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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
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1
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.
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2
Parenteral Lacosamide for
Partial-Onset Seizures
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3
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
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4
Parenteral Lacosamide for Partial-Onset Seizures:
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.
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5
Parenteral Lacosamide for Partial-Onset Seizures:
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.
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6
Parenteral Lacosamide for Partial-Onset Seizures:
Study 2: Population and Methods

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
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7
Parenteral Lacosamide for Partial-Onset Seizures:
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.
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8
Parenteral Lacosamide for Partial-Onset Seizures:
Study 3: Population and Methods

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.
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9
Parenteral Lacosamide for Partial-Onset Seizures:
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.
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10
Perampanel Drug Interactions
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11
Perampanel Drug Interactions:
Background

Perampanel is a selective, noncompetitive antagonist
of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic 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
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12
Perampanel Drug Interactions:
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.
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13
Perampanel Drug Interactions:
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.
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14
Cardiovascular Risks
Associated with AEDs
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15
Cardiovascular Risks Associated with AEDs:
Study Population and Methods

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.
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16
Cardiovascular Risks Associated with AEDs:
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.
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17
Cardiovascular Risks Associated with AEDs:
Potential Vascular Risks of Newer AEDs

Chuang et al19 studied metabolic changes related to
use of older CYP enzyme-inducing and enzymeinhibiting 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.
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18
Cardiovascular Risks Associated with 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.
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19
Economic Advantages of
Combination AED Therapy
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20
Economic Advantages of Combination AED Therapy:
Study Population and Methods

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.
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21
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.
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22
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.
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23
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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24
References
1.
Lowenstein DH. The management of refractory status epilepticus: an update. Epilepsia. 2006;47(suppl
1):35–40.
2.
McTague A, Kneen R, Kumar R, Spinty S, Appleton R. Intravenous levetiracetam in acute repetitive seizures
and status epilepticus in children: experience from a children’s hospital. Seizure. 2012;21:529–534.
3.
Hottinger A, Sutter R, Marsch S, Ruegg S. Topiramate as an adjunctive treatment in patients with refractory
status epilepticus: an observational cohort study. CNS Drugs. 2012;26:761–772.
4.
Chung SS. New treatment option for partial-onset seizures: efficacy and safety of lacosamide. Ther Adv
Neurol Disord. 2010;3:77–83.
5.
Biton V, Rosenfeld WE, Whitesides J, Fountain NB, Vaiciene N, Rudd GD. Intravenous lacosamide as
replacement for oral lacosamide in patients with partial-onset seizures. Epilepsia. 2008;49:418–424.
6.
Beyreuther BK, Freitag J, Heers C, Krebsfanger N, Scharfenecker U, Stohr T. Lacosamide: a review of
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7.
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.
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.
© 2013 Direct One Communications, Inc. All rights reserved.
25
References
11. 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.
© 2013 Direct One Communications, Inc. All rights reserved.
26
References
21. Cavazos R, Simons R, Fain R, Powers A, Wang Z. Health outcomes associated with sequential 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.
© 2013 Direct One Communications, Inc. All rights reserved.
27
References
13. Goodwin H, Hinson HE, Shermock KM, Karanjia N, Lewin JJ 3rd. The use of lacosamide in refractory status
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status epilepticus. Seizure. 2012;21:198–201.
18. Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy and safety of intravenous lacosamide in
refractory nonconvulsive status epilepticus. Acta Neurol Scand. 2011;123:142–146.
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.
22. Hukkanen J. Induction of cytochrome P450 enzymes: a view on human in vivo findings. Expert Rev Clin
Pharmacol. 2012;5:569–585.
© 2013 Direct One Communications, Inc. All rights reserved.
28
References
23. 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.
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.
26. 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. 2012. Epub ahead of print.
27. 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.
28. 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.
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.
© 2013 Direct One Communications, Inc. All rights reserved.
29
References
33. 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.
34. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–319.
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2012;21:466–470.
37. Cavazos R, Simons R, Fain R, Powers A, Wang Z. Health outcomes associated with sequential 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.
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.
40. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and
epilepsies: report of the ILAE commission on classification and terminology, 2005–2009. Epilepsia.
2010;51:676–685.
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.
© 2013 Direct One Communications, Inc. All rights reserved.
30