Randomized, Placebo-Controlled Trial of Transdermal Rivastigmine for the Treatment of Encephalopathy in Liver Cirrhosis (TREC Trial)

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 < 0.03). There were no differences in electroencephalography results between treatment groups. Conclusions: Transdermal rivastigmine with concomitant lactulose significantly improved cognitive-function in patients with overt HE.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). P. P. Basu et al. 256•

Neural circuitry and immunity

“…These findings provide a rationale for further studies exploring the relationship between altered brain cholinergic signaling, decreased vagus nerve activity and increased inflammatory indices in SAE, hepatic encephalopathy and other inflammatory conditions with a deferent degree of brain impairment for evaluating therapeutic interventions. Promising results from a very recent clinical trial with rivastigmine in cirrhotic patients with hepatic encephalopathy represent one of the first validations of this line of therapeutic explorations [138]. Brain pro-inflammatory signaling, cognitive impairment and behavioral deficiencies have been described in obesity and type 2 diabetes, diseases with metabolic and inflammatory etiology [118,119,139–141] (Fig.…”