Potential conflict of interest: Dr. Bajaj is a consultant for, advises, and received grants from Salix and Ocera. Dr. Heuman received grants from Salix and Ocera. Dr. Sterling is a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He is also a consultant for and is on the speakers' bureau of Schering-Plough. He advises Vertex and Wako. He received grants from Bristol-Myers Squibb and GlaxoSmithKline. He also advises and received grants from Bayers. Dr. Shiffman advises and is on the speakers' bureau of Salix.
Patients with minimal hepatic encephalopathy (MHE) have impaired driving skills, but association of MHE with motor vehicle crashes is unclear. Standard psychometric tests (SPT) or inhibitory control test (ICT) can be used to diagnose MHE. The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1-year follow-up. Patients with cirrhosis were diagnosed with MHE by ICT (MHEICT) and SPT (MHESPT). Self and department-of-transportation (DOT)-reports were used to determine crashes and violations over the preceding year. Agreement between self and DOT-reports was analyzed. Patients then underwent 1-year follow-up for crash/violation occurrence. Crashes in those with/without MHEICT and MHESPT were compared. 167 patients with cirrhosis had DOT-reports, of which 120 also had self-reports. A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self-report (17% vs 0.0%, P = 0.0004) and DOT-reports (17% vs 3%, P = 0.004, relative risk: 5.77). SPT did not differentiate between those with/without crashes. A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT, both self-reported (100% vs 50%, P = 0.03) and DOT-reported (89% vs 44%, P = 0.01). There was excellent agreement between self and DOT-reports for crashes and violations (Kappa 0.90 and 0.80). 109 patients were followed prospectively. MHEICT patients had a significantly higher future crashes/violations compared to those without (22% vs 7%, P = 0.03) but MHESPT did not. MHEICT (Odds ratio: 4.51) and prior year crash/violation (Odds ratio: 2.96) were significantly associated with future crash/violation occurrence. Conclusion: Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospective follow-up compared to patients without MHE. ICT, but not SPT performance is significantly associated with prior and future crashes and violations. There was an excellent agreement between self- and DOT-reports. (HEPATOLOGY 2009.)
Minimal hepatic encephalopathy (MHE) is a prevalent neurocognitive complication of cirrhosis that is diagnosed in up to 80% of patients with cirrhosis. It is associated with increased progression to overt hepatic encephalopathy (OHE) and impaired driving skills.1–3 MHE patients have impaired attention, visuomotor coordination, psychomotor speed, and response inhibition.4 Paper–pencil standard psychometric tests (SPT) or the computerized inhibitory control test (ICT) can be used to diagnose MHE.5 The ICT has been validated for the diagnosis of MHE and is highly correlated with driving simulator performance.6–9 On a driving test, MHE patients required significantly higher interventions to prevent an accident compared with patients with cirrhosis without MHE.10 A recent report showed that MHE patients have a higher risk of motor vehicle crashes and traffic violations on an anonymous driving survey.11 However, because these were not corroborated by the Department of Transportation (DOT), and poor insight in MHE could be associated with underreporting, a prospective study is needed.12
The hypotheses tested during this study were (1) MHE patients have a higher motor vehicle crash rate compared with those without MHE on DOT records within 1 year of psychometric testing; (2) Patients impaired on ICT have a higher crash rate compared with patients impaired on SPT; (3) MHE patients have a higher motor vehicle crash risk compared with those without a prospective follow-up over 1 year; and (4) there is significant underreporting of motor vehicle crashes in MHE patients. Patients with cirrhosis have a higher risk of mortality and adverse economic outcomes when they experience crashes; therefore, prevention is an important goal.13 The deleterious impact of motor vehicle crashes to society and the high prevalence of MHE in cirrhosis make this research question important from a tertiary as well as a public health perspective.
CI, confidence interval; DOT, department of transportation; DST, digit symbol test; ICT, inhibitory control test; MHE: minimal hepatic encephalopathy; NCT, number connection test; OHE, overt hepatic encephalopathy; OR, odds ratio; SPT, standard psychometric tests.
Patients and Methods
All patients with cirrhosis included were between 18 and 65 years of age and were recruited from Medical College of Wisconsin and Virginia Commonwealth University Medical Center. Patients with cirrhosis with recent alcohol use (<3 months), on OHE therapy, on psychoactive drugs (anti-psychotics/anti-anxiety medications/interferon), and those who drove less than 20 miles/week were excluded. Written informed consent was obtained from all patients, and the psychometric testing was performed at one sitting after the consent was signed.
Definition of MHE and Psychometric Testing.
All patients with cirrhosis enrolled were administered a battery of four tests (SPT): (1) number connection test (NCT) A; (2) NCT-B, (3) digit symbol test (DST), and (4) block design test along with the ICT.6, 7 NCT-A and NCT-B evaluate mental processing speed and attention. The block design test evaluates visuospatial coordination, and the DST tests for processing speed. The ICT is a dynamic and demanding test that consists of response to lures and targets in a timed manner; a high lure and low target response are indicative of poor psychometric performance. The ICT is available for free download at www.hecme.tv. Control values for the local population had been determined a priori from a sample of 200 controls who were age and education status balanced to the patients with cirrhosis.6, 7, 9, 12 Impaired psychometric performance greater than 2 standard deviations of controls on any two of the SPT components (NCT-A > 35 seconds, NCT-B > 99 seconds, DST < 68, or block design test < 28) was considered diagnostic of MHE using the SPT (MHE SPT).5 The diagnosis of MHE using the ICT was performed on the basis of more than five lure response (MHE ICT).6, 7
DOT Driving History.
The driving records for all patients, which included all driving offenses (both motor vehicle crashes and traffic violations) within the last year, were requested from the DOTs in Wisconsin and Virginia.
Self-Reported Driving History.
All patients were required to complete a driving history questionnaire, which inquired about driving duration and driving offenses within 1 year of psychometric testing.
Motor vehicle crashes were defined as an accident between the occupant's car when they were driving and another vehicle or the environment. Traffic violations were defined as a moving violation (other than parking violations) that resulted in the issuing of a ticket.
A separate analysis of crashes was performed for MHE SPT and MHE ICT patients. The focus of this study was on crashes, but traffic violations were also assessed.
The institutional review board at the Medical College of Wisconsin and Virginia Commonwealth University approved this protocol.
Nonparametric data were analyzed using Fisher's and continuous variables by t tests.
Analysis of motor vehicle crashes within 1 year of psychometric testing was performed between patients with cirrhosis with MHE (using SPT and ICT) and those without MHE. The relative risk for developing crashes in those with and without MHE was computed. Univariate and backward multivariate logistic regressions were performed using occurrence of crashes as the outcome and with age, sex, educational status, driving duration, and diagnosis of MHE by ICT and SPT as predictors.
Prospective Analysis of Driving Records for Future Driving Offenses.
Based on the classification at enrollment, patients were followed up prospectively for the development of crashes and violations as confirmed by DOT records. Patients who had died, had a liver transplant, had stopped driving, or had developed OHE during the follow-up period were excluded as well as those patients with objective evidence in their driving records as having resumed alcohol or illicit drugs. A time to failure analysis using Kaplan-Meier analysis with comparison of the groups using Wilcoxon rank sum test was performed. In addition, a Fisher's exact test was used to examine the association between new crashes in the prospective follow-up period and previously assessed MHE separately by SPT and ICT, and between MHE SPT and MHE ICT. Multivariate logistic regression was conducted to model future driving offenses as the outcome, using age, sex, educational status, prior crashes and violations within 1 year, MHE status using SPT, MHE status using ICT, and driving duration. The rate of future driving offenses in those with prior problems was also determined.
Agreement analysis between self-reports and DOT reports were calculated by kappa coefficient. These analyses were conducted using the self-reported crashes as well as the DOT-reported crashes and were repeated using violations as the outcome in place of crashes. To assess the discrepancies between self-reported driving history and DOT-reported number of crashes and violations in these patients with cirrhosis, kappa coefficients corrected for chance were computed to quantify the level of agreement between measures. Confidence intervals on the kappa coefficients for crashes and traffic violations as well as statistical tests of the kappa value were used to quantify the extent that the agreement between the self-reported measures and the DOT measures differed from chance.
A total of 167 patients with cirrhosis were included; all had DOT records. Of these 120 had self-report and 109 patients had prospective 1-year records (Fig. 1). Demographic, driving, and cirrhosis characteristics of the entire cirrhosis group are shown in Table 1. One hundred twenty-seven patients were from Wisconsin, and 40 were from Virginia.
Table 1. Baseline Demographic Variables
Patients with Cirrhosis (n = 167)
MHE, minimal hepatic encephalopathy; HCV, chronic hepatitis C; MELD, Model for End-Stage Liver Disease; ICT, inhibitory control test; NCT-A, number connection test-A; NCT-B, number connection test-B; DST, digit symbol test; BDT, block design test.
53 ± 9
Educational status (years)
13 ± 2
11 ± 2
Child class (A/B/C)
Cause of cirrhosis (HCV/alcohol/HCV + alcohol/cryptogenic/others)
Driving experience (years since obtaining a driving license)
36 ± 11
MHE diagnosis using SPT (any 2 of the following: NCT-A > 35 seconds, NCT-B > 99 seconds, DST < 68, or BDT < 28)
MHE diagnosis using ICT (lures > 5)
Of the 167 patients, 97 had MHE diagnosed by ICT, and 91 were diagnosed with MHE SPT. One hundred eleven patients had concordance between their MHE diagnosis using both techniques (65 positive and 44 negative by both). Thirty-two patients had MHE by ICT and not SPT, and 26 were diagnosed as MHE by SPT but not by ICT. These were highly correlated (r = 0.4, P = 0.0001), but kappa was 0.29 with a 95% confidence interval (CI), 0.02 to 0.57, indicating fair agreement.
Motor Vehicle Crashes: DOT Reports.
In the 167 patients in whom DOT data were available, there were 18 motor vehicle crashes. Three patients had one traffic violation and one crash each. All crashes were car crashes adjudged to be the patient's fault. None was associated with alcohol. The crashes were property damage in 13 cases and were associated with injury in five cases. The details of MHE diagnosed by ICT versus SPT and individual tests are shown in Figs. 2, 3, and 4 and Table 2.
Table 2. Individual Psychometric Tests and the Risk of Motor Vehicle Crashes
Self-Reported Motor Vehicle Crashes (n = 120)
DOT-Reported Motor Vehicle Crashes (n = 167)
Yes (n = 10)
No (n = 110)
Yes (n = 18)
No (n = 149)
There was a significantly worse performance on ICT and DST in those with self-reported motor vehicle crashes compared with those who did not have a self-reported crash. ICT lures were also significantly higher in patients who had a DOT-reported crash compared with those who did not. A high ICT lure and low DST raw score indicate poor psychometric performance. There were no significant differences in the demographics, alcoholic cause, and other psychometric tests between the groups. The statistically significant comparisons between those with and without crashes are in bold.
P = 0.04,
P = 0.03,
P = 0.04.
BDT, block design test; DOT, department of transportation; DST, digit symbol test; ICT, inhibitory control test; MHE, minimal hepatic encephalopathy; NCT-A, number connection test-A; NCT-B, number connection test-B.
On logistic regression, MHE diagnosed by ICT was the only variable significantly associated with motor vehicle crashes (odds ratio [OR], 5.72; 95% CI, 1.22–26.76; P = 0.0009). The relative risk calculated for patients with MHE diagnosed by ICT experiencing a DOT-reported crash was 5.77, with a 95% CI ranging from 2.01 to 16.6.
Motor Vehicle Crashes: Self-Reports.
Of the120 patients, 69 were diagnosed with MHE ICT and 71 with MHE SPT (Fig. 2B). In these 120 patients with cirrhosis, 10 had crashes (all had one each) over the last year. These were all crashes between cars, all were the patient's fault, and none was associated with a high blood alcohol level.
The details of MHE diagnosed with ICT versus SPT and individual tests are shown in Figs. 2, 3, and 4 and Table 2.
All patients who self-reported crashes had MHE diagnosed by ICT. In this instance, the relative risk becomes too large to compute; the probability in the control condition (those without MHE) for the denominator of the ratio was zero.
Traffic Violations: DOT Reports over 1 Year.
There were 18 violations that were confirmed by the state DOT. Three patients had one violation and one crash each. Most (14, 80%) traffic violations were speeding tickets, two were failure to stop, and one was for driving too slowly. Of the 12 speeding tickets, eight were given for speeds between 11 and 19 mph over the limit, three for less than 10 mph over the limit, and two for driving more than 20 mph over the speed limit.
Of the 18 violations reported by the DOT, 12 (67%) were caused by patients who had MHE diagnosed with ICT compared with nine (50%) with MHE diagnosed with SPT. This comparison was not statistically significant (P = 0.31).
Rates of violations according to the DOT were similar between patients with MHE diagnosed by ICT (12 of 97, 12.3%) compared with patients without MHE diagnosed with ICT (6 of 70, 9%, P = 0.33). Similarly, rates of traffic violations were not significantly different between patients with MHE diagnosed by SPT (9 of 91, 10%) compared with those diagnosed without MHE using SPT (9 of 76, 12%, P = 0.54).
None of the variables, age, educational status, duration of driving, MHE diagnosed by ICT, or MHE diagnosed by SPT, was statistically associated with violations on multivariate regression. There were no significant differences in individual psychometric tests between those with and without a violation reported by the DOT.
Traffic Violations: Self-reports over 1 Year.
In these 120 patients with cirrhosis who self-reported, 14 admitted to traffic violations (all had one each), of which 12 were speeding tickets, one was failure to obey a traffic signal, and one was driving the wrong way. Of the 14 violations, 10 (71%) were MHE diagnosed by ICT, and 12 (86%) were MHE diagnosed by SPT (P = 0.64). There was no statistical difference between the presence of MHE diagnosed by ICT and self-reported violations (MHE diagnosed by ICT positive: 10 of 69, 15% versus MHE diagnosed by ICT negative: 4 of 51, 8%, P = 0.4). There was a statistically higher prevalence of self-reported traffic violations in MHE diagnosed by SPT–positive patients (12 of 91, 13%) compared with those were negative for MHE using SPT (2 of 76, 3%, P = 0.001). There were no significant differences in the demographics, driving duration, and individual psychometric tests in patients who had admitted to a traffic violation or not within the last year.
None of the individual SPT components was able to reliably predict the occurrence of crashes and violations over the preceding year.
The 120 patients who had both self-assessment and DOT reports were compared for discrepancies in the traffic violation and motor vehicle crashes. The discrepancies were divided into those in which the self-reported offenses were more than the DOT-reported ones (Self > DOT) and vice versa (DOT > self).
Motor Vehicle Crashes.
There was a discrepancy in only two patients, and both these patients had not mentioned a crash that was discovered on the DOT records. Kappa coefficients calculated for agreement between the DOT and self-report for motor vehicle crashes was 0.90 (95% CI, 0.72–1.08), indicating strong agreement.
Five patients had discrepancies in the self-reported and DOT-reported violations, two of which were self greater than DOT, and three were DOT greater than self. Two of three patients whose DOT reports had traffic violations that were not reported by them had been diagnosed with MHE by both SPT and ICT, and all of these three violations were speeding tickets. Kappa for agreement between DOT and self-reported violations were significant, with a kappa of 0.80 (95% CI, 0.62–0.98).
Future Driving Offenses: Prospective Follow-up.
Of the 109 patients who had data at the 1-year follow-up, 66 were MHE diagnosed by ICT, and 80 were MHE diagnosed by SPT. Thirty-two were lost to follow-up, 10 were followed for less than 1 year, eight developed OHE, four died of liver-related complications, and four stopped driving for reasons unrelated to their liver disease.
Eighteen patients had experienced a traffic violation or motor vehicle crash over the previous year (11 crashes and seven violations). All motor vehicle crashes involved cars, and all violations were speeding tickets. None of the patients had alcohol-associated crashes, and all incidents were their fault.
There was no significant difference between the percentage of patients who had future driving offenses with MHE diagnosed by ICT (n = 18; offenses, 15; 83%) compared with those with MHE diagnosed by SPT (n = 18; offenses, 17; 94%, P = 0.62).
There was a significantly higher rate of future driving offenses in the MHE diagnosed by ICT (15 of 66, 22%) compared with those without (3 of 43, 7%, P = 0.03). There was no difference between those positive (17 of 80, 21%) and negative (1 of 29, 4%, P = 0.18) for MHE diagnosed by SPT. Using a Kaplan-Meier method with Wilcoxon rank test, patients with MHE diagnosed by ICT were significantly more likely to have future driving offenses compared with those without MHE diagnosed by ICT (P = 0.031). Twenty-eight patients had a prior DOT-reported crash or traffic violation, of which 36% had a future event compared with only 14% of those without a prior DOT-reported crash or violation (P = 0.01).
On multivariate logistic regression with future offenses as the outcome, MHE diagnosed by ICT was statistically associated as a risk factor (OR, 4.51; 95% CI, 1.12–19.39), as were DOT reports of prior crash or violation (OR, 2.96; 95% CI, 1.12–7.82), whereas age was protective (OR, 0.94; 95% CI, 0.86–0.99).
The current study demonstrates a significantly higher rate of motor vehicle crashes in MHE patients defined by the ICT over the preceding year using official driving records and self-report compared with patients without MHE. The findings also demonstrate that ICT was superior to SPT for identification of patients at risk of crashes on prospective follow-up and in the prior year. There was also a significant agreement between the number of crashes and traffic violations admitted by the patients compared with the official DOT records.
The striking observation is the significantly higher rate of motor vehicle crashes in the MHE diagnosed by ICT patients (16%) compared with those without MHE diagnosed by ICT (4%). This is far in excess of the baseline rates of crashes in the population of Virginia and Wisconsin, which range between 3% and 3.3% annually.14, 15 The crashes were the fault of the drivers, and none was associated with alcohol use. The inherent attention deficits and response disinhibition contribute to the driving impairment, along with the predisposition to fatigue.16–20 These results are in line with prior studies that have shown that MHE patients have poor on-road driving test performance.10, 21 This paper also confirms and extends these findings by comparing the self-reported and DOT-reported rates of motor vehicle crashes and traffic violations in patients with cirrhosis with and without MHE. These findings should be specifically considered in the light of the fact that the included age range of patients is considered the safest group with regard to driving outcomes compared with the very young and those older than 70 years of age. This makes the case for an intrinsic difficulty in driving rather than age or lack of driving experience to be the factors associated with the high rate of crashes in the MHE diagnosed by ICT group. Interestingly, traffic violations were not significantly associated with the presence or absence of MHE by SPT or ICT in this paper. Using violations was not part of the a priori hypothesis, because they are highly dependent on the underlying behavior of the patient and also on the chance of a traffic police presence when they occur. In contrast, most motor vehicle crashes are registered in the official DOT database and represent an immediate and extreme driving outcome.
This paper shows that ICT performance is a significantly better indicator of real-world consequences of MHE than the SPT. This may be in part attributable to the relatively stringent criteria required for MHE diagnosis using SPT, in other words, more than 2 standard deviations beyond controls on two tests. However, this is also in line with our a priori hypothesis, because the ICT is a dynamic and demanding test that involves the subject reacting within a fixed period to certain predetermined stimuli, similar to the demands of driving. A high ICT lure response is a sign of frontal lobe immaturity that results in impaired response inhibition.8 Response inhibition involves selective attention to a subset of a complex environment requiring activation of appropriate meanings during learning and activation of appropriate memories at encoding and retrieval. DST is affected by poor processing speed and is a sensitive test for the detection of early impairment. Therefore, it is not surprising that the ICT and DST, which rely on intact frontal lobe activation, would be significantly impaired in patients with prior crashes compared with those without prior crashes. These findings extend the correlation between ICT lures and driving simulator results into the field of actual driving. This should increase the implementation of this test in practice, especially because a normal ICT performance is only associated with crashes in 3% of cases, similar to the background rates.
The current study demonstrates that patients with cirrhosis, with or without MHE, were to a large extent truthful about their crashes and violations. There were five instances in which crashes and violations were not admitted on the self-report but were found on the DOT report. Although it may be possible that this could be a willful misrepresentation, it could also be attributed to confusion as to the actual date of these events. None of the traffic violations and crashes was driving-under-the influence, which indicates that this was not an outcome that patients would need to conceal from a hepatologist who may be evaluating them for transplantation in the future. Conversely, there were two instances in which the self-admitted questionnaire yielded a higher number of violations than those reported by the DOT. This was attributable to the violations having occurred out-of-state. This is against our a priori hypothesis. These findings, however, are in line with those for obstructive sleep apnea patients.22 MHE patients overestimate their driving skills when directly questioned, even though they admit to most driving outcomes truthfully.12 This demonstrates a disconnect between their driving history and their personal interpretation of it and affirms the appropriateness of directly asking the patients for events in their driving history, not their personal assessment of their driving skills, without the need for DOT inquiry.
Patients with cirrhosis have a higher risk of mortality and adverse economic outcomes when they experience motor vehicle crashes; therefore, the prevention of these crashes is essential.13 However, the medicolegal aspect of crashes in MHE cannot be ignored, considering recent reports.23 Complicating this are varying clinician responsibilities to report to the DOT in different US states.24, 25 Although this study shows that MHE patients are statistically more likely to have a history of crashes and develop future problems, this still only applies to 8%-16% of patients with MHE (depending on mode of diagnosis). There are several competing inputs that have to be balanced while driving, and medical impairments only affect them partially. Decisions while operating a car are made on a strategic, tactical, and operational level. The strategic or topmost levels, such as route planning, are not likely to be affected by MHE.26 However, the tactical decisions, including passing and operational decisions such as handling the steering and brakes, are likely impacted by MHE.10 These are similar to the struggles faced by those performing assessments in older adults and those with attention-deficit disorder.27–29
Importantly, a history of crashes and violations was also significantly associated with future driving offenses. Therefore, merely being diagnosed with MHE should not trigger a referral to DOT and should not pose any medicolegal liability to the testing physician. Also, because testing for MHE and subsequent treatment can improve the patients' quality of life, potential liability issues should not hinder the diagnosis of MHE.30 However, a careful elicitation of driving history and discussion with the patients and their families should be performed during clinic visits. Those patients with a higher prior motor vehicle crash and violation rate and with MHE may benefit from official DOT assessment.
The current study is limited by the use of the individual state DOTs, which would necessarily restrict the DOT reports to that state; this may underestimate the DOT-reported traffic outcomes. Because the number of MHE diagnosed by ICT patients in the whole group were higher than MHE diagnosed by SPT, it could be possible that the increased rates of crashes in MHE diagnosed by ICT are higher because of this high number. However, despite this increased number, there was a statistically higher lure number in those with crashes both by their report and by the DOT.
In conclusion, the study demonstrates that patients with MHE diagnosed with ICT have a significantly higher rate of motor vehicle crashes both over the last year and on prospective follow-up for 1 year compared with those without MHE and the background rate in the state. There was a high agreement between patients' self-reports and DOT reports with respect to motor vehicle crashes and traffic violations. Further research into the effect of MHE therapy on these driving outcomes is warranted.