Case Report

Massive Valproic acid overdose, a misleading case

Abstract

Seizures are often attributed to a low plasma concentration of Antiepileptic drugs, although sometimes it can be due to a high plasma concentration of the antiepileptic drug. This case report describes a very severe valproic acid intoxication including paradoxical seizures, which was initially held for a subtherapeutic valproic acid treatment. Applied treatment strategy based on available evidence is discussed. A more careful clinical evaluation at admission might have guided the treating physicians to the right diagnoses from the start. The important lesson is that several antiepileptic medicines, as valproic acid, can cause seizures in overdose.

The antiepileptic drug valproic acid is regularly prescribed to reduce seizures in epileptic patients. There is an increase in the number of prescriptions of this drug as a result of broadening therapeutic use, including its use as a mood stabilizer in patients with bipolar and affective disorders and as migraine prophylaxis [1]. If a patient with seizures is presented at the emergency department (ED) while the patient is on valproic medication, it is important to realize that the patient might have subtherapeutic as well as supratherapeutic plasma concentrations [2,3]. Diagnosis of valproic acid intoxication is not always easy if, as in this case, no plasma concentration is available. Clinical characteristics are not typical and when intoxication with valproic acid is not suspected, the diagnosis can easily be missed. Seizures can be a sign of a subTherapeutic dose as well as, more rarely, an overdose [2-4]. We describe a very severe valproic acid intoxication. At first, the treating physicians thought the seizures were caused by a subtherapeutic valproic acid plasma concentration, which turned out to be very high.

A 41-year-old man had a medical history of epilepsy due to a cyst in the right temporal lobe caused by gliosis. He was treated with 1 g of valproic acid, twice a day. Last Epileptic seizure was half a year ago. At 6:30 AM, on the day of admission, he fell out of bed at his home, which woke his wife. She found him snoring and not responding. Although he was moving his arms and legs rhythmically and is incontinent for urine, she did not think that this could be a

manifestation of epilepsy. She covered him with a sheet and waited for him to wake up. Eight hours later, the patient was still not awake; his wife then decided to consult a general practitioner. At 3:30 PM, the general practitioner found the patient in coma and referred him to our hospital.

The patient arrived at the ED at 4:30 PM. He was in deep coma (Glasgow Coma Scale E1M1V1) and was directly intubated for mechanical ventilation. The pupils were normal and responding to light. The temperature was 34?C, heart rate 80 beats/min, and blood pressure 80/40 mm Hg. The remainder of the physical examination revealed no abnormalities. The following were the blood gases results: pO2 248 mm Hg (with oxygen supply), pCO2 40 mm Hg. Other laboratory results were pH 7.22, bicarbonate 16 mmol/L, glucose 6.9 mmol/L, Na+

153 mmol/L, ionized Ca⁺⁺ 0.9 mmol/L, ionized Mg⁺⁺ 0.63 mmol/L, creatinine 95 umol/L, bilirubin 2 umol/L, alkaline phosphatase 64 U/L, gamma glutamyl transferase 27 U/L, aspartate aminotransferase 51 U/L, alaine aminotransferase 44 U/L, lactate dehydrogenase 535 U/L, hemoglobin 9.1 mmol/L, leucocytes count 8.3 x 10 9/L, thrombocytes count 133 x 10 9/ L, lactate 5.3 mmol/L, Creatinine kinase 1580 U/L with normal muscle brain fraction, and C-reactive protein b7 mg/L. The increased creatinine kinase could be due to muscular cell damage. A computed tomography scan of the brain revealed a cyst with gliosis in the right temporal lobe, unchanged in shape and size compared with earlier scans and no edema or hydrocephalus. The diagnosis of the treating physicians was postepileptic state with hypothermia and rhabdomyolysis due to lying on the floor for hours or else a nonconvulsive epileptic state. Initially, valproic acid 1 g, twice a day, was continued to prevent seizures. He was on the mechanical ventilator and sedated with propofol. Propofol was chosen to reduce epileptic activity and to facilitate neurological evaluation if necessary.

Thereafter, the patient was admitted to the intensive care unit at 5:00 PM. Fluid administration was started to treat hypotension and prevent kidney dysfunction. Despite sufficient fluid administration, hypotension persisted, and therefore, norepinephrine was started. Thereupon, blood pressure improved, and adequate diuresis was restored. Magnesium was corrected. In spite of the efforts to warm the patient, his body temperature initially decreased to 30?C. Twenty-four hours passed with active warming before his body temperature was 36?C. Seizures were not observed in this period. To exclude nonconvulsive epileptic state, an

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electroencephalography was performed, which showed no epileptic activity. Slowed triphasic waves were present, consistent with diffuse encephalopathy due to postanoxic, metabolic, or toxic encephalopathy. To establish whether the patient could be intoxicated, blood and urine were sampled. The valproic plasma level at admission appeared to be very high (1308 mg/L; therapeutic range, 50-150 mg/L). No intoxication with carbon monoxide, opiates, or benzo- diazepines, etc, was present. Plasma level of acetaminophen was less then 2 mg/L. No other xenobiotics causing intoxication were found. Laboratory examination after 24 hours showed a persistent metabolic acidosis (pH 7.34, HCO3 18.1 mmol/L, base excess -9.3 mmol/L), hyperna- tremia (156 mmol/L), leucopenia (L 1.7 x 10 9/L),

thrombocytopenia (66 x 10 9/L), hyperammonemia (123 umol/L), and elevated ASAT (178 U/L), ALAT (70 U/L), and LDH (1474 U/L). Creatinine kinase was increased to 10.000 U/L without renal dysfunction. Peak lipase plasma activity was 3409 U/L. The physical and laboratory results were consistent with a severe valproic acid intoxication. The diagnosis was communicated to his wife; thereafter she discovered that her husband had presumably ingested more than 100 tablets of 1 g of valproic acid and brought the empty medication strips from home. After the diagnosis was established, activated charcoal 40 g, every 3 hours, and L-carnitine were administered, and of course, the valproate administra- tion was stopped. Thereafter, the valproic acid plasma levels decreased to therapeutic concentrations in 3 days (961 mg/L 12 hours after admission, 622 mg/L 23 hours after admission, 204 mg/L 36 hours after admission, and 79 mg/L 55 hours after admission). Thirty-six hours after admission, the patient awoke. A psychiatrist was consulted. The patient appeared not to be suicidal anymore. laboratory examinations were normalized within 7 days. The patient’s subsequent hospital admission was uncomplicated, and he was discharged after 17 days. He recovered from this intoxication without sequelae.

Symptoms due to overdose of valproic acid are various and contain several organ systems as described in this case. Neurotoxic effects are headache, dizziness, ataxia, tremors, and central nervous system depression from drowsiness to coma, sometimes accompanied by cerebral edema and paradoxical seizures [4-6]. Serum concentrations greater than 850 mg/L invariably cause coma [4]. Respiratory depression can occur [4]. gastrointestinal complaints consist of nausea, vomiting, and diarrhea. Even pancreatitis can occur [5,7]. Hepatotoxicity is not often reported in acute overdose, although after chronic administration, up to 44% of valproic acid-treated patients have abnormal results for liver function tests [8]. Occasionally bilirubin is increased or prothrombin time is prolonged [8]. Hyperammonemia can occur without hepatic failure due to increased renal production and blockage of hepatic metabolism and may be responsible for coma [4-6]. Other Metabolic effects are metabolic acidosis with increased anion gap and elevated

lactate, hyperosmolality, and electrolyte abnormalities, such as hypernatremia, hypocalcemia, or hypoglycemia [4,7]. Thrombocytopenia, leucopenia, and methemoglobinemia are reported also [4]. Acute renal failure caused by hypotension or rhabdomyolysis can occur. Other clinical findings in overdose include hypothermia and tachycardia [7].

The described case concerned a very severe valproic acid intoxication when plasma concentrations are considered [1,4,5,9]. Peak valproic acid plasma concentrations greater than 450 mg/L are more likely to be associated with moderate or major adverse outcome and greater than 850 mg/L are more likely to be associated with multiple- organ dysfunction [4]. Patients with a severe valproic acid intoxication often present with CNS depression to deep coma, respiratory depression, and hypotension. In mild intoxications, there are often no symptoms [1,4]. Our patient presented with coma, seizures, respiratory depression, hypotension, lactic acidosis, hyperammonemia, rhabdomyo- lysis, hypothermia, and increased lipase. The time of ingestion remains uncertain. Most likely, the patient took an overdose just before he went to sleep. Peak concentrations range from 1 to 18 hours after ingestion [4]. The plasma half- life time was prolonged in the patient presented. The half-life of valproic acid is 8 to 14 hours but can be prolonged up to 42 hours after an overdose. Elimination of the drug follows first-order kinetic. Treatment depends on the severity of intoxication. Most valproic acid intoxications are mild and are treated with supportive care [1,4,9]. In our patient, endotracheal intubation was needed, and vasopressor, activated charcoal and L-carnitine treatment was provided. Hemodialysis or hemoperfusion was considered in this severe valproic acid intoxication. Despite the high-protein bounding of valproic acid, it is important to realize that in overdoses, the free valproic acid fraction is increased. In therapeutic concentrations (50-150 mg/L), protein binding is 90% to 95%, and in toxic concentrations (N300 mg/L), protein binding is less than 35%. At valproic acid blood levels greater than 300 mg/L, hemodialysis is effective to remove a significant amount of the drug because of the progressive elevation of free drug [5,10,11]. After initial supportive treatment, clinical condition improved gradually; therefore, extracorporeal elimination of valproic acid was not instituted. A second reason to consider hemodialysis is severe hyperammonemia in valproic acid overdose because in patients with valproic acid intoxication and cerebral edema, mortality is high [5]. Hyperammonemia is thought to be a pathogenic factor for cerebral edema in valproic acid toxicity. There seems to be no correlation between valproic acid peak concentration and hyperammonemia [5]. In case of ammonia levels greater than 400 umol/L, most authors agree that hemodialysis should be considered [5,12]. Clearance of ammonia has been shown to be approximately a 10-fold increased by hemodialysis. Although it remains unclear if extracorporeal removal improves clinical out- come, it can be considered in case of deteriorating neurological conditions and hemodynamic instability

[4,5,12,13]. Hemodialysis was not started because ammonia plasma level was 123 umol/L and because the patient was clinically not deteriorating [9,11,14].

To prevent further drug absorption, activated charcoal was administered in multiple doses. Multiple-dose activated charcoal significantly reduces plasma half-life of valproic acid [15]. If delayed release preparations are ingested, whole bowel lavage should be considered in patients with increasing valproic acid plasma concentrations [10,15]. In this case, whole bowel lavage was not needed because concentrations were decreasing already.

Valproic acid appears to function through regional changes in concentration of ?-amino butyric acid, the principal inhibitory brain neurotransmitter. Naloxone has been administered to reverse CNS depression, however, frequently ineffectively and with no effect on clinical outcome. Therefore naloxone was not used in our case. Benzodiazepines, propofol, or other anticonvulsants are sometimes necessary in case of seizures.

Valproic acid is metabolized in the liver via direct glucuronide conjugation by mitochondrial ? oxidation and cytosolic ? and ?1 oxidation. Less than 3% is excreted unchanged in the urine. ? oxidation is the most important way of metabolism at therapeutic levels. When entering the mitochondria, valproic acid uses L-carnitine as a cofactor [7]. In chronic therapy with valproic acid, L-carnitine deficiency can exist. In cell culture experiments, inhibition of hyperammonemia and ketone body formation in hepatocytes by supplying L-carnitine is demonstrated [7]. Therefore, in case of hyperammonemia, coma and Hepatic dysfunction like in our patient, L-carnitine administration 50 mg/kg per day orally can be considered, although there is no evidence for improving clinical outcome [5,7,16].

Retrospectively, could valproic acid intoxication have been suspected earlier? The diagnosis of the treating physicians was postepileptic state with hypothermia and rhabdomyolysis due to lying on the floor for hours or else nonconvulsive epileptic state. In this case, valproic acid intoxication was not suspected at first also because neither the patient’s wife nor the general practitioner informed the treating physician about empty strips or suicidal behavior. Seizures were ascribed to the glioma in the right temporal lobe or subtherapeutic plasma concentration of valproic acid. Nevertheless, some symptoms could have led to the appropriate diagnosis earlier. A prolonged coma due to the postepileptic state is uncommon; in contrary, prolonged coma due to valproate intoxication occurs more often. The ongoing hypothermia could also be a sign of intoxication; certainly, the drop in temperature was suspicious. On admission, there was a lactic acidosis. Differential diagnosis of lactic acidosis consists of increased lactate production, decreased utilization, or unknown mechanisms. Causes of increased lactate production are divided in increased pyruvate production, impaired pyruvate utilization, altered redox state, which is subdivided in enhanced metabolic rate, decreased oxygen delivery, or reduced oxygen utilization.

Lactic acidosis can also be due to D-lactic acidosis. In this case, possible causes were seizures or reduced oxygen utilization due to valproic acid-induced Mitochondrial dysfunction. These characteristics, seizures, prolonged coma, prolonged deep hypothermia, and lactic acidosis, could have led to the correct diagnosis earlier.

Because paradoxical seizures are rare in massive valproic acid overdose, it is understandable that the treating physician was misled. Nevertheless, in this case, the determination of a plasma valproic acid concentration should have been considered at admission for 2 reasons: the seizures could have been caused by subtherapeutic levels of valproic acid as well as by massive overdose. It is clear, for the correct therapeutic intervention that it is very pivotal to know the plasma valproic level at admission if the patient is presented with symptoms as in this case. A suitable therapy for the intoxication would immediately have been started.

The important lesson is that several antiepileptic drugs, such as valproic acid, can cause seizures in massive overdose.

Maaike A. Sikma MD Department of Intensive Care University Medical Centre Utrecht

P.O. Box 85500, 3508 GA Utrecht

The Netherlands E-mail addresses: [email protected]

Judy C. Mier MD Department of Anesthesiology University Medical Centre Utrecht

P.O. Box 85500, 3508 GA Utrecht

The Netherlands E-mail addresses: [email protected]

Jan Meulenbelt MD, Phd Department of Intensive Care University Medical Centre Utrecht

P.O. Box 85500, 3508 GA Utrecht

The Netherlands

National Poisons Information Centre of National Institute

for Public Health and the Environment

P.O. Box 1, 3720 BA Bilthoven

The Netherlands E-mail addresses: [email protected];

[email protected]

doi:10.1016/j.ajem.2007.06.020

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