Persistence of cognitive impairment after resolution of overt hepatic encephalopathy

Abstract

Background & aims: In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE).

Methods: Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (DeltaL(1-2)) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE.

Results: In study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (DeltaL(1-2) > or =1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed > or =1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = -0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing.

Conclusions: In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning.

Figure 1. Learning impairment in patients with cirrhosis and overt hepatic encephalopathy

Figure 1: The 1^st half of the ICT is identical to the 2^nd half, therefore learning capability and working memory can be tested using ICT performance. There was a significant learning effect in normal cirrhotics and those with minimal HE but not in overt HE. This indicates a learning impairment in overt HE despite adequate therapy in these patients. A high number of lures indicates poor psychometric performance on the ICT. 1^st: Lures in the first half, 2^nd: lures in the second half, ICT: inhibitory control test, HE: hepatic encephalopathy, overt HE: recent overt hepatic encephalopathy controlled on lactulose therapy.

Figure 2. Change in lure performance on the ICT in patients before and after the development of overt hepatic encephalopathy

Figure 2A: There was a significant improvement in lures before overt HE development. Figure 2B: After those patients developed overt HE, this learning effect on lures disappeared. Fourteen of 15 (93%) patients were able to learn the ICT before developing overt HE while only 4 (26%) were able to reduce their lures once they developed overt HE (p=0.0001). I–III lures: Lures in the 1^st half of the ICT, IV–VI lures: Lures in the 2^nd half of the ICT, OHE: overt hepatic encephalopathy controlled on lactulose therapy.

Figure 2. Change in lure performance on the ICT in patients before and after the development of overt hepatic encephalopathy

Figure 2A: There was a significant improvement in lures before overt HE development. Figure 2B: After those patients developed overt HE, this learning effect on lures disappeared. Fourteen of 15 (93%) patients were able to learn the ICT before developing overt HE while only 4 (26%) were able to reduce their lures once they developed overt HE (p=0.0001). I–III lures: Lures in the 1^st half of the ICT, IV–VI lures: Lures in the 2^nd half of the ICT, OHE: overt hepatic encephalopathy controlled on lactulose therapy.