Impact of Spectral Severity of Alcoholism on Visual-Evoked Potentials: A Neuropsychiatric Perspective

INTRODUCTION

Alcohol (ethanol) is one of the most widely misused drugs in both developed and developing countries. Neural functional pathologies may exist in alcohol addicts even when no obvious clinical manifestations are apparent. Neural functional pathologies may also exist where fatal complications are evident. In the National Comorbidity Study, 29.2% of respondents with alcohol dependence experienced either an independent or a substance-induced mood disorder within the past 12 months of their assessment, a rate that was 3.9 times higher than those who were not alcohol dependent. Bipolar disorder over the previous year was seen in 1.9% of the respondents with alcohol dependence, a rate 6.3 times greater than nonalcoholics.[123] Thus, factors leading to these observed/induced changes are poorly understood, and there are hardly any ways or means to predict who would develop neural insults and who would not. The question that remains is – If alcohol itself causes insult to the brain and to what extent it can be picked up early? Can we detect or measure the continuity or progressive involvement in any way? The best models used in understanding alcohol-induced brain damage have been retrieved from the studies related to alcohol-induced optic neuropathy, encephalopathy, or seizures. For example, patients with alcohol-related optic neuropathy present with a bilateral, progressive, painless loss of visual acuity, dyschromatopsia, and subsequent disc changes including marked temporal disc pallor and retinal nerve fiber layer loss mainly in the papillomacular bundle. Early detection and prompt management may decrease visual impairment and aid in reversing the optic nerve damage and revival in visual status.[4] It has been achieved clinically with the use of visual-evoked potential (VEP), which serves as an important means of obtaining reproducible, qualitative, and quantitative data on the function of the visual pathways and the visual cortex.[5]

A few studies have reported changes in VEP following alcohol consumption. A study in Spain found that the amplitude of VEP increases with pattern reversal, at a blood alcohol level (BAL) of 0.8 g/kg.[6] In the USA, Krull et al.[7] found that alcohol increases the latency of a 250-ms negative component (N2) only in the absence of sleep deprivation. Other studies found no correlation between the level of alcohol consumption and VEP parameters for the first deflection.[8] Quintyn et al.[9] studied changes in the vision of 16 people after consumption of a small quantity of alcohol. Their results indicated that alcohol consumption caused no significant difference in performance. Further, VEP has also been shown to identify how its specific morphological pattern depending on BAL can help us know the severity of the brain involvement. Visual target detection in a treatment-naïve alcohol-dependent (TNAD) sample versus age and gender comparable nonalcoholic controls was investigated by Fein and Andrew.[10] The significant reduction in P3b amplitude in TNAD reflected the effects of active alcohol abuse.

Petit et al.[11] have concluded that elevated alcohol cue reactivity may lead to poorer inhibitory performance in heavy social drinkers and may be considered as an important vulnerability factor in developing alcohol misuse when assessing event-related potentials (ERPs) in them.

Another ERP study by Petit et al.[12] showed that reduced processing of alcohol cues predicts abstinence in recently detoxified alcoholic patients in a 3-month follow-up period. Abstainers presented with decreased P3 amplitude in this study.

While alcohol dependence is associated with augmented automatic attentional biases early in processing, escape drinking was found to be related with more controlled attentional biases to active alcohol cues during a relatively later stage in processing. This was reported in a recent study by Dickter et al.[13]

Recently, occipital ERPs to addiction-related stimuli in detoxified patients with alcohol dependence and their association with 3-month relapse were studied by Matheus-Roth et al.[14] Their results indicated a sensitivity of occipital ERPs to addiction-related stimuli.

However, scanty data exist for the utility of VEP on the progression of neural abnormalities related to spectral severity of alcoholism when it comes to neuropsychiatric implications.

There is a dire need for a study which can explore comprehensively or conceptually empirical evidence or a neurophysiological biomarker which could help us develop preventive vigilance for identifying those who could develop such neuropsychiatric complications. In this context, the present study aimed at evaluating the impact of spectral severity of alcoholism through VEP to understand the emergence of any specific pattern or morphometric abnormalities related to alcohol-induced neuropsychiatric presentation.

METHODOLOGY

RESULTS

A total of 668 sample subjects were screened for obtaining 15 patients each in six subgroups of alcohol spectral severity for studying VEP abnormalities. The mean age of 90 cases of alcohol dependence was 37.71 ± 11.49 years while that of 180 healthy age- and sex-matched volunteers was 39.43 ± 10.67 years while their mean age did not differ significantly and both groups were comparable for age and gender as seen from Table 1. Among six different subgroups of alcohol use disorder/related complications, participants who had physical complications were found to be the oldest among six subgroups with mean age of 47.67 ± 15.53 years while those who have been abstinent for more than 6 months were the youngest (31.20 ± 4.55 years). Mean age of onset for psychiatric comorbidity was far earlier (33.75 ± 13.45 years) than both central nervous system (CNS)-induced complications (42.67 ± 4.04 years) and physical complications.

Table 1 Mean±standard deviation of age and duration of abuse in all the study groups

Tables 2 and 3 show quantitative analysis of VEP using one-way ANOVA for six subgroups so as to identify which of them (N70 latency, P100 latency, N155 latency, and P100 amplitude) might have significant impact on differentiating six subgroups of alcohol spectral severity. We found N70 latency getting significant and distinctive findings in the subgroups of physical complications and psychiatric comorbidities. However, P100 latencies were found to be significantly prolonged in alcohol intoxication, alcohol withdrawal, alcohol-induced physical, psychiatric and neurological complications; therefore, P100 latency delay could be a common, but indistinguishable pathway for alcohol-induced neural insults as observed in our study. When we further compared N155 latencies among these six subgroups, only those with hepatic encephalopathy (physical complications) were found to have highest delay and could be significantly differentiated from the other subgroups. Going a step further, P100 amplitude was significantly lower in patients of alcohol withdrawal and patients of hepatic encephalopathy and alcohol-induced epilepsy, providing us another matrix of association wherein dual associations could be formed. Thus, P100 latency delay and P100 amplitude reduction both are found to be significant only in the subgroup of alcohol-induced epilepsy which can be differentiated from the subgroup of intoxicated patients where P100 amplitude reduction is insignificant, and alcohol withdrawal patient can be differentiated from the patient of alcohol-induced epilepsy when N70 latency parameter has been used.

Table 2 Integration of quantitative results of visual-evoked potential latencies (ANOVA)

Table 3 Integration of quantitative results of visual-evoked potential amplitude (ANOVA)

All these quantitative results are also depicted in Figure 1.

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Figure 1

Integration of quantitative results. (a) VEP Latencies of left eye, (b) VEP Latencies of right eye, (c) P100 amplitude in left eye, (d) P100 amplitude in right eye

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Nevertheless, as shown in Table 4, not all patients necessarily resulted in such observations. The relative percentage of abnormal waveform morphology, latency delay, and amplitude reduction could be segregated with variable quantum of patients, for example, predominantly extended latencies (62.5%) with a statistically highly significant difference (P < 0.001) as compared to healthy controls were observed in cases of alcohol withdrawal syndrome while severe VEP abnormality as in both latency delay and amplitude reduction was found in 75% patients with psychiatric comorbidity and 66.67% patients with neurological complications. Interestingly, an explicit finding of prominent interocular differences was a feature present in 25% of patients with complications. Finally, abnormal waveform morphology, poorer reproducibility, and differentiation ability of the evoked complex which frequently had an atypical shape were obtained in 33.34%. A composite view of representative waveforms obtained in each group is illustrated in Figure 2.

Table 4 Relationship of visual-evoked potential responses with spectral severity of alcoholism

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Figure 2

Visual-evoked potential waveforms in the spectral severity of alcoholism

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DISCUSSION

Alcohol-induced physical/neuropsychiatric complications are etiologically and phenotypically complex. It is evident that a chronic alcohol exposure typically leads to Vitamin B12 or folate deficiency, and over a time, these deficiencies cause accumulations of formic acid and its derivatives, which further inhibit(s) the electron transport chain and mitochondrial function, resulting in the disruption of Adenosine Triphosphate (ATP) production and ultimately impairing the ATP-dependent axonal transport system. Clinicians often need to detect early complications or ideally pick up vulnerable patients for whom such complications are likely to happen in the near future; however, unfortunately, there are hardly any biologically identifiable ways/markers to discern such disposing states. The acute effects of alcohol on the visual cortical/neural system have previously been evaluated with VEP;[67819202122] some of them validated VEP to help in differentiating from normal or alcoholic withdrawal patients, but none of them ever thought for spectral severity or set of specific emerging VEP patterns that might predict the endophenotypic state of the alcohol-induced neuropsychiatric complications. The N75, P100, and N135 components are found to be generated from the striate cortex (V1) or the extrastriate cortex. Alcohol-induced CNS suppression and nerve conduction delay have been reported to be mediated by gamma-aminobutyric acid (GABA), glycine, and adenosine.[23] GABA and glycine are the main inhibitory neurotransmitters in the CNS. Alcohol also increases the level of adenosine, which contributes to the sedative actions of alcohol. Furthermore, interactions of alcohol with myelin or the Ca-ATPase pump at the synapses also may explain these neurophysiological changes.[24] Thus, our study is the first one documented to evaluate and putatively search for optimal neurophysiological biomarkers for differentiating alcohol spectral severity by empirically identifying specific set of patterns obviously discernable (if any) on VEP in six divided set of subgroups of patients. The previous data from >20 studies[92526272829303132333435] [Table 5] showed few robust pointers for usefulness of VEPs in relation to alcohol use disorder (s) not only in in vivo animal experimentations but also in humans helping to differentiate subgroup of patients who had been abstinent for more than 3 months to those who are either intoxicated or having withdrawal. To our surprise, we noted couple of critical studies by Urban et al. and Nazliel et al., who reported that only 28% and 15% of alcoholics had abnormal findings on VEP, which is in contrast to most studies including ours with 75% patients with psychiatric comorbidity and 66.67% patients with neurological complications. Certainly, this is very unique way of neurophysiological differentiation on spectral severity of alcoholism as observed and conceptually derived for the first time ever in the literature [Table 4] from our study. Nevertheless, such relative percentage of abnormal waveform morphology, latency delay, and amplitude reductions in VEP as biomarker clearly holds us back in reaching to unified consolidative neurobiological markers until our understanding and technological advances get widen in the future. An ultimate and implicit goal of the work described in this article is to develop more effective prevention techniques. Increased understanding of the biological mechanisms and genetic impact associated with a specific type of increased vulnerability to alcoholism could enhance prevention efforts in several ways. For instance, PRVEP abnormalities obtained in asymptomatic chronic alcoholics of our study suggest that they may be useful in the detection of early changes and in following the progress of cases with the chronic addiction. This study adds further evidence and emphasis to the sparse literature of usefulness of VEP in a wide spectrum of alcohol abuse seen in young adults. This also helps to establish the importance of a visual electrophysiological evaluation as a valuable adjunct to detailed psychiatric assessment of alcoholics and provides a decent recommendation for VEP to be a part of their routine examination as it might be a useful marker which may help to clearly classify the spectral severity of alcoholism and help in early rehabilitation of addicts.

Table 5 Comparison of various studies related to alcohol use disorder and visual-evoked potentials

Given the multiplicity of experimentally driven and empirical clinical findings of VEP in spectrum of alcoholism, we could elucidate the ingredient of progressively more profound and consistent observable patterns of association that might potentially differentiate the kind of variety of alcohol-related spectra. The importance of a neurophysiological marker's (VEP) precision, accuracy, sensitivity, and specificity cannot be overemphasized. Although it is unlikely that researchers will find a single marker to satisfy all clinical needs, they may eventually develop combinations of markers for specific clinical purposes, from unselective screening (i.e., drinking versus not drinking) to confirming a suspicion of alcohol induced. The conceptual overview espoused here is ripe for both further preclinical experimental testing and exploratory therapeutic interventions. Should this prove to be true, our findings we believe would contribute to a stronger basis for clinical care and a more objective assessment of alcohol-related complications or help in identifying that might relapse or would have neuropsychiatric complications in the future and such phenomena deserve explorations.