Cognitive deficits persisting in patients with alcohol dependence syndrome after detoxification

Abstract

Background:

Alcohol-related cognitive deficits (ARCDs) have received little clinical recognition due to doubts regarding the etiopathogenesis and lack of consensus in the diagnostic guidelines.

Aim:

The present study aimed at evaluating the pattern of cognitive deficits in patients of alcohol dependence without dementia, and assessing the relationship between these subtle cognitive deficits and alcohol use parameters.

Materials and Methods:

The study included randomly selected, consenting, non-delirious patients of alcohol dependence syndrome (ADS) without dementia, admitted in the de-addiction ward. Cognition was assessed by Mini Mental State Examination (MMSE) of the Diagnostic Interview for Genetic Studies at admission and after 7 days of detoxification. “T-test” was used to assess cognitive improvement and residual deficits, while correlation analysis was used to compare the relationship between alcohol use parameters and MMSE scores.

Results:

We recruited 63 male patients with mean age of 38.62 (±9.61) years. Significant improvement was noted in cognition post-detoxification. However, most of the subjects had subtle cognitive deficits which may fall within the realm of ARCD, mainly in domains of attention/concentration, recall, language, and visuo-constructional skills (P < 0.05). The cognitive deficits correlated with duration and severity of alcohol dependence (P < 0.05), however, were independent of daily alcohol quantity.

Conclusion:

Subtle cognitive deficits may persist in patients of ADS without dementia, even after successful detoxification. They may be easily missed despite contact with mental health professionals, as these deficits may only be evident on neuro-psychological testing.

Alcohol is a global public health issue owing to its vast array of associated complications.[1] Excessive and prolonged use of alcohol can lead to permanent structural and/or functional brain damage progressing to cognitive deficits and dementia.[2] Cognitive deficits specifically related to sustained alcohol abuse have received little attention in spite of the growing magnitude of alcohol-related problems.[3]

Alcohol-related cognitive deficits (ARCDs) lack definitive clinical recognition, predominantly due to the lack of a distinct pathophysiological profile. There is little consensus on characteristics of alcohol-related dementia (ARD) as well.[4] Whether the cognitive impairment or dementia is due to the direct result of ethanol neurotoxicity or due to another underlying pathology (thiamine deficiency or head injury, for instance) or if it is multifactorial, is unknown at present.[5] The correlation between amount and duration of alcohol consumption and occurrence of ARCD is not well established.[6]

Various confounding factors complicate the assessment of ARCD. Among others, they include lifestyles of alcohol abusers, associated complications such as head injury, psychiatric, and other substance abuse co-morbidities, and a higher rate of vascular risk factors, which by themselves may independently predispose an individual to cognitive decline.[7] Due to differences in methodology and the symptoms being assessed, it may be difficult to interpret the results of neuro-psychological and psychometric studies evaluating ARCD Studies have focused on ARD more than on ARCD. Some unanswered questions are: does ARCD persist after detoxification, and are they present in alcohol-dependent patients without dementia. The relationship of ARCD in detoxified patients without dementia with age, duration of alcohol use, severity of withdrawal symptoms, and other dependent variables needs assessment.

Subtle cognitive deficits in immediate post-detoxification and abstinent phases are often missed in clinical practice as formal cognitive assessments are not conducted routinely. ARCD can adversely impact psychotherapy like Motivational Interviewing, Motivation Enhancement Therapy, and Cognitive Behavior Therapy for addiction as patients with cognitive deficits struggle to process novel concepts, remember them, and implement them in daily practice. ARCD can also adversely affect compliance to pharmacological regimes prescribed to address craving and relapse.

The present study aimed at evaluating the patterns of cognitive deficits in alcohol-dependent patients who do not have ARD or amnesia and to assess the relationship between these subtle cognitive deficits and various alcohol use parameters.

MATERIALS AND METHODS

This study was conducted in the Psychiatry and De-Addiction ward at a tertiary care, government medical teaching hospital in New Delhi, India, from 2010 to 2013. All successive admitted male patients between 18 and 60 years of age with a diagnosis of alcohol dependence syndrome (ADS) and uncomplicated alcohol withdrawal as per International Classification of Diseases, Diagnostic Criteria for Research: 10^th edition (ICD-10, World Health Organization, 1993),[8] who provided written informed consent to participate in the study and undergoing indoor detoxification were included. The protocol was approved by the Institutional Ethics Committee (IEC) of the institute (as a part of thesis protocol for MD Psychiatry, Batch 2010).

The patients were evaluated for delirium at baseline using Delirium Rating Scale (Trzepacz et al., 1988).[9] Those who were oriented and scored below 10 on the DRS were considered for recruitment. Cognitive status was initially assessed at the time of admission by the free-for-use Modified Mini Mental State Examination (MMMSE) of the Diagnostic Interview for Genetic Studies, translated and validated into Hindi (DIGS).[10] DIGS MMMSE has a combined score of 35 as opposed to a score of 30 in the original MMSE (Folstein et al.)[11] (DIGS MMMSE has 5 extra marks for attention and concentration). Alcohol-dependent patients who scored 27 or more on DIGS MMMSE were recruited, implying that patients with severe cognitive deficits and dementia were excluded from the study.

The other exclusion criteria included co-morbid psychiatric disorders [excluded after screening through Mini International Neuropsychiatric Inventory,[12] severe medical illnesses (hepatic encephalopathy, uncontrolled diabetes, and hypertension), dependence on other substances excluding nicotine, history of head injury, and mental retardation. To rule out co-morbid medical illnesses, comprehensive clinical, and neurological examination, including elaborate laboratory investigations (with ultra-sonogram whole abdomen) was done after admission. Patients diagnosed with severe/uncontrolled hypertension or diabetes were also excluded as these are vascular risk factors for cognitive impairment and may confound with ARCD.

Participants were assessed on Clinical Institute Withdrawal Assessment–Alcohol revised (CIWA-Ar) for severity of alcohol withdrawal syndrome (AWS) at baseline (day of admission).[13] Alcohol Use Disorders Identification Test (AUDIT) was used to define the severity of ADS, and patients scoring more than 10 on AUDIT were included in the study.[14] The patients were randomized and detoxified using either the fixed tapering dose (FTDR) or symptom-triggered (STR) lorazepam regimen.[15] The present study is in conjunction or ancillary to a broader study which compared the effectiveness of symptom-triggered and fixed-dose lorazepam regimes for successful alcohol detoxification. A sample size of 60 was taken in the original study considering the prevalence of ADS in India to be 3%. The DIGS MMMSE was repeated 7 days after successful detoxification in both regimes to check for persisting cognitive deficits if any.

All data were recorded systematically and analyzed using SPSS version 17.0. Normally distributed continuous variables were compared by the independent t-tests, while Chi-square tests were used to compare categorical variables. Correlation analysis was used to compare the relationship between various alcohol use parameters and MMMSE scores.

RESULTS

A total of 82 admitted patients meeting the inclusion criteria were asked to enroll in the study, of which 77 provided written informed consent. All were accompanied by a close relative throughout their stay in hospital and for all evaluations. One patient left against medical advice on the first day due to family issues. Twelve patients had co-morbid severe medical complications (ECG abnormalities, liver cirrhosis, uncontrolled diabetes and deranged laboratory investigations). One patient consumed alcohol after admission and was excluded. Finally, 63 patients completed the study.

The mean age of recruited cases was 38.62 (±9.61) years, and the total duration of alcohol consumption was 17.12 (±8.21) years [Table 1]. All subjects were males, reflecting the profile of subjects seeking de-addiction treatment at our center. The average baseline AUDIT score was 31.55 (out of total score of 40), reflecting high severity of ADS. Only 3 patients had mild AWS, whereas 60 had moderate to severe alcohol withdrawal symptoms.

Table 1:

Socio-demographic and clinical variables of the study group (N=63)

Parameter		Mean±S.D
Age		38.62 (± 9.61)
Duration of alcohol consumption		17.12 (± 8.21)
Audit score		31.55 (± 3.92)
CIWA-Ar score at admission		14.38 (± 5.36)
Alcohol Withdrawal Severity	Mild (CIWA-Ar score <8)	3
	Moderate to severe (CIWA-Ar score >8)	60
Education	12th pass and above	44 (70%)
	Below 12th	19 (30%)

CIWA-Ar-Clinical Institute Withdrawal Assessment-Alcohol Revised

The results show that there was a significant difference between baseline and final MMMSE scores post-detoxification (P < 0.05), suggesting that initial cognitive impairment may have been influenced by their state of alcohol withdrawal. Scores improved considerably at the end of the study; however, many did not achieve full scores [Table 2]. Most of the patients had subtle cognitive deficits despite successful detoxification which may fall within the realm of ARCD. On subanalysis of post-detoxification MMMSE scores, our patients had these deficits in the domains of recall, attention/concentration, language, and visuo-constructional skills.

Table 2 :

Changes in scores of MMMSE domains of subjects with alcohol dependence who underwent successful detoxification

Change in MMMSE domains	Baseline Score (Day 0)	Final Score (Day 14)	Mean Change	Std. Deviation	t	Significance (2-tailed)
MMMSE (0-35)	29.94	33.45	- 3.51	1.85	- 15.50	0.000*
Registration (0-3)	2.98	3.00	- 0.02	0.12	-1.00	0.321
Recall (0-3)	2.40	2.78	- 0.38	0.53	- 8.29	0.000*
Orientation (0-10)	9.54	9.98	- 0.44	0.64	- 5.49	0.005*
Attention/Concentration (0-10)	7.38	9.36	- 1.98	1.10	- 14.11	0.000*
Language (0-8)	6.98	7.45	- 0.47	0.48	- 5.97	0.000*
Visuo-constructional (0-1)	0.66	0.88	- 0.22	0.45	- 4.79	0.000*

MMMSE–Modified Mini Mental State Examination; * - Significant atP value of 0.01

At the time of admission, the patients had significant deficits in domains of attention and concentration, followed by recall, visuo-constructional skills, language, and orientation. Registration was the least affected parameter and was relatively preserved before detoxification, with most of the subjects achieving full scores. Hence, no significant change in the domain of registration was observed after detoxification (P = 0.321).

When post-detoxification MMMSE scores were compared with baseline MMMSE scores, the most significant improvement was in the domain of attention/concentration and language, although deficits persisted in the visuo-constructional domain and recall [Table 2]. Still, most patients did not achieve the full scores in all of these domains. We surprisingly observed near complete improvement in orientation upon successful detoxification (mean score of 9.54 to 9.98), in spite of including only non-delirious patients in the sample (P < 0.05).

On evaluating the association of cognitive impairment with various alcohol use parameters [Table 3], we found that duration and severity of ADS significantly correlated with (P < 0.05) both baseline MMMSE scores and change in MMMSE scores. However, the final MMMSE scores post-detoxification was independent of these variables. There was no impact of the type of detoxification regime, amount of usual alcohol intake, and duration since the last alcohol intake on cognition. Also, MMMSE scores did not correlate with age (R = -.25, P value 0.058) and literacy levels (R = 0.116, P value 0.365).

Table 3:

Correlation between alcohol use parameters and MMMSE scores (P)

Parameters	Baseline MMMSE	Final MMMSE	Change in MMMSE	Remarks
Usual Alcohol Intake (Quantity) (Pearson’s Correlation-2 tail significance)	0.931 (0.017)	0.636 (0.019)	0.895 (- 0.010)	Cognitive deficits were independent of the quantity of intake
Time Since Last Intake (Pearson’s Correlation-2 tail significance)	0.509 (0.085)	0.079 (0.227)	0.058 (0.251)	Cognitive deficits were independent of time elapsed since last intake
Lorazepam Regimen - FTDR and STR (Univariate ANOVA)	0.196	0.449	0.237	Cognitive deficits were independent of detoxification regimen
Severity of Alcohol Dependence (AUDIT) (Pearson’s Correlation-2 tail significance)	0.004** (-0.357)	0.507 (-0.085)	0.001** (0.401)	Improvement in MMMSE occurred even with severe dependence and it correlated with severity of dependence
Duration of Alcohol Dependence (Pearson’s Correlation-2 tail significance)	0.022* (-0.289)	0.448 (-0.097)	0.014* (0.307)	Improvement in MMMSE occurred even with long duration of dependence and it correlated with duration of alcohol intake
Severity of alcohol withdrawal-CIWA Ar score (Pearson’s Correlation - 2 tail significance)	0.001** (-0.590)	0.001** (-0.435)	0.001** (0.477)	Improvement in MMMSE occurred even with severe alcohol withdrawal and improvement continued after withdrawal was managed adequately

MMMSE—Modified Mini Mental State Examination, FTDR—Fixed Tapering Dose Regimen, STR—Symptom-Triggered Regimen, AUDIT—Alcohol Use Disorders Identification Test, ANOVA—Analysis of variance. * - Significant at P value of 0.01. ** - Significant at P value of 0.001

DISCUSSION

This study was conducted with the aim of assessing subtle cognitive deficits not amounting to Dementia in subjects with alcohol dependence and their specific characteristics if any. Further, if they persist, how do they correlate with various alcohol use parameters? In addition, we evaluated the differential impact of detoxification on improvement in various domains of cognition.

We found that cognitive deficits not amounting to dementia (MMMSE score more than 22) in subjects with ADS improved following successful detoxification, as seen by pre- and post-detoxification MMMSE scores (mean scores of 29.94 and 33.45, respectively, improvement of 3.51 points). However, many participants did not achieve full scores after detoxification (7^th day post-detoxification, duration of detoxification varied depending upon the regime followed) suggesting that subtle cognitive deficits do persist in such individuals. We found that these residual post-detoxification cognitive deficits are more likely to be in the domains of attention-concentration, recall, language, and visuo-spatial domains (P < 0.001).

Cognitive deficits in the domains of attention-concentration, recall, language, and visuo-spatial domains will adversely impact success of psychotherapeutic approaches (Motivational Interviewing, Motivation Enhancement Therapy, Cognitive Behavior Therapy for addiction, etc.) as patients with cognitive deficits struggle to process novel concepts, remember them and implement them in daily practice in relation to substance-related behaviors. ARCD can also adversely affect compliance to pharmacological regimes prescribed to address craving and relapse. Further, as ARCDs are often missed and/or not assessed formally in routine practice, relapses are often attributed to lack of motivation and poor compliance rather than to subjects being cognitively impaired, thereby contributing to poor prognostic outcomes.

Whether these cognitive deficits persist for a longer time after detoxification is a matter of further prospective research. Some studies have reported that complete abstinence for as little as a week, resulted in improvement in cognition.[16] Some authors have postulated that improvement in cognitive domains may continue over long periods of abstinence, extending up to several months to years while certain residual cognitive impairments may persist.[17] The improvement in motor abilities and cognition has been shown to be accompanied by reversal of white matter shrinkage.[18,19] Deficits due to thiamine deficiency may persist longer (spatial memory impairment and increased perseverative behavior) while the effects of chronic ethanol exposure (working and episodic memory impairment) improve/recover with prolonged abstinence.[20]

Patients with dementia or cognitive deficits due to alcohol (ARD/ARCD) have a different neuro-psychological profile compared to patients with other types of dementia. Patients with alcohol-related dementia are unlikely to demonstrate language impairments.[21,22] in our study, patients did show impairments in language but recovered significantly post-detoxification. ARD patient groups show deficits in verbal learning and overall delayed recall compared to healthy subjects and subjects with Alzheimer’s disease.[23,24] ARD groups performed poorly on visuo-spatial measures (copying tasks and clock drawing), executive functions, working memory and motor speed compared to healthy controls,[23,25,26] similar to our sample. If these deficits persist over long periods following detoxification, these could potentially serve as a marker for dementia syndrome associated with alcohol dependence.

The clinical profile of ARD seems to reflect both cortical and subcortical pathology,[24] supported by neuro-imaging findings of hypometabolism in frontal cortices, along with basal ganglia and thalamus.[27] Reflecting a compromised fronto-cortico-cerebellar functional network, impairments in executive functioning and working memory commonly endure following short-term abstinence.[28] Similar to these findings, we found that in spite of improvement, some cognitive deficits persisted in these domains at least over the short term.

Patients with ARCD show anterograde amnesia and impaired recall of past events, with comparatively spared implicit and procedural memories.[29] The recall was better for more remote time periods compared to immediate recall. Similarly, we found that our patients had significant disturbances in short-term recall of the given words in MMMSE test. Alcohol-abstinent people over a period of up to a year may show improved attention, working memory, problem-solving ability and better visuo-spatial functioning. However, impairments in areas of learning and short-term memory are more persistent.[30]

We tried to correlate the cognitive deficits with various alcohol use parameters, to evaluate the impact of pattern of alcohol use on cognition. Most of our patients were moderate to heavy drinkers. We found that their cognitive deficits were independent of the quantity of usual alcohol intake. Light-to-moderate alcohol consumption is reportedly associated with a lower risk of dementia[31] while heavy drinking is associated with a higher risk.[32,33] Some evidence suggests that limited drinking within this range in earlier adult life may be protective against dementia later.[34,35] More recent studies concluded that even heavy regular drinking is neither a direct cause of cognitive impairment[29] nor is it protective for dementia.[36] We may conclude that moderate to severe alcohol consumption leads to cognitive impairment which may not amount to dementia in short term.

In our study, the baseline cognitive impairment was greater in severe alcohol dependence with longer duration of alcohol intake. Similarly, other studies have reported direct association between decline in cognitive performance and chronicity and severity of use of alcohol.[37] Chronicity and severity of alcohol use also determine the rate and the extent of cognitive recovery.[19]

Binge drinking and multiple withdrawals may significantly exacerbate cognitive impairment due to greater neuronal damage.[38,39,40] We did not take into account the number of previous attempts at detoxification. Still, considering that these alcohol-dependent subjects had long durations of intake and greater severity of withdrawal, it may be assumed that many would have made past unsuccessful attempts.

Limitations

There are certain limitations to the present study. The findings are ancillary as the study had been powered to assess the effectiveness of symptom-triggered and fixed-dose Lorazepam regimes for successful detoxification and not assess ARCD. As in most studies of substance use, it included only self-reported measures of alcohol consumption which raises possibility of recall bias and intentional misreporting. Only MMMSE was used to assess cognition, which may have missed some important domains of cognition. However, we wanted to use scales of universal clinical applicability as much as possible. Follow-up was not done to evaluate the course of these cognitive deficits: whether they persisted or remitted over time.

CONCLUSION

From the findings of our study, we can conclude that while successful detoxification can help improve cognitive impairment observed in acute stages of alcohol withdrawal, subtle cognitive deficits persist even after successful short-term detoxification in most alcohol-dependent subjects. These deficits usually persist in the domains of short-term recall, working memory, language, attention/concentration, and visual-spatial measures. Our study suggests that with no subjective memory impairment, these subtle cognitive deficits may be easily missed despite contact with mental health professionals, as these are only evident on neuro-psychological testing.

Further, longitudinal studies are required to assess the course of these subtle deficits with continued alcohol use versus abstinence, to evaluate the timeframe within which these deficits recover and specific markers which may help identify individuals who are prone for developing an alcohol dementia syndrome.

Authors’ contributions

All the authors have contributed significantly in designing, conducting and framing the research paper.

Ethics approval statement

The study has been approved by the institutional ethical Committee of Dr Ram Manohar Lohia Hospital New Delhi. The study has been performed in accordance with ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Conflicts of interest

There are no conflicts of interest.

Data availability statement

The data will be shared with the journal/ prospective researchers by the authors as per the regulations.

Funding Statement

Nil.