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© 2013 Direct One Communications, Inc. All rights reserved. 1

Anticonvulsant Treatment of Epilepsy and Refractory Status Epilepticus: Recent Clinical Trials

Sarah Aminoff Kelley, MD

Johns Hopkins Hospital, Baltimore, Maryland

A REPORT FROM THE 66th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY


Refractory Status Epilepticus (RSE)

Refractory seizures continue for a prolonged period or do not respond to a standard protocol of a benzodiazepine plus 1 or 2 additional antiepileptic drugs (AEDs).1

Older AEDs (eg, valproic acid, phenobarbital) are frequently used for RSE, and newer AEDs (eg, levetiracetam,2 topiramate3) are often tried.

Anesthetics or higher doses of barbiturates and benzodiazepines may be used but have many side effects.

Consequently, there is no clear best choice for treating RSE.


Parenteral Lacosamide for Partial-Onset Seizures


Parenteral Lacosamide for Partial-Onset Seizures:

Background and Rationale

Lacosamide is a relatively new AED approved for marketing in Europe and the United States for adjunctive treatment of partial-onset seizures in adults with epilepsy.4

Ideal medication for treating critically ill patients:

» Novel mechanism of action enhances slow inactivation of sodium channels without affecting fast activity.4

» Has similar efficacy in both parenteral and oral forms, without causing many sedating and cardiovascular effects of other parenteral options5

» Relatively few drug-drug interactions6



Study 1: Population and Methods

Sutter et al7 evaluated the safety and efficacy of parenteral lacosamide as an adjunctive treatment of RSE.

Largest lacosamide study reported to date; only controlled clinical trial using this drug for RSE.

Compared 59 consecutive lacosamide-treated patients observed from January 2005–December 2011 with 62 historical controls treated before 2005

Controls were slightly older and more likely to have suffered nonconvulsive status epilepticus or stroke.



Study 1: Results

Seizures stopped immediately in ~ 40% of patients with RSE.

Patients treated with lacosamide are more likely to have earlier RSE relief and less likely to die.

Less anesthetic needed and potential for lower overall morbidity and mortality

No serious adverse outcomes

Only significant differences between control and lacosamide-treated groups were addition of the study drug, a higher proportion of patients treated with topiramate, and more frequent continuous EEG monitoring.




Alam et al8 tested lacosamide in 178 patients 6–90 years of age with status epilepticus or acute repetitive seizures.

Most patients were treated for nonconvulsive status epilepticus.

All patients monitored with continuous video EEG

All but 42 patients excluded:

» Some patients excluded for prior treatment with lacosamide

» Seven patients had post-anoxic brain injury and later had a complete lack of response to lacosamide



Study 2: Results

Lacosamide (median dose, 150 mg) terminated the seizures in 20 (57%) of the remaining 35 patients.

Some patients required subsequent dosage titration to control their seizures.

Lacosamide was most often the third- or fourth-line medication used.

Other anticonvulsants that had been tried included levetiracetam, phenytoin, lorazepam, and midazolam.

No patient experienced a serious adverse event after receiving lacosamide.




Newey and Hantus9 retrospectively analyzed 84 adults with wide-ranging etiologies (eg, stroke, brain tumors, epilepsy) who began having seizures while on continuous EEG monitoring and then progressed to status epilepticus.

More than half of the patients had nonconvulsive status epilepticus.

All patients had not received lacosamide previously.



Study 3: Results

After treatment with two other anticonvulsants (most often, levetiracetam and phenytoin) failed, 15.7% of the patients responded within 4 hours of starting treatment with parenteral lacosamide.

82% of the patients stopped having seizures 48 hours after treatment with lacosamide.

No abnormalities in blood pressure, liver or kidney function, or PR interval occurred.


Perampanel Drug Interactions


Perampanel Drug Interactions:

Background

Perampanel is a selective, noncompetitive antagonist of -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-type glutamate receptors10

Recently approved in both the United States and Europe for adjunctive treatment of partial-onset seizures, with or without secondarily generalized seizures, in patients 12 years of age and older

Mainly metabolized by the cytochrome P (CYP) 3A4 system

Clearance increased by concomitant administration of CYP3A4 enzyme inducers (carbamazepine, oxcarbazepine, phenytoin)11



Study Population and Methods

Laurenza et al12 investigated the safety and efficacy of perampanel when used concomitantly with CYP3A4 enzyme inducers.

Data were collected during three large, phase III, double-blind pivotal trials.10,13,14

Patients were studied for 19 weeks.



Results

Concomitant administration of CYP3A4 enzyme inducers reduced plasma perampanel levels.

Median percent change in seizure frequency, as well as response rate to perampanel, was more robust when perampanel was given concomitantly without CYP3A4 enzyme inducers and lowered when these drugs were also being taken.

Patients taking CYP3A4 enzyme inducers should be started at higher doses of perampanel or titrated more frequently to compensate for the greater oral clearance of the drug.


Cardiovascular Risks Associated with AEDs


Cardiovascular Risks Associated with AEDs:


Karve et al18 retrospectively analyzed whether cardiovascular events occurred more frequently in patients taking statins with:

» CYP450 enzyme inducers, eg, phenytoin, carbamazepine, phenobarbital, primidone

» CYP450 noninducers, eg, topiramate, oxcarbazepine, lamotrigine, gabapentin, pregabalin, levetiracetam, zonisamide, tiagabine, valproic acid

Patients were followed for at least 60 days.

Data were collected from a chart review of primary care clinic notes.



Results

The incidence of myocardial infarction, stroke, transient ischemic attack, congestive heart failure, or angina in patients taking statins was the same whether or not they were also being treated with CYP450 enzyme-inducing AEDs.



Potential Vascular Risks of Newer AEDs

Chuang et al19 studied metabolic changes related to use of older CYP enzyme-inducing and enzyme-inhibiting AEDs and lamotrigine.

Use of the older medications led to increased levels of vascular risk markers (cholesterol, homocysteine, others) not noted with lamotrigine use.

Risk of a negative vascular outcome has not been well studied in patients using newer AEDs.



Potential Risks in the Newly Diagnosed

Kim et al20 investigated vascular risk factors (lipid profile, homocysteine level, and apolipoprotein B [ApoB]:ApoB/A1 ratio) in newly diagnosed patients with epilepsy at baseline and 6 months after the patients started taking levetiracetam, oxcarbazepine, or topiramate monotherapy.

Homocysteine levels and ApoB:ApoB/A1 ratios increased significantly; however, there was no clear difference between the AEDs used.

The authors suggested that cardiovascular risk factors should be monitored in all patients taking AEDs.


Economic Advantages of Combination AED Therapy


Economic Advantages of Combination AED Therapy:


Cavazos et al21 studied combination AED therapy, seizure control, and healthcare costs in patients for whom monotherapy failed.

Over 34,000 patients with a first-time diagnosis of partial-onset seizures were identified from an insurance database.

Patients were excluded if they were being treated with an anticonvulsant for a disorder unrelated to epilepsy (eg, neuropathic pain, migraine, bipolar disorder) or had never used more than one AED.


Economic Advantages of Combination AED Therapy:

Results

Compared with patients on sequential monotherapy or monotherapy followed by combination therapy, patients using a combination of AEDs from the start were hospitalized less often and had lower medical costs.

The authors suggested that improved seizure control in an insured, mostly working-class population may be obtained with combination AED therapy from the outset.


Treatment of Drop Seizures in Children

Thome-Souza and Valente22 investigated the efficacy of combination valproate and lamotrigine therapy in 60 children with drop seizures.

Most children were given valproate, lamotrigine, and a benzodiazepine.

Approximately 25% achieved complete control of their drop seizures.

A little over one half of the children experienced 50%–75% control.

There was no control group, and other anticonvulsants were not examined.


Response Rates of Intractable Seizures

Sugai et al23 analyzed the efficacy of various AEDs in almost 300 children and young adults with 1–3 seizure symptoms and mostly frontal-lobe epilepsy.

< 25% response rate with valproate for partial seizures

25%–50% response rate with carbamazepine for secondarily generalized tonic-clonic seizures

> 75% response rate with use of potassium bromide, zonisamide, or lamotrigine for tonic seizures; zonisamide for secondarily generalized tonic-clonic seizures; carbamazepine for clonic seizures; and phenytoin for hypermotor seizures


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8. Alam K, Mullin PD, Park S, Berger K, Rosengart AJ. Lacosamide in the treatment of refractory status epilepticus and repetitive seizures. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2.237.

9. Newey CR, Hantus S. Intravenous lacosamide is safe and effective in treating refractory status epilepticus in a critically-ill population: a large retrospective case series. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2.227.

10. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79:589–596.


References11. Fycompa [package insert]. Woodcliff Lake, NJ: Eisai, Inc; October 2012.

12. Laurenza A, Gidal B, Hussein Z, et al. Evaluation of efficacy and safety of perampanel in the presence of concomitant CYP3A4-inducing AEDS: analyses from the perampanel phase 3 clinical trials. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2.211.

13. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia. 2013;54:117–125.

14. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:1408–1415.

15. Bullman J, Nicholls A, Van Landingham K, et al. Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers. Epilepsia. 2011;52:1351–1358.

16. Gedde-Dahl A, Devold HM, Molden E. Statin medication in patients treated with antiepileptic drugs in Norway. Pharmacoepidemiol Drug Saf. 2012;21:881–885.

17. Candrilli SD, Manjunath R, Davis KL, Gidal BE. The association between antiepileptic drug and HMG-CoA reductase inhibitor co-medication and cholesterol management in patients with epilepsy. Epilepsy Res. 2010;91:260–266.

18. Karve S, Mitra D, Rajagopalan K, Blum D, Grinnell T, Bollu V. Impact of concomitant use of antiepileptic drugs and statins on risk of cardiovascular events. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 205.

19. Chuang YC, Chuang HY, Lin TK, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012;53:120–128.

20. Kim DW, Shen Y, Lee S, Kim JH. Effects of new generation antiepileptic drugs on vascular risk factors in newly diagnosed epilepsy patients. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2.214.


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monotherapy and combination therapy with antiepileptic drugs in patients with partial onset seizures. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 202.

22. Thome-Souza M, Valente K. Maintenance of valproate and lamotrigine efficacy during one year in a large series of patients with drop attacks. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2.212.

23. Sugai K, Nakagawa E, Komaki H, et al. Effective antiepileptic drugs for intractable partial epilepsies in children and young adults are different among actual seizure symptoms. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2.128.


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19. Sutter R, Marsch S, Ruegg S. Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus: A large comparative cohort study. Presented at the Joint Annual Meeting of the Swiss SNG Neurological Society, the Swiss Society of Biological Psychiatry SGBP, and the Swiss Society for Behavioral Neurology; November 8–10, 2012; Basel, Switzerland.

20. Alam K, Mullin PD, Park S, Berger K, Rosengart AJ. Lacosamide in the treatment of refractory status epilepticus and repetitive seizures. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 237.

21. Newey CR, Hantus S. Intravenous lacosamide is safe and effective in treating refractory status epilepticus in a critically-ill population: A large retrospective case series. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 227.

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24. Fycompa [package insert]. Woodcliff Lake, NJ: Eisai, Inc; October 2012.

25. Laurenza A, Gidal B, Hussein Z, et al. Evaluation of efficacy and safety of perampanel in the presence of concomitant CYP3A4-inducing AEDS: analyses from the perampanel phase 3 clinical trials. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 211.

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29. Gedde-Dahl A, Devold HM, Molden E. Statin medication in patients treated with antiepileptic drugs in Norway. Pharmacoepidemiol Drug Saf. 2012;21:881–885.

30. Candrilli SD, Manjunath R, Davis KL, Gidal BE. The association between antiepileptic drug and HMG-CoA reductase inhibitor co-medication and cholesterol management in patients with epilepsy. Epilepsy Res. 2010;91:260–266.

31. Karve S, Mitra D, Rajagopalan K, Blum D, Grinnell T, Bollu V. Impact of concomitant use of antiepileptic drugs and statins on risk of cardiovascular events. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 205.

32. Chuang YC, Chuang HY, Lin TK, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012;53:120–128.


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newly diagnosed epilepsy patients. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 214.

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38. Thome-Souza M, Valente K. Maintenance of valproate and lamotrigine efficacy during one year in a large series of patients with drop attacks. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 212.

39. Machado VH, Palmini A, Bastos FA, Rotert R. Long-term control of epileptic drop attacks with the combination of valproate, lamotrigine, and a benzodiazepine: a “proof of concept,” open label study. Epilepsia. 2011;52:1303–1310.

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41. Sugai K, Nakagawa E, Komaki H, et al. Effective antiepileptic drugs for intractable partial epilepsies in children and young adults are different among actual seizure symptoms. Presented at the 66th Annual Meeting of the American Epilepsy Society; November 30–December 4, 2012; San Diego, CA. Poster P2 128.

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