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levels were normal. Plasma renin and catecholamine levels slightly elevated (Table 1). During the next few months, his blood pressures ranged from 80 to 100/40 to 70 mm of mercury while on a regimen of hydralazine and propranolol. Both medicines were gradually reduced in dosage, but this was associated with a rise in the blood pressure, requiring an increase in the antihypertensive medication dosage. Renal angiography was repeatedly cancelled because of intercurrent colds and ear infections. At 13 months of age, the blood pressure was 80/60 mm of mercury while the infant was receiving hydralazine and propranolol. Subsequently both medications were tapered and discontinued by 16 months. At 17 months of age, the blood pressure was 100/50 mm of mercury and a peripheral renin value was 0.42 ng per liter per second. His blood pressure remained normal over the following 17 months. At 34 months of age, the patient's blood pressure was 90/60 mm of mercury and growth and development were normal. were
Discussion Hypertension in infants and young children is generally considered secondary.3 Recently, however, a few authors have described essential hypertension in newborns and infants.34 Little is known about the incidence and natural history of essential hypertension in this age range. Essential hypertension in infants must remain a diagnosis of exclusion, after other disorders have been excluded by a thorough investigation. The common secondary causes of hypertension in newborns and infants are renal artery thrombosis following umbilical artery catheterization, coarctation of the aorta, renal artery stenosis, and other renal or endocrinologic abnormalities.3 All of these disorders, and other known causes of hypertension, were excluded in our patients by history, appropriate investigation, and clinical course. The cause of their hypertension could not be determined. Although serum catecholamine levels were mildly elevated in our second patient, urinary HVA and VMA values were normal, and the clinical course was not felt to be consistent with neuroblastoma or pheochromocytoma. Both of the patients had slightly elevated renin values early in their illnesses, which may have reflected a stress response or a transient renal or renovascular insult. Perhaps low-salt intake in the first patient contributed to the elevated serum renin level, but a 24-hour urine specimen was not collected for correlating sodium with renin content. Some authors suggest that administering theophylline may raise the blood pressure, but others have shown that if there is any increase in the blood pressure, it is mild.5 In addition, the first patient's blood pressure became normal while he continued taking theophylline. Until the early 1970s it was generally thought that hypertension in children was persistent, unless surgically correctable, and carried a poor prognosis.67 Recently a few studies suggest that hypertension detected in infancy or childhood may resolve with medical treatment and later blood pressures remain normal without any medication.38 In contrast to our patients, most in those studies had hypertension due to renovascular or renal parenchymal disease, and the hypertension usually persisted for considerably longer periods than it did in our patients. We elected to treat our patients' hypertension because patient 1 had left ventricular hypertrophy on an electrocardiogram and patient 2 had symptoms of agitation, although it is possible that the blood pressures would have reverted to normal in both patients without any treatment.
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In summary, the two cases presented in this report demonstrate that significant essential hypertension may occur in infants and can resolve within months. Therefore, hypertensive infants who initially require medication to control their blood pressure should be evaluated frequently and have trials of reduced medicine dosage to avoid prolonged and unnecessary treatment of a normal blood pressure. REFERENCES
1. Task Force on Blood Pressure Control in Children: Report of the Second Task Force on Blood Pressure Control in Children-1987. Pediatrics 1987; 79:124 2. Rocchini AP: Childhood hypertension: Etiology, diagnosis, and treatment. Pediatr Clin North Am 1984; 31:1259-1273 3. Adelman RD: The hypertensive neonate. Clin Perinatol 1988; 15:567-585 4. Ogborn MR, Crocker JFS: Investigation of pediatric hypertension. Am J Dis Child 1987; 141:1205-1209 5. Esquivel M, Burns RJ, Ogilvie RI: Cardiovascular effects of enprofylline and theophylline. Clin Pharmacol Ther 1986; 39:395-402 6. Buck CW: The persistence of elevated blood pressure first observed at age five. J Chronic Dis 1972; 26:101-104 7. Still JL, Cottom D: Severe hypertension in childhood. Arch Dis Child 1967; 42:34-39 8. Passwell J, Rosenthal T, Boichis H, et al: Transient renovascular hypertension in childhood. Eur J Pediatr 1984; 141:254-255
Valproic Acid-Associated Encephalopathy GARY L. JONES, MD, PhD FUMISUKE MATSUO, MD J. RICHARD BARINGER, MD WALTER H. REICHERT, MD Salt Lake City
MOST REPORTS of valproic acid (VPA)-associated encephalopathy have been of cases in the pediatric population. In most of these patients, the serum ammonia concentration was elevated, and VPA was used in combination with other antiepileptic drugs. We report the case of a woman with VPA-associated encephalopathy to emphasize this as a possible diagnosis in adults and to consider the possibility that this may be an underreported side effect to which physicians should be alert.
Report of a Case The patient, a 59-year-old woman with a seizure disorder since age 38, was transferred from a community hospital because of prolonged confusion after a generalized seizure. Her seizures had been well controlled with the use of phenytoin, as she reportedly had only four "spells" in the previous 20 years. According to witness accounts, each seizure was similar: without warning, the patient would lose consciousness and show "stiffness and shaking of all extremities," which lasted a minute or less, but there was no incontinence. The patient was confused for about two hours after the event. She had had no history of head trauma, and in 1981 a computed tomographic scan of the (Jones GL, Matsuo F, Baringer JR, et al: Valproic acid-associated encephalopathy. West J Med 1990 Aug; 153:199-202) From the Department of Neurology, University of Utah School of Medicine (Drs Jones, Matsuo, and Baringer), and the Western Neurological Associates (Dr Reichert), Salt Lake City. Reprint requests to Gary L. Jones, MD, PhD, Department of Neurology, University of Utah School of Medicine, 50 N Medical Dr, Salt Lake City, UT 84132.
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ABBREVIATIONS USED IN TEXT CPS = carbamoyl-phosphate synthetase EEG = electroencephalogram VPA = valproic acid
head was normal. Nevertheless, electroencephalograms (EEGs) in 1969, 1970, and 1981 showed 3-Hz spike-andwave or polyspike-and-wave activity with sleep. In the two months before admission to the referring hospital, the patient was admitted at least twice to yet another community hospital where she was considered to be in a "nonconvulsive status," both on clinical grounds and by EEG. She was treated on each occasion with the intravenous administration of diazepam, and on the second admission phenobarbital was added to her existing phenytoin regimen. A subsequent neurologic evaluation by one of us (WH.R.) suggested a diagnosis of primary generalized epilepsy with an atypical spike-and-wave EEG pattern. A regimen of VPA (divalproex sodium) was started, and a phenobarbital taper was begun. Four days later she had 'a witnessed generalized tonic-clonic seizure at home and was admitted to the referring hospital. On admission, drug concentrations were 10.2, 16.4, and 43.9 /g per ml for phenytoin, phenobarbital, and VPA, respectively. The phenobarbital taper was continued, while VPA and phenytoin dosages were increased. Although she regained consciousness, her postictal recovery was protracted. On the third hospital day the patient again had a witnessed generalized tonic-clonic seizure even though blood phenytoin and VPA concentrations were in the therapeutic ranges. Because she remained encephalopathic several hours after the latest seizure, she was transferred to the University of Utah Medical Center. The patient's medical history was notable only for her seizure disorder; the family history was noncontributory. Medications on transfer included phenytoin (Dilantin), 100 mg irtravenously every six hours; phenobarbital, 60 mg per nasogastric tube every eight hours; and divalproex (Depakote), 500 mg per nasogastric tube every eight hours. A neurologic examination was remarkable for stupor. The patient occasionally moved all extremities spontaneously and reproducibly to pain. She did not respond to visual threat and had roving eye movements. Her fundi were normal, pupils were reactive to light, and there was no evidence of other cranial nerve deficits. Deep tendon reflexes were 1 + to 3 + and were symmetric. Bilateral Babinski's signs were present. The major differential diagnosis established on admission included both petit mal (absence) status and metabolic encephalopathy. Because her recent history was suggestive of primary generalized epilepsy, petit mal stupor was strongly considered. A plasma ammonia level measured on admission, however, was elevated at 116 umol per liter (normal 7 to 27). The remainder of the chemistry profile was normal except for the y-glutamyl transferase level, which was elevated at 183 units per liter (normal 0 to 33). Her cerebrospinal fluid was normal, as was the rest of her laboratory evaluation. Both VPA and phenobarbital were discontinued, and lactulose was given by nasogastric tube. An EEG showed a mixture of diffuse slowing, 2- to 3-Hz spikeand-wave activity, and polyphasic sharp transients. An early subsequent plasma ammonia level measured more than 300 /4mol per liter, but during the next two days her mental state improved remarkably as her plasma ammonia level decreased to normal (22 /mol per liter on day of discharge). Subsequent EEGs showed a return to normal.
Discussion Valproic acid has become widely used in treating generalized seizure disorders. The most common toxic effects are gastrointestinal, including anorexia, nausea, and vomiting, but these are transient and can usually be controlled by adjusting the dosage or by making sure the drug is taken with food.' Other gastrointestinal toxic effects include an asymptomatic increase in liver enzyme activities, which return to normal after discontinuing the drug.2 Of greater significance is the hepatic failure3'4 and Reye's syndromelike symptoms5'6 that have been associated with VPA use, particularly when combined with other antiepileptic drugs in infants or young children. There are, however, recent reports of hepatic failure in older children receiving monotherapy.' 8 Nervous system toxicity has been documented in numerous reports since 1973 and includes a spectrum of symptoms from drowsiness to stupor and coma. Early discussions focused on possible metabolic or epileptogenic actions of VPA to account for the encephalopathy. It is not the result of hepatocellular toxicity, as stupor and coma occur independently of abnormal increases in liver enzyme levels or the clinical syndrome associated with hepatic failure.9 When VPA use was found to be associated with an increased serum ammonia concentration, much discussion centered on the relationship between the hyperammonemia and encephalopathy. The hyperammonemia, like the encephalopathy, occurs in the absence of other indices of hepatic failure. In 1979 Sackellares and colleagues reported the cases of two adults and two children in whom confusion, stupor, or coma occurred within hours to weeks after VPA was added to a regimen that included at least two other antiepileptic agents.'0 In each patient the EEG was similar, revealing generalized, rhythmic, high-amplitude, bisynchronous 1.5to 3-Hz delta activity, along with bursts of spikes and waves. Intravenous diazepam was given because continued seizure activity was suspected, but there was further slowing ofthe EEG activity and clinical worsening. Each patient became fully alert within a few days after VPA therapy was discontinued. The authors thought it unlikely that the symptoms were caused by metabolic disturbances because routine serum chemistry results were normal. Sackellares and co-workers considered the possibility of an epileptogenic effect but concluded that because of the clinical and EEG worsening induced by diazepam, this was not likely. These authors did not measure serum ammonia concentrations. One of the earliest reports of VPA-associated hyperammonemia appeared in 1980 when Coulter and Allen described the case of a young girl who became lethargic while receiving VPA and who was noted to have a mildly elevated serum ammonia level.11 Also, Sills and associates reported a case of pronounced hyperammonemia in a patient who had been receiving VPA for a long time.12 In 1981 Ruwat and colleagues described a prolonged generalized seizure and persistent lethargy in an 11-year-old girl two days after VPA was added to a regimen of clonazepam and ethosuximide. 13 Although routine serum chemistry results-including a liver profile-were normal, serum ammonia levels rose as high as 126 ,mol per liter (normal 11 to 28), requiring the discontinuation of VPA. Numerous additional studies have since appeared documenting the association of VPA therapy with hyperammonemia and sometimes encephalopathy.'4"-1 Most are in children and show EEG abnormalities similar to those discussed earlier, especially when hyperammonemia is substantial. Not all studies showed hyperammonemia with
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VPA monotherapy,21,23 although all studies reported its occurrence in patients treated concomitantly with other antiepileptic drugs. In one study the mean plasma ammonia concentration in patients receiving antiepileptic agents other than VPA was 25 Amol per liter (normal range 10 to 30); the mean value in patients receiving VPA with other antiepileptic drugs was 46 gmol per liter, but levels as high as 140 /tmol per liter were seen.15 Based on these studies, several general statements can be made regarding the role of VPA in hyperammonemia and encephalopathy. With and without encephalopathy, hyperammonemia is being increasingly documented in both adults and children. There is little doubt that VPA, even in monotherapy and with drug concentrations in the reference range, produces abnormal elevations of serum ammonia. Such elevations occur in the absence of other indices of hepatic dysfunction, such as elevated aminotransferase levels. Symptoms typically occur soon-within days-after starting VPA therapy, and they resolve promptly after its discontinuation. While the dependence of serum ammonia levels on VPA concentrations is uncertain (it appears to have little dose dependence), it is clear that other antiepileptic drugs may potentiate the VPA effect. The relative potency of the common antiepileptic agents in potentiating the VPA-associated hyperammonemia remains unclear, but phenytoin, phenobarbital, and carbamazepine are all effective. Also evident is that there is little correlation of the serum ammonia concentration with the encephalopathy associated with VPA therapy, and this has led some to refute the causal role of ammonia in such encephalopathy. In any case, the prompt discontinuation of VPA is uniformly associated with a remission of symptoms, an abatement of EEG abnormalities, and a reduction of serum ammonia levels. Considerable speculation has taken place regarding possible mechanisms of VPA-induced hyperammonemia. The structure of VPA and its metabolites has been compared with that of certain pentaenoic acid derivatives, which are short-chain fatty acids known to uncouple mitochondrial oxidative phosphorylation.27 Based on the effects of these and other short-chain fatty acids in rodents, some authors have speculated that VPA or its metabolites might act by inhibiting the activity of ornithine carbamoyltransferase and carbamoyl-phosphate synthetase (CPS), or the activator of CPS, N-acetylglutamate.28 In rodents, VPA has been shown to directly inhibit baseline and activated hepatic mitochondrial CPS activity.29 Indeed, patients with a partial deficiency of CPS appear more susceptible to VPA, and overt cerebral edema associated with hyperammonemia has been documented in such patients treated with VPA.9'30 Other evidence of mitochondrial dysfunction induced by VPA includes increased alanine, lactate, pyruvate, glycine, and serine concentrations and decreased aspartate, glutamate, glutamine, free coenzyme A, and acetyl-CoA concentrations.29 31 Thus, although the mechanism of the VPAinduced hyperammonemia remains unclear, it may be due to the depletion of mitochondrial acetyl-CoA and decreased production of N-acetylglutamate, the obligatory activator of the first enzyme of the urea cycle, CPS. The case we present herein typifies the relatively rapid occurrence-four days in this patient-of encephalopathy after the initiation of VPA therapy and likewise the relatively rapid resolution-two days-after the discontinuation of VPA. Although lactulose was administered to our patient, this may in retrospect have been unnecessary. A particularly intriguing question is the possible contribution of seizure activity to the encephalopathy in our patient and others. In rare instances, VPA has been reported to exacer-
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bate seizures or increase epileptogenic activity,32 and we have just documented fully the speculations about the role of seizures in VPA-associated encephalopathy. Little attention has been given, though, to the possible effect of hyperammonemia in lowering the seizure threshold. It is known that ammonia is preferentially detoxified in the brain to glutamine and therefore depletes the available glutamic acid. Because glutamic acid is a precursor of -y-aminobutyric acid, the major mediator of central inhibition, notable elevations of serum (and brain) ammonia levels may thus lower the seizure threshhold and thereby provide a "metabolic" explanation for at least some of the EEG abnormalities and mental state changes seen in VPA-associated encephalopathy. REFERENCES
1. Herranz JL, Arteaga R, Armijo JA: Side effects of sodium valproate in monotherapy controlled by plasma levels: A study in 88 pediatric patients. Epilepsia 1982; 23:203-214 2. Sussman NM, McLain LW Jr: A direct hepatotoxic effect of valproic acid. JAMA 1979; 242:1173-1174 3. Suchy FJ, Balistreri WF, Buchino JJ, et al: Acute hepatic failure associated with the use of sodium valproate: Report of two fatal cases N Engl J Med 1979; 300:962-966 4. Donat JF, Bocchini JA, Gonzalez E, et al: Valproic acid and fatal hepatitis. Neurology (NY) 1979; 29:273-274 5. Gerber N, Dickinson RG, Harland RC, et al: Reye-like syndrome associated with valproic acid therapy. J Pediatr 1979; 95:142-144 6. Young RSK, Bergman I, Gang DL, et al: Fatal Reye-like syndrome associated with valproic acid (Letter). Ann Neurol 1980; 7:389 7. Konig S, Scheffner D, Rauterberg-Ruland I, et al: [Fatal hepatic failure in a normally developed 5-year-old boy caused by VPA monotherapy]. Monatsschr Kinderheilkd 1987; 135:310-313 8. Van Egmond H, Degomme P, de Simpel H, et al: A suspected case of lateonset sodium valproate-induced hepatic failure. Neuropediatrics 1987; 18:96-98 9. Janssen F, Rambeck B, Schnabel R: Acute valproate intoxication with fatal outcome in an infant. Neuropediatrics 1985; 16:235-238 10. Sackellares JC, Lee SI, Dreifuss FE: Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia 1979; 20:697-703 11. Coulter DL, Allen RJ: Secondary hyperammonemia: A possible mechanism for valproic acid encephalopathy. Lancet 1980; 1:1310-1311 12. Sills JA, Trefor-Jones RH, Taylor WH: Valproate hyperammonemia and hyperglycinemia. Lancet 1980; 2:260-261 13. Ruwat MBBS, Borkowski WJ, Swick HM: Valproic acid and secondary hyperammonemia. Neurology (NY) 1981; 31:1173-1174 14. Marescaux C, Warter JM, Micheletti G, et al: Stuporous episodes during treatment with sodium valproate: Report of seven cases. Epilepsia 1982; 23:297305 15. Murphy JV, Marquardt K: Asymptomatic hyperammonemia in patients receiving valproic acid. Arch Neurol 1982; 39:591-592 16. Batshaw ML, Brusilow SW: Valproate-induced hyperammonemia. Ann Neurol 1982; 11:319-321 17. Campostrini R, Paganini M, Boncinelli L, et al: [Alterations of the state of consciousness induced by valproic acid: 6 case reports]. Riv Patol Nerv Ment 1983; 104:23-34 18. Tartara A, Manni R: Sodium valproate 'encephalopathy ': Report of three cases with generalized epilepsy. Ital J Neurol Sci 1985; 6:93-95 19. Zaccara G, Paganini M, Campostrini R, et al: Hyperammonemia and valproate-induced alterations of the state of consciousness: A report of 8 cases. Eur Neurol 1984; 23:104-112 20. Williams CA, Tiefenbach S, McReynolds JW: Valproic acid-induced hyperammonemia in mentally retarded adults. Neurology (NY) 1984; 34:550-553 21. Haidukewych D, John G, Zielinski JJ, et al: Chronic valproic acid therapy and incidence of increases in venous plasma ammonia. Ther Drug Monit 1985; 7:290-294 22. Gaskins JD, Hold RJ, Postelnick M: Nondosage-dependent valproic acidinduced hyperammonemia and coma. Clin Pharm 1984; 3:313-316 23. Zaccara G, Paganini M, Campostrini R, et al: Effect of associated antiepileptic treatment on valproate-induced hyperammonemia. Ther Drug Monit 1985; 7: 185-190 24. Kugoh T, Yamamoto M, Hosokawa K: Blood ammonia level during valproic acid therapy. Jpn J Psychiatry Neurol 1986; 40:663-668 25. Ratnaike RN, Schapel GJ, Purdie G, et al: Hyperammonaemia and hepatherapy: Enhancement by combination with totoxicity during chronic valproate other antiepileptic drugs. Br J Clin Pharmacol 1986; 22:100-103
202 26. Iinuma K, Hayasaka K, Narisawa K, et al: Hyperamino-acidaemia and hyperammonaemia in epileptic children treated with valproic acid. Eur J Pediatr 1988; 148:267-269 27. Schmid RD: Propionic acid and dipropylacetic acid in the urine of patients treated with dipropylacetic acid. Clin Chim Acta 1977; 74:39-42 28. Gruskay JA, Rosenberg LE: Inhibition of hepatic mitochondrial carbamyl phosphate synthetase by acyl CoA esters: Possible mechanism of hyperammonemia in the organic acidemias. Pediatr Res 1979; 13:475 29. Thurston JH, Carroll JE, Hauhart RE, et al: A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and
ALERTS, NOTICES, AND CASE REPORTS carnitine metabolism in infant mice: Possible clinical significance. Life Sci 1985; 36:1643-1651 30. Bourrier P, Varache N, Alquier P, et al: [Cerebral edema with hyperammonemia in valpromide poisoning-Manifestation in an adult of a partial deficit in type I-carbamylphosphate synthetase]. Presse Med 1988; 17:2063-2066 31. Turnbull DM, Dick DJ, Wilson L, et al: Valproate causes metabolic disturbance in normal man. J Neurol Neurosurg Psychiatry 1986; 49:405-410 32. Chadwick DW, Cumming WJK, Livingstone I, et al: Acute intoxication with sodium valproate. Ann Neurol 1979; 6:552-553
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levels were normal. Plasma renin and catecholamine levels slightly elevated (Table 1). During the next few months, his blood pressures ranged from 80 to 100/40 to 70 mm of mercury while on a regimen of hydralazine and propranolol. Both medicines were gradually reduced in dosage, but this was associated with a rise in the blood pressure, requiring an increase in the antihypertensive medication dosage. Renal angiography was repeatedly cancelled because of intercurrent colds and ear infections. At 13 months of age, the blood pressure was 80/60 mm of mercury while the infant was receiving hydralazine and propranolol. Subsequently both medications were tapered and discontinued by 16 months. At 17 months of age, the blood pressure was 100/50 mm of mercury and a peripheral renin value was 0.42 ng per liter per second. His blood pressure remained normal over the following 17 months. At 34 months of age, the patient's blood pressure was 90/60 mm of mercury and growth and development were normal. were
Discussion Hypertension in infants and young children is generally considered secondary.3 Recently, however, a few authors have described essential hypertension in newborns and infants.34 Little is known about the incidence and natural history of essential hypertension in this age range. Essential hypertension in infants must remain a diagnosis of exclusion, after other disorders have been excluded by a thorough investigation. The common secondary causes of hypertension in newborns and infants are renal artery thrombosis following umbilical artery catheterization, coarctation of the aorta, renal artery stenosis, and other renal or endocrinologic abnormalities.3 All of these disorders, and other known causes of hypertension, were excluded in our patients by history, appropriate investigation, and clinical course. The cause of their hypertension could not be determined. Although serum catecholamine levels were mildly elevated in our second patient, urinary HVA and VMA values were normal, and the clinical course was not felt to be consistent with neuroblastoma or pheochromocytoma. Both of the patients had slightly elevated renin values early in their illnesses, which may have reflected a stress response or a transient renal or renovascular insult. Perhaps low-salt intake in the first patient contributed to the elevated serum renin level, but a 24-hour urine specimen was not collected for correlating sodium with renin content. Some authors suggest that administering theophylline may raise the blood pressure, but others have shown that if there is any increase in the blood pressure, it is mild.5 In addition, the first patient's blood pressure became normal while he continued taking theophylline. Until the early 1970s it was generally thought that hypertension in children was persistent, unless surgically correctable, and carried a poor prognosis.67 Recently a few studies suggest that hypertension detected in infancy or childhood may resolve with medical treatment and later blood pressures remain normal without any medication.38 In contrast to our patients, most in those studies had hypertension due to renovascular or renal parenchymal disease, and the hypertension usually persisted for considerably longer periods than it did in our patients. We elected to treat our patients' hypertension because patient 1 had left ventricular hypertrophy on an electrocardiogram and patient 2 had symptoms of agitation, although it is possible that the blood pressures would have reverted to normal in both patients without any treatment.
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In summary, the two cases presented in this report demonstrate that significant essential hypertension may occur in infants and can resolve within months. Therefore, hypertensive infants who initially require medication to control their blood pressure should be evaluated frequently and have trials of reduced medicine dosage to avoid prolonged and unnecessary treatment of a normal blood pressure. REFERENCES
1. Task Force on Blood Pressure Control in Children: Report of the Second Task Force on Blood Pressure Control in Children-1987. Pediatrics 1987; 79:124 2. Rocchini AP: Childhood hypertension: Etiology, diagnosis, and treatment. Pediatr Clin North Am 1984; 31:1259-1273 3. Adelman RD: The hypertensive neonate. Clin Perinatol 1988; 15:567-585 4. Ogborn MR, Crocker JFS: Investigation of pediatric hypertension. Am J Dis Child 1987; 141:1205-1209 5. Esquivel M, Burns RJ, Ogilvie RI: Cardiovascular effects of enprofylline and theophylline. Clin Pharmacol Ther 1986; 39:395-402 6. Buck CW: The persistence of elevated blood pressure first observed at age five. J Chronic Dis 1972; 26:101-104 7. Still JL, Cottom D: Severe hypertension in childhood. Arch Dis Child 1967; 42:34-39 8. Passwell J, Rosenthal T, Boichis H, et al: Transient renovascular hypertension in childhood. Eur J Pediatr 1984; 141:254-255
Valproic Acid-Associated Encephalopathy GARY L. JONES, MD, PhD FUMISUKE MATSUO, MD J. RICHARD BARINGER, MD WALTER H. REICHERT, MD Salt Lake City
MOST REPORTS of valproic acid (VPA)-associated encephalopathy have been of cases in the pediatric population. In most of these patients, the serum ammonia concentration was elevated, and VPA was used in combination with other antiepileptic drugs. We report the case of a woman with VPA-associated encephalopathy to emphasize this as a possible diagnosis in adults and to consider the possibility that this may be an underreported side effect to which physicians should be alert.
Report of a Case The patient, a 59-year-old woman with a seizure disorder since age 38, was transferred from a community hospital because of prolonged confusion after a generalized seizure. Her seizures had been well controlled with the use of phenytoin, as she reportedly had only four "spells" in the previous 20 years. According to witness accounts, each seizure was similar: without warning, the patient would lose consciousness and show "stiffness and shaking of all extremities," which lasted a minute or less, but there was no incontinence. The patient was confused for about two hours after the event. She had had no history of head trauma, and in 1981 a computed tomographic scan of the (Jones GL, Matsuo F, Baringer JR, et al: Valproic acid-associated encephalopathy. West J Med 1990 Aug; 153:199-202) From the Department of Neurology, University of Utah School of Medicine (Drs Jones, Matsuo, and Baringer), and the Western Neurological Associates (Dr Reichert), Salt Lake City. Reprint requests to Gary L. Jones, MD, PhD, Department of Neurology, University of Utah School of Medicine, 50 N Medical Dr, Salt Lake City, UT 84132.
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ABBREVIATIONS USED IN TEXT CPS = carbamoyl-phosphate synthetase EEG = electroencephalogram VPA = valproic acid
head was normal. Nevertheless, electroencephalograms (EEGs) in 1969, 1970, and 1981 showed 3-Hz spike-andwave or polyspike-and-wave activity with sleep. In the two months before admission to the referring hospital, the patient was admitted at least twice to yet another community hospital where she was considered to be in a "nonconvulsive status," both on clinical grounds and by EEG. She was treated on each occasion with the intravenous administration of diazepam, and on the second admission phenobarbital was added to her existing phenytoin regimen. A subsequent neurologic evaluation by one of us (WH.R.) suggested a diagnosis of primary generalized epilepsy with an atypical spike-and-wave EEG pattern. A regimen of VPA (divalproex sodium) was started, and a phenobarbital taper was begun. Four days later she had 'a witnessed generalized tonic-clonic seizure at home and was admitted to the referring hospital. On admission, drug concentrations were 10.2, 16.4, and 43.9 /g per ml for phenytoin, phenobarbital, and VPA, respectively. The phenobarbital taper was continued, while VPA and phenytoin dosages were increased. Although she regained consciousness, her postictal recovery was protracted. On the third hospital day the patient again had a witnessed generalized tonic-clonic seizure even though blood phenytoin and VPA concentrations were in the therapeutic ranges. Because she remained encephalopathic several hours after the latest seizure, she was transferred to the University of Utah Medical Center. The patient's medical history was notable only for her seizure disorder; the family history was noncontributory. Medications on transfer included phenytoin (Dilantin), 100 mg irtravenously every six hours; phenobarbital, 60 mg per nasogastric tube every eight hours; and divalproex (Depakote), 500 mg per nasogastric tube every eight hours. A neurologic examination was remarkable for stupor. The patient occasionally moved all extremities spontaneously and reproducibly to pain. She did not respond to visual threat and had roving eye movements. Her fundi were normal, pupils were reactive to light, and there was no evidence of other cranial nerve deficits. Deep tendon reflexes were 1 + to 3 + and were symmetric. Bilateral Babinski's signs were present. The major differential diagnosis established on admission included both petit mal (absence) status and metabolic encephalopathy. Because her recent history was suggestive of primary generalized epilepsy, petit mal stupor was strongly considered. A plasma ammonia level measured on admission, however, was elevated at 116 umol per liter (normal 7 to 27). The remainder of the chemistry profile was normal except for the y-glutamyl transferase level, which was elevated at 183 units per liter (normal 0 to 33). Her cerebrospinal fluid was normal, as was the rest of her laboratory evaluation. Both VPA and phenobarbital were discontinued, and lactulose was given by nasogastric tube. An EEG showed a mixture of diffuse slowing, 2- to 3-Hz spikeand-wave activity, and polyphasic sharp transients. An early subsequent plasma ammonia level measured more than 300 /4mol per liter, but during the next two days her mental state improved remarkably as her plasma ammonia level decreased to normal (22 /mol per liter on day of discharge). Subsequent EEGs showed a return to normal.
Discussion Valproic acid has become widely used in treating generalized seizure disorders. The most common toxic effects are gastrointestinal, including anorexia, nausea, and vomiting, but these are transient and can usually be controlled by adjusting the dosage or by making sure the drug is taken with food.' Other gastrointestinal toxic effects include an asymptomatic increase in liver enzyme activities, which return to normal after discontinuing the drug.2 Of greater significance is the hepatic failure3'4 and Reye's syndromelike symptoms5'6 that have been associated with VPA use, particularly when combined with other antiepileptic drugs in infants or young children. There are, however, recent reports of hepatic failure in older children receiving monotherapy.' 8 Nervous system toxicity has been documented in numerous reports since 1973 and includes a spectrum of symptoms from drowsiness to stupor and coma. Early discussions focused on possible metabolic or epileptogenic actions of VPA to account for the encephalopathy. It is not the result of hepatocellular toxicity, as stupor and coma occur independently of abnormal increases in liver enzyme levels or the clinical syndrome associated with hepatic failure.9 When VPA use was found to be associated with an increased serum ammonia concentration, much discussion centered on the relationship between the hyperammonemia and encephalopathy. The hyperammonemia, like the encephalopathy, occurs in the absence of other indices of hepatic failure. In 1979 Sackellares and colleagues reported the cases of two adults and two children in whom confusion, stupor, or coma occurred within hours to weeks after VPA was added to a regimen that included at least two other antiepileptic agents.'0 In each patient the EEG was similar, revealing generalized, rhythmic, high-amplitude, bisynchronous 1.5to 3-Hz delta activity, along with bursts of spikes and waves. Intravenous diazepam was given because continued seizure activity was suspected, but there was further slowing ofthe EEG activity and clinical worsening. Each patient became fully alert within a few days after VPA therapy was discontinued. The authors thought it unlikely that the symptoms were caused by metabolic disturbances because routine serum chemistry results were normal. Sackellares and co-workers considered the possibility of an epileptogenic effect but concluded that because of the clinical and EEG worsening induced by diazepam, this was not likely. These authors did not measure serum ammonia concentrations. One of the earliest reports of VPA-associated hyperammonemia appeared in 1980 when Coulter and Allen described the case of a young girl who became lethargic while receiving VPA and who was noted to have a mildly elevated serum ammonia level.11 Also, Sills and associates reported a case of pronounced hyperammonemia in a patient who had been receiving VPA for a long time.12 In 1981 Ruwat and colleagues described a prolonged generalized seizure and persistent lethargy in an 11-year-old girl two days after VPA was added to a regimen of clonazepam and ethosuximide. 13 Although routine serum chemistry results-including a liver profile-were normal, serum ammonia levels rose as high as 126 ,mol per liter (normal 11 to 28), requiring the discontinuation of VPA. Numerous additional studies have since appeared documenting the association of VPA therapy with hyperammonemia and sometimes encephalopathy.'4"-1 Most are in children and show EEG abnormalities similar to those discussed earlier, especially when hyperammonemia is substantial. Not all studies showed hyperammonemia with
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VPA monotherapy,21,23 although all studies reported its occurrence in patients treated concomitantly with other antiepileptic drugs. In one study the mean plasma ammonia concentration in patients receiving antiepileptic agents other than VPA was 25 Amol per liter (normal range 10 to 30); the mean value in patients receiving VPA with other antiepileptic drugs was 46 gmol per liter, but levels as high as 140 /tmol per liter were seen.15 Based on these studies, several general statements can be made regarding the role of VPA in hyperammonemia and encephalopathy. With and without encephalopathy, hyperammonemia is being increasingly documented in both adults and children. There is little doubt that VPA, even in monotherapy and with drug concentrations in the reference range, produces abnormal elevations of serum ammonia. Such elevations occur in the absence of other indices of hepatic dysfunction, such as elevated aminotransferase levels. Symptoms typically occur soon-within days-after starting VPA therapy, and they resolve promptly after its discontinuation. While the dependence of serum ammonia levels on VPA concentrations is uncertain (it appears to have little dose dependence), it is clear that other antiepileptic drugs may potentiate the VPA effect. The relative potency of the common antiepileptic agents in potentiating the VPA-associated hyperammonemia remains unclear, but phenytoin, phenobarbital, and carbamazepine are all effective. Also evident is that there is little correlation of the serum ammonia concentration with the encephalopathy associated with VPA therapy, and this has led some to refute the causal role of ammonia in such encephalopathy. In any case, the prompt discontinuation of VPA is uniformly associated with a remission of symptoms, an abatement of EEG abnormalities, and a reduction of serum ammonia levels. Considerable speculation has taken place regarding possible mechanisms of VPA-induced hyperammonemia. The structure of VPA and its metabolites has been compared with that of certain pentaenoic acid derivatives, which are short-chain fatty acids known to uncouple mitochondrial oxidative phosphorylation.27 Based on the effects of these and other short-chain fatty acids in rodents, some authors have speculated that VPA or its metabolites might act by inhibiting the activity of ornithine carbamoyltransferase and carbamoyl-phosphate synthetase (CPS), or the activator of CPS, N-acetylglutamate.28 In rodents, VPA has been shown to directly inhibit baseline and activated hepatic mitochondrial CPS activity.29 Indeed, patients with a partial deficiency of CPS appear more susceptible to VPA, and overt cerebral edema associated with hyperammonemia has been documented in such patients treated with VPA.9'30 Other evidence of mitochondrial dysfunction induced by VPA includes increased alanine, lactate, pyruvate, glycine, and serine concentrations and decreased aspartate, glutamate, glutamine, free coenzyme A, and acetyl-CoA concentrations.29 31 Thus, although the mechanism of the VPAinduced hyperammonemia remains unclear, it may be due to the depletion of mitochondrial acetyl-CoA and decreased production of N-acetylglutamate, the obligatory activator of the first enzyme of the urea cycle, CPS. The case we present herein typifies the relatively rapid occurrence-four days in this patient-of encephalopathy after the initiation of VPA therapy and likewise the relatively rapid resolution-two days-after the discontinuation of VPA. Although lactulose was administered to our patient, this may in retrospect have been unnecessary. A particularly intriguing question is the possible contribution of seizure activity to the encephalopathy in our patient and others. In rare instances, VPA has been reported to exacer-
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bate seizures or increase epileptogenic activity,32 and we have just documented fully the speculations about the role of seizures in VPA-associated encephalopathy. Little attention has been given, though, to the possible effect of hyperammonemia in lowering the seizure threshold. It is known that ammonia is preferentially detoxified in the brain to glutamine and therefore depletes the available glutamic acid. Because glutamic acid is a precursor of -y-aminobutyric acid, the major mediator of central inhibition, notable elevations of serum (and brain) ammonia levels may thus lower the seizure threshhold and thereby provide a "metabolic" explanation for at least some of the EEG abnormalities and mental state changes seen in VPA-associated encephalopathy. REFERENCES
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