OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Methsuximide	77-41-8	C12-H13-N-O2
Ethosuximide	77-67-8	C7-H11-N-O2

ANNOTATED BIBLIOGRAPHY

References updated: 01 July 2016

• Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 498-516.

  (Expert review of anticonvulsants and liver injury published in 1999; methsuximide is not discussed).
• Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 423-42.

  (Review of anticonvulsant induced liver injury; methsuximide is not discussed).
• McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 583-607.

  (Textbook of pharmacology and therapeutics).
• Livingston S, Pauli L. Celontin (PM-396) in the treatment of epilepsy. Pediatrics 1957; 19 (4 Pt 1): 614-8. [PubMed: 13419432]

  (Among 136 patients with various types of poorly controlled seizures treated with methsuximide for 6-15 months, beneficial results were found largely in those with minor motor and psychomotor seizures, and routine blood tests were reported to remain normal).
• French EG, Rey-Bellet J, Lennox WG. Methsuximide in psychomotor and petit-mal seizures. N Engl J Med 1958; 258: 892-4. [PubMed: 13541681]

  (Among 106 adults and children with varying types of poorly controlled seizures treated with methsuximide, 30 dropped out and 49 [48%] reported some degree of improvement, side effects being drowsiness, nausea and vomiting, constipation, rash [n=9], confusion and headaches; no mention of jaundice or hepatotoxicity).
• Karch SB. Methsuximide overdose. Delayed onset of profound coma. JAMA 1973; 223: 1463-5. [PubMed: 4740029]

  (18 year old girl with epilepsy took an overdose of 10 g of methsuximide and developed dizziness, followed by somnolence and then deep coma 9 hours later, persisting for 72 hours; ALT, AST, Alk P and bilirubin levels were normal).
• Reynolds NC Jr, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981; 31: 480-4. [PubMed: 7194443]

  (Mentions that both methsuximide and ethosuximide have been associated with triggering attacks of acute intermittent porphyria).
• Wilder BJ, Buchanan RA. Methsuximide for refractory complex partial seizures. Neurology 1981; 31: 741-4. [PubMed: 6894634]

  (Among 21 patients with refractory complex partial seizures treated with methsuximide, 8 had a complete and 7 a partial response; side effects included somnolence, headache, ataxia, skin rash, nausea and malaise, but “most were not serious”; no mention of hepatotoxicity or serum enzyme elevations).
• Coulter DL. Ethosuximide-induced liver dysfunction. Arch Neurol 1983; 40: 393-4. [PubMed: 6847455]

  (1 year old boy developed ALT elevations one month after ethosuximide was added to a chronic regimen of valproate and phenobarbital that continued to worsen after stopping valproate [bilirubin normal, ALT 69 rising 229 U/L, GGT 175 U/], resolving rapidly when ethosuximide was stopped).
• Browne TR, Feldman RG, Buchanan RA, Allen NC, Fawcett-Vickers L, Szabo GK, Mattson GF, et al. Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions. Neurology 1983; 33: 414-8. [PubMed: 6403891]

  (Among 26 adults with poorly controlled, complex partial seizures treated with methsuximide, 8 had a clinical response and continued on therapy; side effects included drowsiness, gastrointestinal complaints, hiccups, irritability, headache and ataxia, but there was “no serious idiosyncratic hemopoietic, hepatic, or renal toxicity”).
• Tennison MB, Greenwood RS, Miles MV. Methsuximide for intractable childhood seizures. Pediatrics 1991; 87: 186-9. [PubMed: 1987529]

  (Among 23 children with various forms of intractable seizures treated with methsuximide, 15 had a 50% or greater decrease in seizures; 4 had side effects requiring discontinuation, include 2 with rash; no details provided).
• Hurst DL. Methsuximide therapy of juvenile myoclonic epilepsy. Seizure 1996; 5: 47-50. [PubMed: 8777552]

  (Among 5 adolescent girls with juvenile myoclonic epilepsy treated with methsuximide, all became seizure free and 4 could stop all other anticonvulsants; there were no serious adverse events).
• Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999; 21: 489– 501. [PubMed: 10612272]

  (Review of anticonvulsant hypersensitivity syndrome: triad of fever, rash and internal organ injury occurring 1-8 weeks after exposure to anticonvulsant, liver being most common internal organ involved. Occurs in 1:1000-1:10,000 initial exposures to phenytoin, carbamazepine, phenobarbital or lamotrigine, unrelated to dose, perhaps predisposed by valproate; liver injury arises 1-4 weeks after onset of rash and ranges in severity from asymptomatic ALT elevations to icteric hepatitis to ALF; high mortality rate with jaundice; other organs include muscle, kidney, brain, heart and lung. Pseudolymphoma syndrome and serum sickness like syndrome are separate complications of anticonvulsants; role of corticosteroids uncertain; cross reactivity among the agents should be assumed; methsuximide is not mentioned).
• Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Clevel Clin J Med 1999; 66: 239-45. [PubMed: 10199060]

  (Clinical review of anticonvulsant syndrome, which occurs in 1-5/10,000 users, higher risk in African Americans and affected siblings; liver involvement common, but most cases are anicteric; other manifestations include facial edema, lymphadenopathy, bone marrow aplasia, pseudolymphoma, thyroiditis, interstitial nephritis, switching to valproate, levetiracetam or benzodiazepines is safe; methsuximide is not mentioned).
• Sigler M, Strassburg HM, Boenigk HE. Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood. Seizure 2001; 10: 120-4. [PubMed: 11407955]

  (Among 112 children with intractable epilepsy treated with methsuximide, there were no serious or irreversible adverse events and 50% had a decrease in seizure frequency).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]

  (Among ~50,000 liver transplants done in the US between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 10 were attributed to phenytoin, 10 to valproate and 1 to carbamazepine, but none to ethosuximide or methsuximide).
• Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. [PubMed: 18341684]

  (Review of all anticonvulsants; mentions that there is no known clinically significant hepatotoxicity associated with ethosuximide).
• Penovich PE, Willmore LJ. Use of a new antiepileptic drug or an old one as first drug for treatment of absence epilepsy. Epilepsia 2009; 50 Suppl 8: 37-41. [PubMed: 19702732]

  (Review of the therapy of absence seizures, mentions that side effects of ethosuximide "tend to be a challenge"; no mention of methsuximide or of hepatotoxicity).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 11 [8%] were due to anticonvulsants, including phenytoin [8], valproate [2], and carbamazepine [3], but none were attributed to ethosuximide or methsuximide).
• Hoepner R, May TW, Rambeck B, Ottenottebrock H, Valentin R, Brandt C. Symptoms and course of intoxication with mesuximide--a case report. Epilepsy Behav 2012; 25: 129-30. [PubMed: 22818365]

  (31 year old woman on multiple antiepileptic drugs developed worsening somnolence and was found to have abnormally elevated methsuximide levels; no mention of ALT elevations or hepatotoxicity).
• Knowles SR, Dewhurst N, Shear NH. Anticonvulsant hypersensitivity syndrome: an update. Expert Opin Drug Saf 2012; 11: 767-78. [PubMed: 22794330]

  (Updated review of anticonvulsant hypersensitivity syndrome associated with phenytoin, phenobarbital, lamotrigine and carbamazepine and rarely with zonisamide, valproate and oxcarbazepine; methsuximide is not mentioned).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury from the US enrolled in a prospective database between 2004 and 2012, anticonvulsants were implicated in 40 cases, including one attributed to ethosuximide, but none to methsuximide).
• Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. [PubMed: 23348233]

  (Concise review of indications and side effects of anticonvulsants; mentions that ethosuximide is the first line drug recommended for treatment of absence seizures, but does not mention methsuximide).