditary disorders involving peripheral nerves, history of intake of any neurotoxic drug, or history of any traumatic lesion possibly affecting brainstem functions were excluded from the study. The control group comprised of an equal number of agematched healthy volunteers having no risk factor that may lead to neuropathy. All healthy volunteers were nonsmokers. They were selected from medical/paramedical staff of our institute; some healthy attendants of the patients were also included in the control group.
Smoking pack years were calculated from mode of smoking (bidi, cigarette, or hookah), daily consumption, and the total number of years for which the patient had been smoking.
One pack year was 20 cigarettes smoked everyday for 1 year. [8] For bidi, cigarette equivalents were calculated by applying a factor of 0.5 to the number of bidis; [9] and for hookah, 12.5 g of loose tobacco was equivalent to one packet of 20 cigarettes. [10] The spirometry was carried out on Transfer Test Model 'C' (P. K. Morgan, Kent, UK). Inhaled short-acting bronchodilators were withheld for 6 hours before the test; long-acting β-agonists, 12 hours before the test; and sustained-release theophyline, 24 hours before the test. Spirometric indices were calculated using the best out of 3 technically satisfactory performances as per recommendations of the American Thoracic Society. [11] The following parameters were recorded: peak expiratory fl ow rate (PEFR), forced expiratory volume in the fi rst second (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC%.
Electrophysiological studies were carried out on a computerized nerve conduction testing equipment: RMS EMG EP MARK II (Recorders and Medicare Systems Pvt. Ltd., Chandigarh, India); the settings were as shown in Table 1.

Procedure of BAEP
The patient was put at ease and was made to lie down with eyes closed, relaxed on a couch, in a soundproof and air-conditioned room. After thorough cleaning of the electrode recording sites on the scalp, electrolyte paste was applied on the recording surface of disk electrodes and then Ag/AgCl electrodes were affi xed at predetermined positions on the scalp according to 10/20 international system of electrode placement. [12] The signals were picked by electrodes and were fi ltered, amplifi ed, averaged, displayed on the screen of RMS EMG EP MK2, and recorded. Subsequently, interpeak latencies (IPLs) were calculated.
The normal BAEP recording consists of fi ve or more vertexpositive and vertex-negative waves [ Figure 1] arising within 10 milliseconds of auditory stimulus. [13] Latencies of waves I, II, III, IV, and V, together with interpeak latencies of I-III, I-V, and III-V, and amplitudes of waves I and V were measured from recordings.

Mini-mental status examination
All included subjects, including COPD patients and healthy volunteers, were analyzed for their mental status using the Mini-Mental Status Examination Questionnaire (MMSEQ). [14] Statistical analyses The data of healthy volunteers and COPD patients was analyzed by incorporating the same in two different groups. The data were examined for normal distribution, and transformations were made where appropriate. The group means and the standard deviations for each variable were calculated in healthy volunteers group and COPD group separately. The statistical signifi cance of difference between group means of various parameters between healthy volunteers group and COPD group was analyzed by using independent sample t test, and a P value <.05 was considered statistically signifi cant. Individual Two types of clicks were produced: one, moving the earphone diaphragm away from eardrum (rarefaction click); and the other, moving it in the opposite direction (condensation or compression click). In this study, stimulus with alternating polarity was used. Recording electrodes: The volume-conducted evoked responses are picked up from scalp by electrodes. Two reference electrodes were attached to left and right mastoids, designated as A1 and A2 respectively; one active electrode on vertex, labeled as Cz; and one as ground electrode to forehead, termed as Fz. All the electrodes were plugged to the junction box. Skin-to-electrode impedance was monitored and kept below 5 KΩ. Recommended montage for BAEP: Channel I: Cz-A1 Channel 2: Cz-A2 Ground: Fz COPD patients having BAEP abnormality beyond the range of 'mean ± 3' standard deviation from healthy volunteers were considered as having signifi cant BAEP abnormality. The BAEP abnormalities in COPD patients were correlated with patients` characteristics, including age, duration of illness, quantum of smoking, spirometric indices (FEV 1 , FEV 1 /FVC%, and PEFR), and the MMSEQ scores. The data obtained was statistically analyzed using Pearson's correlation. All statistical analyses were carried out with the help of SPSS (version 14.0), Chicago, software.

Results
We included 80 male subjects comprising of 40 COPD patients and 40 age-matched healthy volunteers. All subjects were aged 40 years or more. The characteristics of subjects included in the present study were as shown in Table 2. The COPD patients had a post-bronchodilator FEV 1 less than 80% of the predicted value, along with an FEV 1 /FVC% not more than 70%. They had an increase in FEV 1 less than 200 mL, or less than 12% of baseline value 20 minutes after 2 puffs of inhaled salbutamol given via a metered-dose inhaler using a spacer. The duration of symptoms in all patients with COPD was 5 years or more. All healthy volunteers were nonsmokers and had no symptoms suggestive of any disease. As expected, their spirometric indices were statistically different from COPD patients. Table 3 provides summaries [mean ± SD] of variables of BAEP wave patterns recorded over left ear and right ear separately in healthy volunteers group, comparing the same with those in COPD group. Over left ear, the latencies of waves I, III, and V in COPD patients were prolonged signifi cantly as compared to the healthy volunteers. The latencies of waves II and IV were also increased in COPD group but had no statistical signifi cance. Over the right side, there was signifi cant prolongation of the latencies of waves III, IV, and V in COPD group as compared to the healthy volunteers.
The interpeak latencies (IPLs) of III-V and I-V were signifi cantly prolonged in the COPD patients as compared to healthy volunteers over both ears; in addition, interpeak latency of I-III was signifi cantly prolonged in the COPD group over right ear.
Amplitude of the wave I-Ia in the COPD patients was signifi cantly decreased when compared to that in healthy volunteers, over both ears respectively. Similarly, amplitude of the wave V-Va in the COPD patients was signifi cantly decreased when compared to that in healthy volunteers, over both ears respectively.
Individual COPD patients who had any BAEP abnormality were also analyzed, and the details are shown in Table 4. The BAEP abnormality was considered to exist when there was     Figure 2]. Similarly, the latencies of wave III over left ear correlated negatively with FEV 1 ; the correlation was statistically signifi cant [ Figure 3]. The correlation between amplitude of wave I-Ia recorded over left ear and smoking pack years was a negative one and statistically signifi cant [ Figure 4]. Other correlations were not statistically signifi cant.
The correlations between the variables of BAEP wave patterns recorded over right ear and the characteristics of COPD patients were as shown in Table 6. The correlation between amplitude of wave I-Ia and duration of illness was a weak positive one [ Figure 5]; the correlation between amplitude of wave V-Va and MMSEQ scores was a weak negative one [ Figure 6]; though both were statistically signifi cant. Other correlations between BAEP variables and the characteristics of COPD patients were not signifi cant.

Discussion
Before we discuss and compare the observations in our study with those of other studies, we feel it is worthwhile to consider signifi cant differences between characteristics of the study subjects included in our study and those of the subjects in other studies [ Table 7]. Kayacan et al. [4] included 32 patients with COPD having age 61 ± 8.8 years. They have not described the details of the inclusion and irreversibility criteria. Atis et al. [5] included 21 patients with severe COPD according to the criteria [15] of the American Thoracic Society (1987). Some of the patients included had clinical evidence of neuropathy. In our study, all COPD patients were signifi cant smokers and had irreversible/partially reversible airfl ow limitation, a defi ning characteristic of COPD. Other studies did not have conformity regarding the reversibility criteria as recommended in Global Initiative for Chronic Obstructive Lung Disease (GOLD)    guidelines, [7] which were taken into consideration in the present study. Moreover, quantum of smoking in our study was more despite a lower mean age of COPD patients when compared to that in previous two studies.
In our study, we included stable COPD patients with mildto-moderate airfl ow obstruction and with no clinical features suggestive of any neuropathy. Our objective was to assess the impaired brainstem auditory evoked potentials in stable COPD patients [and perhaps early in the course of their disease] with no clinical features of any neurological defi ciency -the COPD patients that are usually seen at the level of general clinical practice. This study group was not evaluated in previous studies. It is not reasonable to compare prevalence of peripheral neuropathy observed in our study with that observed in other previous studies due to differences in the characteristics of subjects included in various studies.  The common BAEP abnormalities observed in COPD patients in our study and previous studies include prolongation of latencies of waves I, III, V; and interpeak latencies of I-III and III-V. In addition, our study found decreased amplitudes of waves I-Ia and V-Va. Though none of the COPD patients included in the present study had signifi cant hypoxemia or hypercarbia, the existing medical literature suggests that hypoxemia results in peripheral nerve damage by harming the vaso nervosum. In the early stages of ischemia, mechanisms to reduce peripheral neuropathy are activated, but these become insuffi cient over time and obvious neuropathy is inevitable in chronic hypoxemia. [16] It has been hypothesized that the abnormal BAEP fi ndings are due to brainstem hypoxia which increases with the severity of COPD. Sohmer et al. demonstrated depression of the auditory nerve-brainstem evoked response, as well as vestibular and visual evoked potentials during severe hypoxemia in cats. [17] In addition to chronic hypoxemia and hypercapnia, other associated factors in patients with COPD, including tobacco smoking; malnutrition; and drugs used in COPD treatment, like long-acting inhaled β2 agonists, inhaled anticholinergic agents, inhaled glucocorticoids, and sustained release theophyline, may be possibly associated with neuropathy seen in COPD patients. [16,18,19] Though none of our patients had signifi cant hypoxemia, they had longer duration of illness and more smoking pack years; so, whether severity of hypoxemia alone or the chronicity and severity of hypoxemia together contribute to development of peripheral neuropathy needs to be evaluated in future studies. As COPD patients in our study were heavy smokers, the possibility of the contents of cigarette smoke leading to BAEP abnormalities remains.
We could not fi nd any correlation between the BAEP parameters and pulmonary function test parameters, except BAEP latency of waves I and III with FEV 1 on left side. The poor correlation in spite of signifi cant BAEP abnormalities is probably due to the narrow range of patients' characteristics and pulmonary function parameters in our patients as we included relatively stable patients during the early course of COPD, having mildto-moderate airfl ow obstruction.
To conclude, in the present study, we observed signifi cant BAEP abnormalities on electrophysiological evaluation in 26/40 [65%] studied stable male COPD patients with mild-tomoderate airfl ow obstruction (and with no clinical neuropathy), and these patients had signifi cant smoking history with no signifi cant hypoxia or hypercapnia.