Study of brainstem auditory evoked response and biochemical markers in patients of alcohol use disorder

INTRODUCTION

Alcoholism refers to chronic continual drinking or periodic consumption of alcohol which is characterized by impaired control over drinking, frequent episodes of intoxication, and preoccupation with alcohol and the use of alcohol despite adverse consequences.^[1] In May 2013, the American Psychiatric Association issued the 5^th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM–5). DSM–5 integrates the two DSM–IV disorders, alcohol abuse and alcohol dependence, into a single disorder called alcohol use disorder (AUD) with mild, moderate and severe sub-classifications.^[2] The term alcohol refers to “ethyl alcohol”. The most widely used alcoholic beverages are beer, wine, whisky, vodka, rum gin and brandy and locally brewed beverages. The quantity of alcohol differs among the different types of beverages.

In India, alcohol consumption practices vary across different parts because of the sociocultural diversity and difference in laws governing different states. The estimated numbers of alcohol users in 2005 were 62.5 million, with 17.4% of them (10.6 million) being dependant users^[3] and 20–30% of hospital admissions are due to alcohol-related problems. It is more common among males and young adults.^[4,5]

AUD is a multifactorial disorder that not only can affect several parts of the brain, but also, in general, contracts brain tissues, destroys brain cells, as well as depresses the central nervous system. Alcohol interacts with the brain receptors, interfering with the communication between nerve cells and suppressing excitatory nerve pathway activity.^[6,7]

Event related potentials or evoked potentials (EPs) have been used to assess the functional integrity of the brains of alcoholic patients.^[8] Brainstem auditory evoked response (BAER) is an EP generated by a brief click or tone pip transmitted from an acoustic transducer in the form of an insert earphone or headphone. The BAER comprises seven waves, of which waves I, III, V are the most visible and of more significant clinical value. Recordings of this potential may be clinically analysed according to a number of parameters: morphology; absolute latency and wave I, III and V amplitude; I-III, I-V and III-V Inter-peak latencies (IPLs).^[9]

Liver enzyme levels exhibit a characteristic pattern in chronic alcoholics. The ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) has more clinical utility than assessing individual elevated levels. Mean ratio of 1.45 and 1.3 was found in alcoholic liver disease and post necrotic cirrhosis, respectively. An AST/ALT ratio >2 is characteristically present in alcoholic hepatitis.^[10]

The previous studies have reported abnormal auditory brainstem in patients of AUD; however, the data available is scanty. Furthermore, data from North India is very scarce. Furthermore, to the best of our knowledge, we have not come across any study on the correlations between EPs and biochemical parameters. Therefore, this study has been undertaken to focus on the effects of AUD on BAER, especially in North Indian males and to correlate the parameters of EPs with biochemical variables.

MATERIALS AND METHODS

This case-control study was conducted in the Department of Physiology in collaboration with the Department of Psychiatry at Subharti Medical College and associated Chhatrapati Shivaji Subharti Hospital, Meerut. A total of 80 subjects were taken, 40 healthy non-alcoholic controls and 40 patients of AUD. Subjects in the study group were recruited from patients attending the hospital psychiatry outpatient department as well as inpatients from the psychiatry ward, and the controls were recruited from hospital and college employees and people residing in the campus. Before initiation of the study, approval was obtained from the institutional research and ethical clearance committee of Swami Vivekanand Subharti University, Meerut. The study protocol was in keeping with the ethical guidelines of the 1975 declaration of Helsinki and informed written consent was taken from all the study subjects before beginning of the study.

Recording of BAER

Recording of BAER was carried out in a quiet and dimly lit room with subject in supine position. Surface electrodes were placed at the vertex (Cz), both ear lobes (A1 and A2) and forehead (ground). Monoaural auditory stimulus consisting of rarefaction clicks at an intensity of 90 dB hearing level to the ear stimulated were delivered through an electrically shielded earphone at the frequency of 11.1 Hz. Contralateral ear was masked with pure white noise 40 dB below that of BAER stimulus. A band pass of 100Hz - 3KHz was used to filter out undesirable frequencies in the surroundings. Responses to 2000 click presentations were averaged for 10milliseconds (ms), amplified and displayed on the computer monitor. The BAER test was performed using Octopus NCS/EMG/EP (Clarity) machine. In BAER, the impulses were generated by the brain stem. These impulses when recorded contain a series of peaks and troughs. The positive peaks (vortex positive) were referred to by the Roman numerals I – VII.^[15] The wave latency I, II, III and IV and V, IPLs I-III, I-V and III-V were measured. Recordings of BAER in a patient and a non- alcoholic healthy control are shown in [Figure 1] and [Figure 2] respectively.

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Figure 1:

Recording of brainstem auditory evoked response in a patient of alcohol use disorder.

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Figure 2:

Recording of brainstem auditory evoked response in a non-alcoholic healthy control.

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The auditory brainstem response was considered abnormal when (a) one or more of the IPL I-III, I-V and III-V were greater than mean ± 2.5 S.D values for normal subjects (below 50 years of age) and beyond mean ± 3.0 S.D values for normal subjects (above 50 years of age), (b) Absence of wave III or wave V in the presence of a clearly defined wave I. If wave I could not be identified, the result was not included for analysis.^[12]

RESULTS

DISCUSSION

AUD affects various organ systems including central and peripheral nervous system, cardiovascular system, gastrointestinal system and respiratory system, but this study has primarily focused on the effect of AUD on the function of central nervous system. The present study was undertaken to study the effects of AUD on electrophysiological test, BAER and biochemical parameters and to compare these findings with healthy non-alcoholic controls.

The present study revealed statistically significant increase in the absolute latencies of wave III (P = 0.007), wave V (P = 0.000) of LE and wave V (P = 0.02) of RE in patients of AUD as compared to non-alcoholic controls. IPLs were also statistically significantly increased: I-III (P = 0.000) of LE and I-III (P = 0.000) and I-V (P = 0.01) of RE in patients of AUD. Each wave of BAER is presumed to reflect the activity of different neural sites, so changes in latency of wave provided information about neural dysfunction as I, II, III, IV and V components of BAER, represented conduction of electrical activity at auditory nerve, cochlear nucleus, superior olivary nucleus in pons, lateral lemniscus and inferior colliculus in the mid-brain, respectively. The IPLs between these components reflected neural conduction in corresponding segment of central auditory pathway. IPL between wave I-V, therefore, may prove valuable as brainstem transmission time (BTT). Similar results were observed by Begleiter et al.^[16] who observed significant increase in latencies of wave II, III, IV and V and IPLs I-II, I-III, I-IV and I-V. Various studies by most other authors^[12,17-19] had also reported an abnormal increase in III-V and I-V. Misra and Kalita had attributed the prolongation of wave V latency with alcohol to lowering of body temperature.^[20]

Our findings also indicated that the most peripheral part of the auditory pathway was not affected (wave I), while there was a significant increase in the latency of successive waves. This reflected a decrease in the conduction velocity, not due to deficits at the peripheral organ but suggested pathological changes in the medulla and pontine formation. The increase in BTT may have reflected a direct pathological process of demyelination^[21] and was observed in rats in alcohol for long periods.^[22] Loss of CNS neurons and neuronal connections and axon death^[23] and supported by CT scan evidence of reduction in thalamic density in alcoholics^[24] and changes in membrane properties^[25] had also been suggested as pathogenic mechanisms to explain the BAER alterations. Alcohol caused an increase in lipid permeability of membrane of astrocytes and oligodendrocytes. Recent evidence showed that alcohol also affected glial cells and alters neuroglial interactions. It affected potassium channels on astrocytes and astroglial gap junction permeability which caused an increased leakage of action potential current down the axon.^[26] The effects of chronic alcoholism on intracellular signalling systems in neurons of central and peripheral nervous system requires further investigations.

Chronic alcoholism always had some degree of nutritional deficiency. Alcohol increased the metabolic demand for thiamine which was important in metabolism of glucose. Lack of thiamine prevented neurons from maintaining necessary ATP levels as a result of impaired glycolysis^[27] which caused disappearance of myelin on peripheral nerves resulting in damage of axons and loss of function. All this lead to an increased leakage of current and slowed signal transmission. Demyelination of the auditory tracts and nuclei at the level of the caudal and mid-pons adjacent to the basis pontis has been shown to result in a significant increase in BTT.^[28] Alcoholics were known to suffer from GABA deficiency, either because of its reduced synthesis due to lack of vitamin B6 or because of its accelerated degradation due to increased GABA-T activity^[29] or both; so this effect of alcohol on GABA metabolism and its role in BAEP alterations needs to be investigated in future studies.

Liver enzyme levels exhibited a characteristic pattern in chronic alcoholics. The severity of hyperbilirubinemia reflected the severity of alcoholic hepatitis and was of prognostic value. Serum AST and ALT levels were found to be significantly increased in the patients of AUD as compared to controls (P = 0.000). The AST/ALT ratio was also significantly increased in patients of AUD (P = 0.000) [Table 3]. The AST/ALT ratio was found to be more than 1 which was a possible indication of subclinical alcoholic hepatitis. Alves et al.^[30] had observed in their study that AST/ ALT ratio higher than 1.5 was highly suggestive of alcoholic liver disease and ratio greater than 2 was almost diagnostic. Cohen and Kaplan^[31] also reported that AST/ALT >2 was highly suggestive of alcoholic hepatitis and cirrhosis. They found, in their study, 92% patients with alcoholic liver disease and 70% with post necrotic cirrhosis had AST/ALT ratios >1. The elevated AST-to-ALT ratio in alcoholic liver disease resulted in part from the depletion of vitamin B6 (pyridoxine) in chronic alcoholics.^[32] ALT and AST both use pyridoxine as a coenzyme, but the synthesis of ALT was more strongly inhibited by pyridoxine deficiency than was the synthesis of AST. Alcohol also caused mitochondrial injury, which released the mitochondrial iso-enzyme of AST. The diagnosis of ALD was clinically challenging as there was no single diagnostic test that confirmed the diagnosis and patients were not that forthcoming about their degree of alcohol consumption.

Furthermore, the previous studies have reported these changes to be reversible after a period of prolonged abstinence so follow-up study with these parameters after treatment and abstinence, is also warranted. A novelty of our study was the determination of correlations between EPs (BAER parameters) and biochemical parameters. Main Pearson’s correlations were determined between BAER and duration of AUD and biochemical parameters [Table 3] and [Table 4]. The findings suggested that duration and severity of AUD affected the BAER and biochemical parameters. The latencies of waves of EPs also were positively correlated with the biochemical parameters which indicated that AUD lead to increased BTT and also lead to subclinical alcoholic hepatitis which was reflected by the increased liver enzymes. Balasubramanian et al. have concluded that the central nervous system was involved in alcoholic and non-alcoholic liver cirrhosis as evidenced by abnormal BAEP latencies parameters in their study.^[33]

CONCLUSION

On the basis of these findings, we concluded that AUD caused an increase in the BTT suggesting possible demyelination of auditory tracts. On analysis of the type of BAER abnormalities, the pathological changes seemed to involve the central part of the base of the mid to upper pons. Pathogenic mechanisms in AUD may be demyelination of auditory tracts at the level of caudal and mid pons adjacent to basis pontis, neurotransmitter deficiency, nutritional deficiency and changes in membrane properties which requires further investigations. Hence, absolute latencies of waves and IPL of BAER were useful in AUD for detecting the early changes in auditory and visual pathways. Increased liver enzymes and AST/ALT ratio suggested subclinical alcoholic hepatitis. A novelty of our study was the correlations between BAER and biochemical parameters. The findings suggested that duration and severity of AUD affected BAER and biochemical parameters.