New anticonvulsants--new adverse effects.

Abstract: Ongoing refinements in pharmacology continue to provide new medications for the treatment of seizure disorders and other neurologic conditions. The authors present the cases of two children who developed relatively uncommon adverse effects to new anticonvulsant medications, including metabolic acidosis with topiramate and hyponatremia with oxcarbazepine. In one of our two patients, intraoperative acidosis related to topiramate was noted. Appropriate investigation with documentation of normal serum lactate resulted in the exclusion of other potentially serious causes of acidosis and in the identification of topiramate as the causative agent. In our second patient, hyponatremia and status epilepticus resulted from therapy with oxcarbazepine. Prompt recognition of hyponatremia, fluid restriction, and cessation of oxcarbazepine therapy resulted in prompt correction of the hyponatremia. We review previous reports of these adverse effects with topiramate and oxcarbazepine, describe the pathophysiology of these metabolic alterations, provide treatment strategies, and make suggestions for monitoring patients during therapy with these anticonvulsant medications.

Key Words: topiramate, metabolic acidosis, oxcarbazepine, hyponatremia

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Physicians today are faced with an ever-increasing pharmacologic armamentarium for the treatment of various neurologic conditions including seizure and behavioral disorders. Despite the beneficial effects and significant improvement in patient well-being resulting from these medications, new medications may also be associated with new adverse effects. We present two patients treated with relatively new anticonvulsant medications who developed adverse effects which included metabolic acidosis with topiramate (Topamax[R], Ortho-McNeil, Raritan, NJ) and hyponatremia with oxcarbazepine (Trileptal[R], Novartis, East Hanover, NJ).

Case Reports

Patient #1: Topiramate-induced Metabolic Acidosis

A 12-year-old, 75 kg adolescent presented for posterior spinal fusion. Her past medical history was positive for depression and attention-deficit hyperactivity disorder which was treated with bupropion (100 mg p.o. q.AM) and topiramate (25 mg p.o. q.AM). The patient had a negative seizure history. The remainder of her past medical history and surgical history were negative. After uneventful IV induction and endotracheal intubation, central and arterial accesses were obtained. Maintenance anesthesia consisted of propofol (100-200 [micro]g/kg/min) and remifentanil (0.3-0.7 [micro]g/kg/min) to allow for the performance of motor and somatosensory-evoked potential monitoring. An initial arterial blood gas (ABG) analysis, drawn 1 hour 38 minutes after the start of the procedure, revealed a pH of 7.28, PaC[O.sub.2] of 39.5 mm Hg, Pa[O.sub.2] of 515 mm Hg and a base deficit of -7.8 mEq/L with a serum bicarbonate of 17.8 mEq/L. At this point, 1 L of lactated Ringers had been administered and the urine output was 300 mL. The acidosis was treated with sodium bicarbonate (50 mEq) administered IV. Arterial blood gas values and the treatment administered are outlined in Table 1. With the second ABG, the serum lactate was 1.2 mMol/L (normal: 0.5-2.2 mMol/L). Total fluids for the case included 5,600 mL of lactated Ringers and 500 mL of hydroxyethyl starch. A total of 250 mEq of sodium bicarbonate was administered. The blood loss was 500 mL with a urine output of 1,775 mL. The patient was admitted to the pediatric ICU. The postoperative serum bicarbonate was 19.9 mEq/L and the value the following morning was 22 mEq/L. No further therapy was administered. The patient was discharged home on postoperative day # 7 on her routine preoperative medications.

Patient #2: Oxcarbazepine-induced Hyponatremia

A 2 year and 10-month-old Caucasian male who weighed 10.2 kg was admitted status post onset of recurrent seizure activity. His past history was significant for premature birth at 24 weeks gestation, Grade III intraventricular hemorrhage (IVH), static encephalopathy, necrotizing enterocolitis (NEC) status post bowel resection, retinopathy of prematurity and a seizure disorder. The patient had been receiving anticonvulsant therapy since discharge from the neonatal ICU at a gestational age of 20 weeks. There was no history of seizure activity following discharge. Anticonvulsant therapy initially included phenobarbital (7.2 mg b.i.d.) which was increased to 8 mg b.i.d. at 6 months of age. At 22 months of age, the phenobarbital was discontinued and therapy with oxcarbazepine (150 mg b.i.d.) was started. The dose was subsequently increased to 180 mg b.i.d. The infant had been free of seizure activity until the day of admission. Tonic-clonic seizure activity was noted in the ambulance on transfer from home to an outside hospital. The initial workup at the outside emergency room revealed a serum sodium level of 120 mEq/L. The patient was treated with lorazepam (1 mg) to stop ongoing seizure activity and was transferred to our pediatric ICU. There was no history of polydipsia or polyuria. Respiratory disease, head trauma and excessive free water feeding were ruled out as potential causes of hyponatremia. The patient's medications at admission included oxcarbazepine (180 mg b.i.d.) and prednisone ophthalmic drops. At arrival, no further seizure activity was noted, and IV hydration with 5% dextrose in normal saline with 10 mEq of KCL per liter was started as maintenance. Admission laboratory evaluation revealed a carbamazepine level of 14.5 [micro]g/mL, serum sodium of 122 mEq/L, urinary sodium of 64 mEq/L, urinary osmolarity of 318 mMol/L, and a serum osmolarity of 280 mMol/L (Table 2). As there was no ongoing seizure activity or alteration in mental status, hypertonic saline was not administered. A diagnosis of syndrome of inappropriate antidiuretic hormone due to oxcarbazepine therapy was made and mild fluid restriction (70% of maintenance) was instituted. The oxcarbazepine was discontinued and carbamazepine started. The following day, the serum sodium concentration was 136 mEq/L. Fluid restriction was discontinued and the patient was discharged home. Follow-up serum sodium obtained as an outpatient the next day was 139 mEq/L. No further problems with sodium or water homeostasis have been noted.

Discussion

Topiramate and Metabolic Acidosis

Topiramate is an anticonvulsant medication used either as monotherapy or adjuvant therapy for the treatment of partial seizures and as adjuvant therapy for the treatment of generalized tonic-clonic seizures. In addition, as was the case with our first patient, topiramate has also been recommended for various behavioral disorders. (1,2) Several potential mechanisms of action have been proposed for topiramate including blockade of glutamate at postsynaptic [alpha]-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA/kainate) receptors, stimulation of [gamma]-aminobutyric acid (GABA) activity, and inhibition of voltage sensitive sodium channels. (3) Topiramate has also been reported to have weak inhibitory activity on carbonic anhydrase isoenzymes II and IV. (3)

Reported side effects of topiramate include dizziness, fatigue, psychomotor slowing, somnolence, headaches, weight loss, distal paresthesias, nephrolithiasis and primary central hyperventilation. In addition, given its effects on carbonic anhydrase, metabolic acidosis may occur related to urinary bicarbonate losses. (4-9) Philippi et al (4) investigated acid-base status in 9 infants and toddlers ranging in age from 5 months to 2.3 years during therapy with topiramate in doses ranging from 8.2 to 26 mg/kg/d. Although blood gas analysis was normal before therapy with topiramate, metabolic acidosis developed in 8 of the 9 patients after 8 to 26 days of therapy. The base deficit was -6.2 to -11.2 mMol/L and the pH was 7.22 to 7.40. Four of the nine patients demonstrated clinical signs of hyperventilation and were treated with oral sodium bicarbonate. The authors recommend monitoring of acid-base status during therapy with topiramate.

Takeoka et al (6) investigated acid-base changes in 30 children during topiramate therapy. Of the 30 patients, 21 had a 10% or more decrease in serum bicarbonate levels. The mean decrease in serum bicarbonate was 4.7 mEq/L with a maximum of 10 mEq/L. Treatment was necessary in only 1 patient who developed tachypnea to compensate for the metabolic acidosis. Topiramate therapy was eventually discontinued in 7 of these 21 children and serum bicarbonate levels returned to baseline values. Takeoka et al also noted that those patients with the most mild reduction of bicarbonate (<10%) were younger, mostly 1 to 3 years of age.

If severe, metabolic acidosis may lead to hyperventilation with Kussmaul respirations, cardiovascular disturbances from depressed cardiac contractility and peripheral arterial vasodilation, central venoconstriction, pulmonary edema and central nervous depression including headache, lethargy, stupor and coma. From our review of the literature, it is apparent that the majority of cases of topiramate-induced metabolic acidosis have not required therapy. The case of topiramate-induced metabolic acidosis we presented was noted intraoperatively which presents a further problem in that it cannot be easily differentiated from other causes of intraoperative acidosis including lactic acidosis from decreased cardiac output, the rare occurrence of acidosis associated with propofol administration, and dilutional acidosis. In our patient, there was no other evidence of ongoing myocardial dysfunction and we indirectly evaluated cardiovascular function by demonstrating a normal serum lactic acid level.

Although the majority of reports of metabolic acidosis related to propofol have occurred with long term infusions in the ICU setting, (10) there are anecdotal reports of the acute onset of metabolic acidosis during the short-term intraoperative/postoperative administration of propofol in both children and adults. (11-16) Three of these reports outline the development of metabolic acidosis related to propofol during its short-term use (50.5, 64, and 66 hours) in an ICU setting. (11-13) The acute onset of metabolic acidosis during the intraoperative administration of propofol has also been noted. (14-16) Kill et al (14) reported the intraoperative development of metabolic acidosis in a 7-year-old boy with osteogenesis imperfecta type 3 who was anesthetized for a fracture repair and received succinylcholine, fentanyl, and a mean propofol infusion rate of 13.5 mg/kg/h for 150 minutes. The serum lactate level increased to 9.2 mMol/L with a base deficit of -8.2 mMol/L. Mehta et al (15) reported severe metabolic acidosis, bradyarrhythmias and renal failure in an 18-month-old child with arthrogryposis after a 5-hour propofol infusion while Burow et al (16) reported the development of acidosis following a 395 minute infusion of propofol in a 31-year-old woman. In our patient, the potential causal relationship between the acidosis and propofol was ruled out by demonstrating a normal lactic acid level. This was necessary since we needed to continue the current anesthetic technique of propofol and remifentanil to ensure effective monitoring of motor and sensory-evoked potentials during spinal surgery. Intraoperative acidosis related to topiramate therapy has been reported by other investigators. (17,18) Ozer and Altunkaya (17) reported intraoperative acidosis in a 58-year-old man during general anesthesia with propofol. A normal anion gap and hyperchloremia demonstrated bicarbonate loss as the cause of the acidosis. Groeper and Mc-Cann (18) reported a case series of adolescents receiving topiramate in whom intraoperative acidosis was noted.

Oxcarbazepine and Hyponatremia

Oxcarbazepine is a ketoanalog of carbamazepine, an anticonvulsant medication that inhibits voltage sensitive sodium channels of neurons and is effective as sole or adjunctive therapy of partial seizures and in the treatment of chronic neuropathic pain. (19,20) Reported side effects of oxcarbazepine include dizziness, somnolence, diplopia, disorders of balance, gait or coordination; convulsions, rash, hyponatremia and alterations in white blood cell count. (19-21)

Hyponatremia, defined by the authors as a serum sodium <125 mEq/L, occurred in 2.5 to 3% of patients treated with oxcarbazepine in clinical trials, with most cases being asymptomatic. (21,22) Hyponatremia in children younger than 6 years old was not noted in a review of 2026 oxcarbazepine-treated patients. (23) They also noted that the frequency of serum sodium levels less than 125 mEq/L increased with age. Holtmann et al reported that hyponatremia (defined by the authors as a serum sodium less than 135 mEq/L) was present without symptoms in 26.6% of children during treatment with oxcarbazepine and that 2 of 75 children had sodium levels less than 125 mEq/L. (24) Borusiak et al (25) reported in a review of 48 pediatric patients receiving oxcarbazepine therapy that 9 were hyponatremic and that the hyponatremia was independent of the dose and serum concentration.

Oxcarbazepine-induced hyponatremia is thought to result from the syndrome of inappropriate secretion of antidiuretic hormone. (26-28) Hyponatremia occurs from either a direct effect on the renal collecting tubules by oxcarbazepine or an enhancement of their responsiveness to circulating antidiuretic hormone. The medication has been shown to result in a decreased excretion of free water load without a concomitant increase in the arginine vasopressin serum levels. (26-28) This mechanism fits with our findings; hyponatremia was present with an elevated urinary sodium concentration and a urinary osmolarity that was greater than the serum osmolarity. Potential risk factors for hyponatremia include advanced age, doses in excess of 30 mg/kg/d (as was the case in our patient) and the concomitant use of other medications which may result in hyponatremia including antidepressants, carbamazepine, and diuretics. (26-28) Serum sodium concentrations return to normal with dose reduction, discontinuation of oxcarbazepine or with restriction of water intake. (21,25,26)

Regardless of the medication used, there is always the potential for the development of adverse effects. Although many of these adverse effects are identified during the initial clinical trials, the real clinical significance of such effects may not become apparent until after the medication is released for general use. Over the past 5 to 10 years, there have been significant advances in the arena of anticonvulsant medication. In most cases, these medications offer the advantage of providing effective control of even refractory seizure disorders with fewer adverse effects than the previously available agents. However, rare yet potentially significant adverse effects may occur. Based on our experience, we recommend routine monitoring of preoperative electrolytes in patients receiving topiramate therapy, and serum sodium concentration monitoring in patients receiving oxcarbazepine. In addition, alternative etiologies should be considered for the acute onset of seizures, even in patients with an underlying seizure disorder.

References

1. Nickel MK, Nickel C, Mitterlehner FO, et al. Topiramate treatment of aggression in female borderline personality disorder patients: a double-blind, placebo-controlled study. J Clin Psychiatry 2004;65:1515-1519.

2. Janowsky DS, Kraus JE, Barnhill J, et al. Effects of topiramate on aggressive, self-injurious, and disruptive/destructive behaviors in the intellectually disabled: an open-label retrospective study. J Clin Psycho-pharmacol 2003;23:500-504.

3. Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia 1999;40:1471-1483.

4. Philippi H, Boor R, Reitter B. Topiramate and metabolic acidosis in infants and toddlers. Epilepsia 2002;43:744-747.

5. Laskey AL, Korn DE, Moorjani BI, et al. Central hyperventilation related to administration of topiramate. Pediatr Neurol 2000;22:305-308.

6. Takeoka M, Holmes GL, Thiele E, et al. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 2001;42:387-392.

7. Ozer Y, Altunkaya, H. Topiramate induced metabolic acidosis (letter). Anaesthesia 2004;59:830.

8. Stowe CD, Bolliger T, James LP, et al. Acute mental status changes and hyperchloremic metabolic acidosis with long-term topiramate therapy. Pharmacotherapy 2000;20:105-109.

9. Ko CH, Kong CK. Topiramate-induced metabolic acidosis: report of two cases. Dev Med Child Neurol 2001;43:701-704.

10. Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998;8:491-499.

11. Cray SH, Robinson BH, Cox PN. Lactic acidemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med 1998;26:2087-2092.

12. Culp KE, Augoustides JG, Ochrock AE, et al. Clinical management of cardiogenic shock associated with prolonged propofol infusion. Anesth Analg 2004;99:221-226.

13. Withington DE, Decell MK, Al Ayed T. A case of propofol toxicity: further evidence of a causal mechanism. Paediatr Anaesth 2004;14:505-508.

14. Kill C, Leonhardt A, Wulf H. Lactic acidosis after short-term infusion of propofol for anaesthesia in a child with osteogenesis imperfecta. Paediatr Anaesth 2003;13:823-826.

15. Mehta N, DeMunter C, Habibi P, et al. Short-term propofol infusions in children. Lancet 1999;354:866-867.

16. Burow BK, Johnson ME, Packer DL. Metabolic acidosis associated with propofol in the absence of other causative factors. Anesthesiology 2004;101:239-241.

17. Ozer Y, Altunkaya H. Topiramate induced metabolic acidosis (letter). Anaesthesia 2004;59:830.

18. Groeper K, McCann, E. Topiramate and metabolic acidosis: a case series and review of the literature. Paediatric Anaesth 2005;15:167-170.

19. Schmidt D, Elger CE. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic agents. Epilepsy Behav 2004;5:627-635.

20. Guay DR. Oxcarbazepine, topiramate, zonisamide, and levetiracetam: potential use in neuropathic pain. Am J Geriatr Pharmacother 2003;1:18-37.

21. Adkoli S. Symptomatic hyponatremia in patients on oxcarbazepine therapy for the treatment of neuropathic pain: two case reports. J Pain Palliat Care Pharmacother 2003;17:47-51.

22. Ryan M, Adams AG, Larive LL. Hyponatremia and leukopenia associated with oxcarbazepine following carbamazepine therapy. Am J Health Syst Pharm 2001;58:1637-1639.

23. Glauser TA. Oxcarbazepine in the treatment of epilepsy. Pharmacotherapy 2001;21:904-919.

24. Holtmann M, Karaue M, Opp J, et al. Oxcarbazepine-induced hyponatremia and the regulation of serum sodium after replacing carbamazepine with oxcarbazepine in children. Neuropediatrics 2002;33:298-300.

25. Borusiak P, Korn-Merker E, Holert N, et al. Hyponatremia induced by oxcarbazepine in children. Epilepsy Res 1998;30:241-246.

26. Sachdeo RC, Wasserstein A, Mesenbrink PJ, et al. Effects of oxcarbazepine on sodium concentration and water handling. Ann Neurol 2002;51:613-620.

27. Cilli AS, Algun E. Oxcarbazepine-induced syndrome of inappropriate-secretion of antidiuretic hormone (letter). J Clin Psych 2002;63:742.

28. Van Amelsvoort T, Bakshi R, Devaux CB, et al. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994;35:181-188.

Zachary Tebb, BS and Joseph D. Tobias, MD

From the University of Missouri School of Medicine, and the Departments of Anesthesiology and Child Health, University of Missouri, Columbia, MO.

Reprint requests to Joseph D. Tobias, MD, Vice-Chairman, Department of Anesthesiology, Chief, Division of Pediatric Anesthesiology, Russell and Mary Shelden Chair in Pediatric Intensive Care Medicine, Professor of Anesthesiology and Child Health, University of Missouri, Department of Anesthesiology, 3W40H, One Hospital Drive, Columbia, MO 65212. Email: [e-mail]

Accepted December 12, 2005.

RELATED ARTICLE: Key Points

* In addition to its anticonvulsant effects, topiramate has also been reported to have weak inhibitory activity on carbonic anhydrase isoenzymes which may result in urinary bicarbonate losses and metabolic acidosis.

* Although the majority of cases of topiramate-induced metabolic acidosis have not required therapy, the intraoperative identification of metabolic acidosis may present additional issues, as the differential diagnosis includes lactic acidosis from decreased cardiac output, the rare occurrence of acidosis associated with propofol administration, and dilutional acidosis.

* Potential risk factors for hyponatremia with oxcarbazepine include advanced age, doses in excess of 30 mg/kg/d and the concomitant use of other medications which may result in hyponatremia, including antidepressants, carbamazepine, and diuretics.

* Oxcarbazepine-induced hyponatremia is postulated to result from either a direct effect on the renal collecting tubules by the medication or an enhancement of their responsiveness to circulating antidiuretic hormone resulting in a decreased excretion of free water load without a concomitant increase in the arginine vasopressin serum levels.

Table 1. Arterial blood gas values of patient #1

Time (from the
induction of              PaC[O.sub.2]  Pa[O.sub.2]  HC[O.sub.3]
anesthesia)         pH    (mmHg)        (mmHg)       (mEq/L)

1 hour 38 minutes   7.28  39.5          515          17.8
1 hour 58 minutes   7.32  34.2          313          17.1
3 hours 9 minutes   7.38  30.6          308          17.8
4 hours 40 minutes  7.46  29.9          298          21.0
6 hours 12 minutes  7.43  30.8          316          19.9

Time (from the
induction of        Base excess  Treatment with sodium
anesthesia)         (mMol/L)     bicarbonate (mEq)

1 hour 38 minutes   -7.8          50
1 hour 58 minutes   -7.9         100
3 hours 9 minutes   -6.3          50
4 hours 40 minutes  -2.3           -
6 hours 12 minutes  -3.8           -

Table 2. Serum chemistry results of patient #2

               [Na.sup.+]  [Cl.sup.-]  HC[O.sub.3.sup.-]
Hospital day   (mEq/L)     (mEq/L)     (mEq/L)

Outside ER     120          86         14
PICU arrival   122          92         23
Following day  136         106         19

                                          Serum & urine
               BUN      Urine [Na.sup.+]  osmolarity
Hospital day   (mg/dL)  (mEq/L)           (mOsm/kg)

Outside ER     7        -                 -
PICU arrival   6        64                280-318
Following day  5        -