Metab Brain Dis DOI 10.1007/s11011-015-9688-7
RESEARCH ARTICLE
Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests M. M. Lauridsen 1,2 & O. B. Schaffalitzky de Muckadell 2 & H. Vilstrup 3
Received: 5 February 2015 / Accepted: 22 May 2015 # Springer Science+Business Media New York 2015
Abstract Minimal hepatic encephalopathy (MHE) is a frequent complication to liver cirrhosis that causes poor quality of life, a great burden to caregivers, and can be treated. For diagnosis and grading the international guidelines recommend the use of psychometric tests of different modalities (computer based vs. paper and pencil). To compare results of the Continuous Reaction time (CRT) and the Portosystemic Encephalopathy (PSE) tests in a large unselected cohort of cirrhosis patients without clinically detectable brain impairment and to clinically characterize the patients according to their test results. The CRT method is a 10–minute computerized test of a patient’s motor reaction time stability (CRTindex) to 150 auditory stimuli. The PSE test is a 20– minute paper-pencil test evaluating psychomotor speed. Both tests were performed at the same occasion in 129 patients. Both tests were normal in only 36 % (n=46) of the patients and this group had the best quality of life, a normal CRP, a low risk of subsequent overt HE, and a low short term mortality. Either the CRT or the PSE test was abnormal in a total of 64 % of the patients (n=83), the CRT in 53 % (n=69) and the PSE in 34 % (n=44). All these patients had a poorer quality of life, low-grade CRP elevation, moderate risk for
* M. M. Lauridsen
[email protected] 1
Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700 Esbjerg, Denmark
2
Department of Gastroenterology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark
3
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, 8200 Aarhus, Denmark
subsequent overt HE, and a higher than 20 % short term mortality. Both tests were abnormal in 23 % (n=30) of the patients and this group had more advanced cirrhosis and a 40 % shortterm mortality. One of the tests was abnormal in the majority of the patients but concordant in only 60 %. Most cirrhosis patients seem to have impairments of different cognitive domains and more domains with advancing disease. Two abnormal tests identified patients with an increased risk of overt HE and death. Keywords Hepatic encephalopathy . Reaction time . Psychometric test . Portosystemic encephalopathy test . Liver cirrhosis
Introduction Minimal hepatic encephalopathy (MHE) is a frequent complication to cirrhosis. The symptoms are by definition not evident at routine clinical examination but nevertheless MHE compromises the patients’ quality of life, poses a considerable burden on the caregivers, and has substantial socioeconomic consequences (Bajaj 2008; Bajaj et al. 2009; Bajaj et al. 2011a; Groeneweg et al. 1998; Ortiz et al. 2005; Schomerus & Hamster 2001). Fortunately, MHE seems to be treatable and thus efforts should be made to diagnose it (Prasad et al. 2007; Bajaj et al. 2011b; Sidhu et al. 2011). Manifestations of MHE include attention deficits, sleepwake disturbances, and slowing of psychomotor speed. The diagnostic mainstay is detection of the cognitive deficits which requires psychometric testing and the recent guidelines on clinical management of HE encourage the use of such tests (Vilstrup et al. 2014). Unfortunately, there is no gold standard test while a number of validated tests are available. Therefore,
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it is recommended to use two methodologically different psychometric tests covering different domains of cognitive deficits, e.g., computerized vs. pen-and-pencil. Regarding the latter, it is recommended to include the most established method, the Portosystemic Encephalopathy Syndrome (PSE) test as a comparator test among patient populations from different centres that may have preferences for and experience with other methods (Vilstrup et al. 2014). In Denmark, health professionals have many years of experience in using the computerized psychometric test, the Continuous Reaction Time test (CRT) (Jakobsen et al. 2010), for diagnosing and grading MHE. Mounting evidence supports is use: we and others have shown that more than half of liver patients with no other cause of brain involvement have an abnormal test result; that there is no learning or tiring effect; that the test result is not age or gender dependent; not related to educational or social status; and that it is not disturbed by sleep deprivation (Elsass 1986; Jakobsen et al. 2010; Lauridsen et al. 2014; Lauridsen et al. 2012; Lauridsen et al. 2013; Elsass et al. 1985). However, the CRT test has not been systematically conducted in parallel with the PSE test and consequently has not been compared with a test of other cognitive domains. There were two aims of this study: Firstly, we simultaneously applied the CRT and the PSE test in a wellcharacterized unselected cohort of cirrhosis patients without clinically recognizable brain disturbance. We used the results to compare the frequencies of abnormal and normal test results. Secondly, we categorized the clinical characteristics of the patients according to their psychometric test results in order to elucidate a connection between cognition and the stage and course of liver disease.
Patients and methods Patients Two hundred and fifty-one patients with liver cirrhosis from 2 centres were consecutively screened for eligibility. One hundred and twenty-nine patients were prospectively included and underwent CRT, PSE and blood tests on the same occasion between February 2013 and August 2014. The included patients also filled out the Sickness Impact Profile questionnaire on quality of life and Epworth Sleepiness Scale and Sleep Timing Sleep Quality questionnaires for sleep assessment as described in detail elsewhere (Groeneweg et al. 1998; Lauridsen et al. 2014). A Dutch reference population sets the SIP baseline (Groeneweg et al. 1998). The severity of co-morbid diseases was assessed using the Charlson Comorbidity index which is described in detail elsewhere (Jepsen et al. 2008). The exclusion criteria, which none of the 129 patients met, were: HE West Haven Grade 1 or more, dementia (MMSE test score below 24), prior cerebral insult, on-going alcohol abuse
or use of psychoactive medication, severe hyponatraemia (pNa < 125 mmol/L), renal failure (creatinine > 1.7 mg/dL), myxoedema, sepsis, on-going anti-HE treatment, or bleeding within a week of the tests. The included patients were aged on average 59 years (range 40–79 years, SD 9.0), 86 were male and 43 female, and they were educated on average for 11 years (range 4–18 years, SD 2.6). Most patients had alcoholic liver disease (107/129, 83 %) (Table 1). In 45 % (58/129) the cirrhosis was diagnosed by liver biopsy, in the remaining by classical combinations of clinical, paraclinical, and image technique criteria. Sixtynine were in Child-Pugh group A, 49 group B, and 11 in group C and according to the exclusion criteria this grading in no case included HE. Thirty-five (27 %) patients had previously had one or more episodes of overt HE. The CRT and PSE tests were conducted by trained staff between 8.00 and 15.00 in an undisturbed location. The PSE test was completed first, and then the CRT test after a short intermission out of the test locality. The clinical course of each patient was followed from inclusion until January 2015 with a median follow up time of 16 months (IQR=6). The Danish National Committee on Health Research Ethics approved the protocol. The continuous reaction time test (CRT) A 10-minutes computerized test that requires a standard lab top computer, simple software, headphones, and a handheld trigger button (EKHO, www.Bitmatic.com, Aarhus, Denmark). Instructing the patient takes 2 min and when the test begins the patient is left alone and undisturbed to complete the test. During the 10minute-test the patient is exposed to 150 sound stimuli (beeps at 500 Hz and 90 dB). The stimuli are given at random intervals from 2 to 6 s and the patient is instructed to press the button as fast as possible in response to each beep. The soft ware registers the response times and calculates the 10, 50 and 90 percentiles and the CRTindex (the ratio: 50 percentile/ (90 minus 10 percentile)). The CRTindex is the main test result and is a measure of intra personal reaction time stability. A
Table 1 Liver cirrhosis aetiology in 129 patients who underwent CRT and PSE measurement at the same occasion
Cirrhosis aetiology
N
Alcohol Hepatitis C Alcohol and hepatitis C Autoimmune Hepatitis Haemochromatosis NASH Alfa-1-antitrypsin deficiency Unknown Total
107 5 3 3 1 1 1 8 129
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value below 1.9 is considered abnormal and may indicate minimal HE. The method measures and combines motor reaction speed, sustained attention, and inhibitory control, which are all key abilities of daily life functioning (Lauridsen et al. 2013).
Statistical analysis Data was managed using EpiData Manager and EpiData EntryClient. We used Graph Pad Prism for Mac for statistical analysis. The CRTindex is a continuous variable that did not show Gaussian distribution. PSE data are discrete variables ranging from −18 to 6 with Gaussian distribution. The correlation between test results was estimated by Pearson’s r. Contingency analysis used Fisher’s exact test. Patients were divided into 4 groups according to their CRT and PSE test results. The groups were compared by estimating differences between group means and significance summarized by ANOVA p values. P values below 0.05 were considered statistically significant.
Results CRT versus PSE test Either the CRTindex or the PHES was abnormal in a total of 64 % of the patients (n=83) and so both were normal in only 36 % (n=46) (Fig. 1). The CRTindex was abnormal in 53 % (n=69) and the PHES was abnormal in 34 % (n=44) of the patients (Table 2). Both results were abnormal in 23 % (n=30). Thus, the CRTindex and the PHES, normal or abnormal, were in accordance in 60 % of the patients and discordant in 40 % of them (p=0.01). Forty three
Both normal
4
2
Anormal CRT
Both abnormal
-20
-10
0
CRTindex
The portosystemic encephalopathy test (PSE) This is a paper-pencil test consisting of 5 sub-tests: Digit Symbol test (DST), Number Connection Test A (NCT-A), Number Connection Test B (NCT-B), Serial Dotting Test (SDOT), and Line Tracing Test (LTT, time and errors). Completing all tests takes about 15 min and presence of staff for guidance and timing is required. Staff calculation of the final test result using age-adjusted norms takes another 5 min. The test score is calculated from the time (seconds) spent on each sub-test and converted into a score that ranges between −3 and 1. The LTT is converted into 2 scores—a time score and an error score. A score of 0 is given for a performance within +/− 1 SD. The total test score, the portosystemic hepatic encephalopathy score (PHES) is the sum of the scores and ranges from −18 to 6. A result below −4 is abnormal and may indicate MHE. We evaluated the test using the norm data provided in the German manual. The test measures attention, working speed and -accuracy, visual orientation, and visuo-spatial construction (Weissenborn 2012). Multiple versions of the test battery are available to prevent the learning effect of repeated testing. There is no gender effect and the test predicts overt HE and death (Montagnese et al. 2011; Kato et al. 2004).
Abnormal PHES
0
PHES Fig. 1 The CRT and PSE tests outcomes were weakly but significantly correlated, r2 =0.10, p=0.0002. The PHES is abnormal when below −4 and the CRTindex when below 1.9
43 % (30/69) of the patients with an abnormal CRTindex also had abnormal PHES, and 68 % (30/44) with an abnormal PHES also had an abnormal CRTindex. The test results were weakly correlated (r2 =0.10, p=0.0002, Figure 1) with a kappa coefficient of 0.45. Characteristics of the groups with abnormal test results The patients were grouped according to their psychometric test performances into 4 groups: no abnormal test, only CRTindex abnormal, only PHES abnormal, and both results abnormal (Table 3). There was no difference in follow up time, the Charlson comorbidity score, the sleep scores, or blood ammonia concentration amongst the groups. The group with two normal test results had the best quality of life (Sickness Impact Profile score), a normal CRP and a relatively low short term risk of subsequent overt HE and death (9 and 10 %). The group with only an abnormal CRTindex had a higher risk for subsequent overt HE and death (21 and 23 %). In the group with only an abnormal PHES more had experienced overt HE (57 %) and there was also a high risk for Table 2 Distribution of PSE and CRT test results. Results are significantly discordant (Fisher’s exact test, p=0.0093) PHES Abnormal
Total Normal
CRTindex Abnormal 23 % (n=30) 30 % (n=39) 53 % (n=69) Normal 11 % (n=14) 36 % (n=46) 46 % (n=60) Total 34 % (n=44) 66 % (n=85) 100 % (n=129)
Metab Brain Dis Table 3
Patient data grouped according to psychometric test results
Demographics Age (years) Sex, % female Education (years) Clinical scores MELD score Child Pugh score Charlson comorbidity index Sleep Timing and Sleep Quality Epworth Sleepiness Scale Quality of life SIP Biochemistry Venous Ammonia (micromol/l) CRP (mg/L) Other Previous OHE Later OHE Death
Both CRT and PSE normal n=46
Only CRT abnormal n=39
Only PSE abnormal n=14
Both CRT and PSE abnormal n=30
ANOVA P value
58.8 33 (15/46) 11
58.6 44 (17/39) 12
63.6 7 (1/14) 10
60.0 33 (10/30) 10
ns ns ns
10.6 6.2 3.3 4.5
11.0 6.9 3.3 3.8
10.4 6.8 3.5 4.4
14.6 7.9 3.7 4.7
0.01 0.001 ns ns
5.4
5.7
7.1
6.60
ns
11.5
13.8
19.25
18.3
0.04
42 5.5
40 8.5
44 13.3
44 11.2
ns 0.04
17 % (8/46) 9 % (4/46) 10 % (5/46)
21 %(8/39) 21 % (8/39) 23 % (9/39)
57 % (8/14) 29 % (4/14) 14 % (2/14)
33 % (10/30) 26 % (8/30) 40 % (12/30)
0.01 0.03 0.02
Values responsible for significant difference are shown in bold. SIP total score is 3.4 in a Dutch reference population
subsequent overt HE and death (29 and 14 %). The group of patients with 2 abnormal psychometric test results had a higher MELD and Child-Pugh score than the other groups and the highest short-term mortality (40 %) (Table 3).
Discussion The central findings of our study were that the results of one or both of the two conceptually different psychometric tests, the CRT and the PSE, were abnormal in the majority of cirrhosis patients without clinically detectable cerebral disturbances; that the abnormal results in half of the cases did not occur in the same patients; and finally that particularly the patients with no abnormal test and with two abnormal tests were clinically clearly distinct groups: the former with no inflammation signs, a good quality of life, and a low risk subsequent overt HE and death; the latter with severe liver related problems and a very high mortality. Specialists in gastroenterology and hepatology deemed our cirrhosis patients mentally unimpaired and carefully screened for competing causes for encephalopathy of other aetiology. Therefore, encephalopathy in these patients likely was MHE. In accordance with earlier reports from us and from others we found a high proportion of patients with abnormal psychometric tests (Lauridsen et al. 2012; Patidar et al. 2014; Nabi et al.
2014; Bajaj et al. 2014; Li et al. 2013). Also, more patients had abnormal results when more than one psychometric test was applied; a phenomenon also present in our earlier study on the CRT and the Critical Flicker Frequency Method (Lauridsen et al. 2011) and in reports on the use of a battery of tests (Montagnese et al. 2011; Goldbecker et al. 2013; Sharma et al. 2010; Maldonado-Garza et al. 2011). This seems not necessarily to imply that all patients would be afflicted if enough tests were applied. There seems to remain a group of cirrhosis patients with no abnormal test result, in our study and others about one third. The majority of the patients had one or more abnormal test results (83/129), and the test results were markedly discordant in the sense that most patients had only one abnormal test (53/83). Adjustments of the established test threshold values did not appreciably change the dissociation. Also, the predictive value of an abnormal CRT test for having an abnormal PSE test was only 43 % (30/79), and conversely that of an abnormal PSE for having an abnormal CRT test 68 % (30/44). The discordance has multiple possible explanations. Firstly, the tests have different measurement characteristics: The CRTindex is a continuous variable based on repeated measurements and is inherently the most precise and sensitive whereas the PHES changes only if the time spent on a sub test skips a full standard deviation which may well blur small performance changes. Secondly, they differ in intrinsic difficulty. Lastly, the two tests evidently measure
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different cognitive qualities. The interpretation of our data, therefore, must be that cirrhosis in most cases compromises some cognitive functions but not the same domains in all patients. Hence, in spite of the discordance the tests are likely to be equally accurate, just for different cognitive targets. It was not trivial into which group the psychometric tests placed the patients: the four groups varied markedly regarding clinical characteristics, the general trend being that the patients were more sick and had higher risk of subsequent overt HE and death in the case of one abnormal test result and particularly so with two abnormal tests. The conspicuous distribution of the clinical and prognostic factors makes it plausible that the grouping of the patients according to their psychometry was not merely a result of random events. This is in accordance with the notion that HE is a continuum of neuropsychiatric disturbances, also as regards MHE. On the other hand, the increased risk of MHE with worsening of liver disease hinders our ability to assess MHE’s independent impact on mortality and OHE risk. Attempting treatment and observing improved cognition in the groups with abnormal psychometry would give further weight to the fact that we have actually identified patients with MHE. This approach is the focus of our further research. The group of patients with no abnormal test result stood out by having a less affected quality of life, no systemic inflammation activation, and the lowest risk for subsequent HE or death (Table 3). Particularly the normal CRP is noteworthy and in accordance with the recent understanding of inflammation as a possible prerequisite and precipitating factor for HE (Sturgeon & Shawcross 2014; Shawcross et al. 2004). Our data suggest that this may also be the case for low grade inflammation in MHE. Along the same lines the lack of difference in ammonia among the groups may suggest that inflammation is a more important risk factor for MHE than is ammonia. Likewise and in accordance with other reports: quality of life was less affected in the case of normal psychometry (Groeneweg et al. 1998; Arguedas et al. 2003). The two groups with one single abnormal result were different from those with no abnormal result and two abnormal results: they seemed to represent an intermediate group that had common traits but also possible differences. Both these groups had low-grade inflammation activation and a clearly elevated risk for overt HE and death compared to the group with no abnormal test. The group with only an abnormal PHES had the highest frequency of former overt HE among all groups (Table 3). This is in accordance with other studies but remains unexplained and may be random (Goldbecker et al. 2013). The group with two abnormal tests comprised 1/4 of the patients and was characterized by higher MELD and ChildPugh scores and a very high short-term mortality (Table 3). Their ammonia, CRP, and risk of subsequent overt HE was as in the two groups with only one abnormal test, so their dismal
prognosis was probably due to their advanced cirrhosis. It is notable that these very sick patients were not identifiable by clinically evident mental deficits although it cannot be completely ruled out that even more careful scrutiny of patients and caregivers might in fact place some of these patients as having West Haven grade 1 HE. Our findings have bearing on the definition and diagnosis of MHE. The condition is defined as the presence of testdependent signs of brain dysfunction in patients with chronic liver disease who are not disoriented or display asterixis (Vilstrup et al. 2014). It is acknowledged that the condition affects several components of cognitive functioning and therefore the use of at least two tests is recommended (Vilstrup et al. 2014). Consensus lacks on whether one or more tests should be abnormal for the patient to have MHE – or whether one or two should be normal to exclude MHE. Our patients illustrate this problem. There is no doubt that the group with two abnormal tests did have MHE and the clinical characteristics also indicate that this group called for special attention for their advanced liver disease. If this group is the focus of attention both tests are needed because either the CRT or the PSE alone could not reliably identify the patients. On the other hand, although this would be a ‘safe’ definition of MHE it is probably not satisfactory because it leaves out the patients with only one abnormal test and problems with daily life activities, for example fitness to drive. In the same way, a normal result of only one of the tests does not preclude meaningful cognitive impairment. Our data may motivate the approach that any cognitive defect measured by an established psychometric method without other cause in a cirrhosis patient without clinical brain impairment denotes the presence of MHE. The consequence of this definition would be that MHE is the rule rather than the exception in cirrhosis patients and that two tests are always necessary to screen the patients with the aim of identifying all cases of MHE and safely exclude MHE. Our data however do not allow establishment of which tests should be chosen. MHE is reported to be relatively easily treatable by lactulose and rifaximin (Prasad et al. 2007; Sidhu et al. 2011) but the definition of the condition is not always very clear in the treatment studies and it remains uncertain which groups of our patients that would benefit from treatment. Due to the lack of standardization of diagnostic criteria for MHE it is still not recommended routinely to treat all cases. Rather, treatment on a case-to–case basis as judged from the effects of MHE on the patient’s daily living is recommended. In conclusion we found that the majority of cirrhosis patients with no clinical brain impairment had cognitive defects by the use of two different psychometric tests. None of the tests did in itself identify all these patients. The distribution of the test results suggests that the patients with no abnormal test had no sign of systemic inflammation and a less affected quality of life. Conversely, those with two abnormal tests had more
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advanced liver disease. Our results show that a parallel use of CRT and PSE test is necessary to find patients with cognitive impairments within the test domain of these methods and to exclude such problems. The results emphasize the need for consensus on how to psychometrically define MHE not least to establish treatment strategies based on an accepted diagnosis.
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