1 long-term parenteral nutrition, 3 and after occupational manIncreasing evidence suggests that manganese deposiganese exposure sufficient to cause Parkinson's-like extrapytion is responsible for the T 1 -weighted magnetic resoramidal symptoms. 4 MRI signal hyperintensities may disapnance imaging (MRI) signal hyperintensity consistently pear after the cessation of manganese administration during observed in pallidum of cirrhotic patients. However, the parenteral nutrition 5 or after liver transplantation. 1 More relationship between blood manganese and the etiology recently, we demonstrated that pallidal manganese concenor severity of liver disease, as well as the neurological trations were markedly elevated in cirrhotic patients who symptomatology in these patients, has not been well esdied in hepatic coma. tablished. In the present study, blood manganese conHepatic encephalopathy (HE) is a spectrum of neuropsychicentrations were measured by atomic absorption specatric disturbances occurring in patients with chronic liver trometry together with MRI and neurological evaluation disease. Variable degrees of impairment of mental function in 57 cirrhotic patients with various etiologies and seare observed, and close clinical examination may disclose exverity of liver disease. Blood manganese concentrations trapyramidal signs. Recent reports evaluating the relationwere elevated in 67% of cirrhotic patients and were sigship between pallidal hyperintensity and neurological sympnificantly higher in patients with previous portacaval toms provide conflicting results. 7-12 Because manganese anastomoses or transjugular intrahepatic portosystemic toxicity may result in both pallidal hyperintensity and in shunt (TIPS). Pallidal signal hyperintensity was ob-Parkinson's-like extrapyramidal symptoms, and because served in 88% of patients, and significant correlations similar symptoms have been described in patients with were demonstrated between blood manganese and palchronic liver disease, we evaluated and attempted to correlidal index (PI) (a measure of pallidal signal hyperintenlate, in the same cirrhotic patients, neurological status, T 1 -sity), as well as Child-Pugh score. Assessment of extrapyweighted pallidal MRI signal intensity, and blood manganese ramidal symptoms using the Columbia rating scale concentrations. revealed a significant incidence of tremor, rigidity, or akinesia in up to 89% of cirrhotic patients. However, PATIENTS AND METHODSthere was no significant correlation between blood manPatients. Fifty-seven patients with biopsy-proven cirrhosis were ganese and extrapyramidal symptoms, although severincluded in the present study. None of them had clinically overt ity of akinesia was significantly greater in Child-Pugh encephalopathy. Clinical and biochemical characteristics are shown C patients. Extrapyramidal symptoms could result from in Table 1. a toxic effect of manganese on basal ganglia dopaminerNeurological evaluation was performed by the same neurologist gic function. These findings further support a rol...

Brain edema, leading to intracranial hypertension and brain herniation, is a major cause of death in fulminant liver failure. Astrocyte swelling is a prominent neuropathological feature in experimental fulminant liver failure. It has been postulated that the osmotic effects of glutamine, generated in astrocytes from ammonia and glutamate in a reaction catalyzed by glutamine synthetase, could mediate brain swelling. Normal rats and rats that received a portacaval anastomosis were infused with ammonium acetate or a sodium acetate control; brain water in cerebral cortex was measured with the gravimetry method, intracranial pressure by means of a cisterna magna catheter and cortical amino acids using high-performance liquid chromatography. Although brain edema was detected in both groups receiving ammonia, it was of a greater magnitude in portacaval anastomosis rats (80.94% + 0.17% vs. 80.24% + 0.09%, p < 0.01), resulting in the development of intracranial hypertension. When portacaval anastomosis rats were infused with ammonium acetate and pretreated with 150 mg/kg methionine-sulfoximine, an inhibitor of glutamine synthetase activity, brain edema was ameliorated and intracranial pressure did not rise. A dose-dependent reduction in brain glutamine levels was seen with increasing doses of methionine-sulfoximine; however, brain edema did not decrease beyond the 150 mg/kg dose, suggesting that the increase in brain water was not solely a result of glutamine accumulation. We conclude that brain edema of a magnitude that results in intracranial hypertension is more likely to develop in rats after portacaval anastomosis receiving a continuous ammonia infusion. The osmotic effects of glutamine appear to mediate, but only in part, the increase in brain water seen in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

as gastrointestinal bleeding, constipation, or sedative use. 1 L-carnitine administration prevents the neurological Symptoms of PSE are generally reversible suggesting a metasymptoms of acute ammonia toxicity. To further evalubolic cause. ate its efficacy in the prevention of hepatic encephalopaOf the possible neurotoxins implicated in PSE, ammonia thy in hyperammonemic conditions, L-carnitine (16 was the first to be incriminated 2 and is still considered a mmol/kg, intraperitoneally [ip]) was administered 1 leading candidate. [2][3][4][5] Neurochemical mechanisms so far prohour before ammonium acetate (NH 4 OAc) (8.5 mmol/kg, posed to explain the neurotoxic effects of ammonia include subcutaneously) to portacaval shunted (PCS) rats. Ceredirect effects on excitatory and inhibitory neurotransmisbrospinal fluid (CSF) ammonia, lactate, and amino acid sion 6,7 and on neuron-astrocytic metabolic trafficking 8 as well levels were measured in relation to deteriorating neuroas effects mediated via glutamine accumulation in brain. 9 logical status in these animals. None of 35 L-carnitineIf sufficiently prolonged or severe, ammonia may also have treated animals showed neurological deterioration after adverse effects on brain energy metabolism. 10,11 In this latter NH 4 OAC administration compared with saline-treated regard, there is evidence to suggest disruption of the malatecontrols; the latter manifested severe encephalopathy aspartate shuttle in brain in experimental PSE. 11 In addition, progressing through loss of righting reflex to coma. Surresults of in vitro studies suggest inhibition of the tricarboxvival rate was 100% in the L-carnitine -treated group ylic acid cycle enzyme a-ketoglutarate dehydrogenase compared with 5% in saline-treated controls. Following (aKGDH) by pathophysiological concentrations of ammonia 12 NH 4 OAC administration to PCS rats, CSF ammonia inand thus the potential for impaired cerebral energy metabocreased to 0.93 { 0.15 mmol/L and 1.24 { 0.15 mmol/L at lism. precoma and coma stages of encephalopathy (P õ .01)Few treatments of hyperammonemic syndromes are specifrespectively. Treatment with L-carnitine reduced CSF ically designed at counteracting the molecular actions of amammonia at both precoma and coma stages; the timemonia. It has been reported that L-carnitine administration course of this protective effect paralleled blood and CSF to mice 1 hour before a lethal injection of ammonium acetate L-carnitine accumulation. CSF alanine and lactate in-(NH 4 OAc) prevents both symptoms of ammonia toxicity and creases following NH 4 OAC administration to PCS rats death. 13 It was suggested that L-carnitine led to decreased were significantly attenuated following L-carnitine blood and brain ammonia in part by induction of ureagenesis. treatment. However, L-carnitine treatment did not leadSubsequently, the ammonia-lowering effects of L-carnitine to significant reductions in plasma ammonia nor CSF or were confirmed in portacaval shunted rats. 14 brain glutamine in these animals. These findings sho...