Abstract
Objectives: Cognitive dysfunction in patients with hepatic encephalopathy (HE) may be caused by alterations in cholinergic neurotransmission. The objective of the study was to evaluate the efficacy and safety of transdermal rivastigmine in improving cognitive function in patients with overt HE. Design: Randomized, controlled pilot study in which patients with grade 2 or 3 HE were treated with lactulose and randomized to receive either transdermal rivastigmine or placebo for 21 days. The modified encephalopathy scale (MES), object recognition test (ORT), trail test (TT), and serum ammonia were assessed at baseline weekly. Electroencephalography was performed at baseline and the final week of the study. Results: Patients were treated with lactulose (20 g/30 mL three times per day) and either transdermal rivastigmine (4.6 mg/d; n = 15) or placebo (n = 15). Transdermal rivastigmine significantly improved MES, ORT, and TT results compared with placebo (P ≤ 0.0001 at all 3 weeks for all 3 assessments). Serum ammonia improved in both treatment groups, although there was significantly greater improvement with placebo than rivastigmine after 2 weeks of treatment (P What is already known about this subject? ? Current approaches to the management of HE are primarily designed to reduce the levels of ammonia and other gut-derived toxins. ? Traditional strategies for HE treatment have included non-absorbable disaccharides (to decrease bowel transit time) or rifamixin (non-absorbable antibiotics to reduce ammoniogenic flora). ? No transdermal cholinomimetic agents have been used with oral lactulose to date, in HE. What are the new findings? ? Transdermal rivastigmine is safe for use in patients with grade 2 & 3 HE. ? Transdermal rivastigmine in combination with oral lactulose in this study is far superior to lactulose alone in improving cognitive function. How might it impact on clinical practice in the foreseeable future? ? Transdermal rivastigmine in combination with oral lactulose can be used safely in clinical practice. ? Transdermal rivastigmine in combination with oral lactulose is efficacious in improving cognitive function in moderate HE (grade 2/3). Further validation through large randomized clinical trials is required before this is adopted in universal clinical practice of treating HE.
Highlights
Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute and chronic liver disease [1] that contributes to the mortality of patients with end-stage liver disease [2]
The demographics of the treatment groups were similar with respect to age, sex, and body mass index (Table 2)
Though the mean modified encephalopathy scale (MES) of both treatment groups leveled off during weeks 2 and 3, the significant effect of transdermal rivastigmine compared with placebo on the mean MES was sustained at weeks 2 and 3 of the study (P < 0.0001 at both weeks). These results suggest that transdermal rivastigmine was significantly more effective than placebo at improving the degree of cognitive dysfunction in HE in patients receiving concomitant lactulose
Summary
Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute and chronic liver disease [1] that contributes to the mortality of patients with end-stage liver disease [2]. This potentially reversible condition [3] is characterized by a variety of symptoms, including changes in consciousness and cognition [4]. The precise pathogenic mechanisms leading to HE are unknown but are primarily believed to involve the accumulation of ammonia and other gut-derived toxins [5]. Accumulation of ammonia and gut-derived toxins can lead to a variety of pathogenic changes, including alterations in neurotransmitter signaling systems [3] [6]. Therapies that may restore cholinergic balance may be useful in the treatment of patients with HE
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