Hyperammonemic encephalopathy

Urea cycle disorders (UCDs) Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with UCDs, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see Precautions). 

In patients who develop unexplained lethargy, vomiting, or changes in mental status, consider hyperammonemic encephalopathy and measure an ammonia level. 

The authors recommended caution when treating patients taking valproate with pivmecillinam because of the risk of hyperammonemic encephalopathy. It seems reasonable... 

In two other cases the addition of topiramate was thought to have precipitated valproate-induced hyperammonemic encephalopathy (1172). Recovery occurred after withdrawal of valproate or topiramate. The authors suggested that topiramate may have contributed to the hyperammonemia by inhibiting carbonic anhydrase and cerebral glutamine synthetase. 

Valproate-induced hyperammonemic encephalopathy has been reviewed (1177). Proton magnetic resonance spectroscopy was performed in a patient with valproate-induced hyperammonemic encephalopathy there was a significant fall in the choline and myoinositol resonances and an increase in glutamine in the hyperintense basal ganglia lesions (1178). A similar pattern has been observed in other hyperammonemic encephalopathies, such as hepatic encephalopathy. In another study in seven patients with valproate-related hyperammonemia serum or cerebrospinal fluid glutamine concentrations were initially raised in most patients, sometimes in the absence of hyperammonemia (1179). 

It is difficult to establish a relation between valproate encephalopathy and increased serum ammonium concentrations. Valproate-induced hyperammonemic encephalopathy has been reported in several single case reports, but still it is difficult to ascertain whether hyperammonemia or valproic acid is the cause of the encephalopathy. In one case valproate was used in combination with lithium, which in itself could have caused encephalopathy by displacement of protein binding or other mechanisms, regardless of hyperammonemia (1181). In a second case it was also impossible to evaluate the effect of hyperammonemia on the level of consciousness, since it involved a woman who took valproic acid (30 g) in addition to... 

Lokrantz CM. Eriksson B, Rosen I, Asztely F. Hyperammonemic encephalopathy induced by a combination of valproate and pivmecilhnam Acta Neurol Scand 2004 109 297-301. 

Kifune A, Kubota F, Shibata N, Akata T, Kikuchi S. Valproic acid-induced hyperammonemic encephalopathy with triphasic waves. Epilepsia 2000 41(7) 909-12. 

Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology 2000 54(l) 230-2. 

Verrotti A, Trotta D, Morgese G, Chiarelli F. Valproate-induced hyperammonemic encephalopathy. Metab Brain Dis 2002 17(4) 367-73. 

Vossler DG, Wilensky AJ, Cawthon DF, Kraemer DL, Ojemann LM, Caylor LM, Morgan JD. Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy. Epilepsia 2002 43(2) 154-9. 

Murphy JV. Valproate-induced hyperammonemic encephalopathy. Epilepsia 2003 44 268. 

Yehya N, Saldarini CT, Koski ME, Davanzo P. Valproate-induced hyperammonemic encephalopathy. J Am Acad Child Adolesc Psychiatry 2004 43(8) 926-7. 

A second, cytosolic CPS activity (CPSII) occurs in mammals as part of the CAD trifunctional protein that catalyzes the first three steps of pyrimidine synthesis (CPSII, asparate tran-scarbamoylase, and dihydroorotase). The activities of these three enzymes—CPSII, aspartate transcarbamoylase, and dihydroorotase—result in the production of orotic acid from ammonium, bicarbonate, and ATP. CPSII has no role in ureagenesis, but orotic aciduria results from hepatocellular accumulation of carbamyl phosphate and helps distinguish CPSI deficiency from other UCDs. Defects in CPSI classically present with neonatal acute hyperammonemic encephalopathy. The plasma citrulline and urine orotic acid concentrations are both low. A definitive diagnosis can be established by enzyme assay of biopsied liver tissue or by mutation analysis. 

Citrulline is exchanged for ornithine across the inner mitochondrial membrane by ORNT-1. Ornithine is produced in the cytosol as the final step in the urea cycle and must be returned to the mitochondrial matrix for transcarbamoyla-tion by OTC. A second ornithine-citrulline antiporter (ORNT-2) is also expressed in the liver mitochondria and may attenuate the severity of disease in patients with HHH (Hyperammonemia, Hyperornithinemia, Homocitrullinuria) disease due to ORNT-1 deficiency. This disorder typically manifests later in life with intermittent hyperammonemic encephalopathy and protein aversion. Intramitochondrial ornithine deficiency causes both hyperammonemia and hyperornithinemia due to a lack of substrate for OTC. Homocitrullinuria occurs due to the use of lysine by OTC as an alternate substrate. The diagnosis is confirmed by mutation analysis. 

AS activity is found in liver, kidney, skin fibroblasts, and some areas of the brain. Patients with citrullinemia classically present with neonatal hyperammonemic encephalopathy. The disease is easily distinguishable by the very high concentration of citrulline in plasma. Urine orotic acid is usually elevated. The major source of circulating citrulline is extrahepatic. Observations of patients with OTC or AS deficiency who have undergone liver transplantation support this finding. Citrulline levels in such patients do not normalize they remain low in the OTC-deficient patients and do not entirely normalize in AS-deficient patients. 

Citrin is an aspartate-glutamate antiporter that has a role both in the urea cycle and in the malate aspartate shuttle. It is necessary for the transport of aspartate produced in the mitochondria into the cytosol, where it is used by AS. Its role in the malate-aspartate shuttle is to transport cytosolic NADH reducing equivalents into the mitochondria, where they are used in oxidative phosphorylation. Defects in citrin cause citrullinemia type II. Patients manifest later-onset intermittent hyperammonemic encephalopathy as in HHH syndrome. 

Treatment for patients with a UCD can be divided into two parts acute management of hyperammonemic encephalopathy and long-term control to prevent further episodes of hyperammonemia while maintaining normal growth and development. 

Evaluate for urea cycle disorders, as hyperammonemic encephalopathy, sometimes fatal, has been associated with valproate administration in these uncommon disorders urea cycle disorders, such as ormithine transcarbamylase deficiency, are associated with unexplained encephalopathy, mental retardation, elevated plasma ammonia, cyclical vomiting, and lethargy... 

Del Rosario, M., Werlin, S.L., Lauer, S.J. Hyperammonemic encephalopathy after chemotherapy. Survival after treatment with sodium benzoate and sodium phenylacetate. X. Clin. Gastroenterol 1997 25 682- 684... 

Duval L, Hautecoeur P, Mahieu M. Encephalopathie hyper-ammoniemique apres prise de cimetidine. [Cimetidine-induced hyperammonemic encephalopathy.) Presse Med 1999 28(ll) 582-3. 

A 24-year-old man with demyelinating disease had fulminant progression of the disease after he experienced valproate-induced hyperammonemic encephalopathy (120). 

Kanamori K, Ross BD, Chung JC, et al. 1996. Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem 67(4) 1584-1594. 

Valproic add, a common anticonvulsant, can accumulate and induce a hyperammonemic encephalopathy, presenting as acutely impaired consciousness, focal neurologic symptoms, and increased seizure frequency. Moreover, valproate-induced hyperammonemic encephalopathy can occur more readily in the child (or adult) with carnitine deficiency or with congenital urea cycle enzymatic defects. In fact, the occult presence of a urea cycle enzymatic defect is occasionally uncovered by the development of valproate-induced encephalopathy an occult enzyme deficiency can even make its first presentation, in the absence of valproate, in the generically stressed critical care patient, young or old (Verrotti et al., 2002 Thakur et al., 2006 Summar et al., 2005). 

Valproate may contribute to hyperammonemia by inhibiting carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Phenobarbital may potentiate the toxic effect of valproate. The electroencephalogram in severe hyperammonemic encephalopathy exhibits continuous generalized slowing, a predominance of theta and delta waves, bursts of frontal intermittent rhythmic delta activity, and triphasic waves (Segura-Bruna et al., 2006). 

Segura-Bruna, N., et al.2006. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand, 114(1) pp. 1-7... 

Several cases of valproate-induced hyperammonemic encephalopathy in different clinical conditions have been described [319 320 J, and another case has been described after 18 years of treatment with the drug in a 38-year-old Chinese woman [321 ]. 

The efficacy of intravenous carnitine and glucose -I- thiamine in valproate-induced hyperammonemic encephalopathy has been reported in a further case [355 ]. 

Starer J, Chang G. Hyperammonemic encephalopathy, valproic acid, and benzodiazepine withdrawal a case series. Am J Drug Alcohol Abuse 2010 36(2) 98-101. 

Young L, Coffey BJ. Bipolar disorder and valproate-induced hyperammonemic encephalopathy in an adolescent with diabetes. J Child Adolesc Psychopharmacol 2010 20(5) 449-52. 

Bphmer T, Bpen A, Hpymork SC. Valproate-induced hyperammonemic encephalopathy, rapidly improved by i.v. carnitine and glucose/thiamine. Scand J Gastroenterol 2010 45(6) 762-3. 

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