Patients who develop extrapyramidal symptoms on a background of cirrhosis and portosystemic shunting (PSS) form a unique subset of so-called acquired hepatocerebral degeneration. The syndrome is different from other forms of Parkinsonism that develop in patients without liver disease and rarely responds to standard treatments for hepatic encephalopathy (HE). Rifaximin is a nonabsorbable antibiotic which has recently been shown to be efficacious in the secondary prevention of recurrent HE. It is postulated to decrease gut ammonia production, bacterial translocation, and endotoxemia.
We report three patients with advanced cirrhosis, evidence of PSS, and debilitating extrapyramidal symptoms including tremor, bradykinesia, cog-wheel rigidity, drooling, loss of facial expression, and shuffling gait whose symptoms dramatically improved after receiving rifaximin 600 mg twice daily for 4 weeks. These patients had failed to respond to 3-6 months of lactulose (20-40 mls three times daily) which aimed to produce 2-3 loose bowel motions each day. Each patient was independently evaluated by a hepatologist (D.S.) and a neurologist (C.C.). Neuropsychometry testing (Number Connection Test [NCT]A/B), venous ammonia, EEG, and magnetic resonance imaging (MRI) brain/DaTscan were performed before and 4 weeks after receiving rifaximin.
Patient 1 (male, 61, alpha-1-antitrypsin deficiency, ammonia 76 μmol/L [normal range 12-50 μmol/L]) was unable to complete the NCTA/B at baseline. On rifaximin his bradykinetic rigidity syndrome, drooling, and gait disturbances resolved. His neurocognitive function dramatically improved and his repeat NCTB test was within the 75th-90th centile for a normal healthy age-matched population. His symptoms resolved 3 months following transplantation when his rifaximin was discontinued. Patient 2 (female, 64, alcohol-related cirrhosis, abstinent, ammonia 67 μmol/L) improved her NCTA test from the 10th to the 50th centile, with resolution of bradykinesia, tremor, and reduction in somnolence. Patient 3 (male, 66, alcohol-related cirrhosis, abstinent, ammonia 67 μmol/l) had remarkable improvement in his asymmetric bradykinetic rigid syndrome, regained facial expression, and was mobile with assistance, whereas previously he had required hoisting. None of the patients had any change in their ammonia level or EEG despite resolution of symptoms. MRI brain post-rifaximin in these patients showed reduction of the high T1 signal in the globus pallidus, imaging features classically associated with Parkinsonism in cirrhosis (Fig. 1).
In summary, rifaximin was efficacious in the treatment of the Parkinsonian phenotype of HE and was independent of blood ammonia levels. This raises the fascinating possibility that reducing systemic endotoxemia and thereby inflammation may ameliorate the extrapyramidal manifestations of PSS in patients with cirrhosis. Larger clinical trials are now warranted.
Beverley Kok, MBBS1
Matthew R. Foxton, M.D.1
Christopher Clough, M.B., Ch.B.2
Debbie L. Shawcross, Ph.D.1
1Institute of Liver Studies, King's College Hospital at King's College London School of Medicine, London, UK
2Movement Disorders Clinic, Department of Neurology, King's College Hospital, London, UK