Teaching Points :::: Seizures

Ridryder 911 · July 11, 2006

I am not aware of any specific that could be used. As well understanding ACTH, ADH levels, would be hard to examine in the prehospital arena. I do consider such if I can get information from clinics, dialysis, or critical care transfers. Fluid therapy is the usual suggested initial treatment (except dialysis of course) and possibility of magnesium IV. This is a far deviation, and I consult the physician, and there has to be outstanding circumstances with patients with Cushing syndrome, or Addison's disease. Usually, I prefer tie KISS method in these cases...LOL

R/r 911

Ace844 · July 11, 2006

Hello Everyone,

Here's a great mnemonic to help you remember the DDX of Seizures::

SICK DRIFTER:

Substrates (sugar, oxygen)

Isoniazid overdose

Cations (Na, Ca, Mg)

Kids (ecclampsia)

Drugs (CRAP: Cocaine, Rum (alcohol), Amphetamines, PCP)

Rum (alchohol withdrawl)

Illnesses (chronic seizure disorder or other chronic disorder)

Fever (meningitis, encephalitis, abscess)

Trauma (epidural, subdural, intraparynchymal hemorrhage)

Extra: toxocologic (TAIL: Theo, ASA, Isoniazid, Lithium) and 3 Anti's: (Antihistamine overdose, Antidepressant overdose, Anticonvulsants (too high dilanitin, tegretol) or benzo withdrawl.

Rat poison (organophospates poisoning)

nbsp · July 12, 2006

In my EMT class were were told not to touch the patient during the seizure, not even to place an OPA or an NPA, NRB, or to bag, because the violence of the movement may mean risk of c-spine damage when the body moves violently while the head is held still. So my question would be, in the case of long, violent seizures, when and how would it be appropriate to step in and start bagging when ALS is not available?

Ridryder 911 · July 12, 2006

Hmm I would read the medical emergency section of my text again. If your instructor informed you not to touch a seizing patient due to c-spine, they were an idiot! Restraining the head or for as that goes any part of the body forcefully, can cause damage, but not to administer or place an NP or OP in a seizing is not going to cause a C-spine fracture. Did they teach not to apply oxygen and suction PRN, as well?..(one has to touch the patient for that as well)

Again, refer to national standards and curriculum. I do worry about instructors that "make up" things as they go.

If your instructor would like to debate this issue, I welcome them to this site.

R/r 911

Ace844 · July 22, 2006

(The American Journal of Emergency Medicine

Volume 24 @ Issue 3 , May 2006, Pages 343-346

doi:10.1016/j.ajem.2005.11.004

Therapeutics

Intranasal midazolam therapy for pediatric status epilepticus

Timothy R. Wolfe MD, and Thomas C. Macfarlane MD

Department of Emergency Medicine, Jordan Valley Hospital, West Jordan, UT 84088, USA

Received 5 November 2005; accepted 7 November 2005. Available online 25 April 2006. )

Abstract

Prolonged seizure activity in a child is a frightening experience for families as well as care providers. Because duration of seizure activity impacts morbidity and mortality, effective methods for seizure control should be instituted as soon as possible, preferably at home. Unfortunately, parenteral methods of medication delivery are not available to most caregivers and rectal diazepam, the most commonly used home therapy, is expensive and often ineffective. This brief review article examines recent research suggesting that there is a better way to treat pediatric seizures in situations where no intravenous access is immediately available. Intranasal midazolam, which delivers antiepileptic medication directly to the blood and cerebrospinal fluid via the nasal mucosa, is safe, inexpensive, easy to learn by parents and paramedics, and provides better seizure control than rectal diazepam.

Article Outline

1. Introduction

2. Discussion

References

1. Introduction

The cumulative lifetime incidence of epilepsy is 3%, with half of these cases beginning in childhood [1]. Approximately 10% to 20% of childhood epilepsy is refractory to medications, resulting in frequent breakthrough seizure episodes [1]. Most of these seizures are brief and resolve without treatment. However, if they persist for more than 5 minutes, prompt intervention is recommended [2]. Early antiepileptic intervention in an actively seizing patient reduces seizure duration, decreasing both morbidity and mortality [3] and [4]. Because most episodes of prolonged seizure activity begin outside the hospital, parents and caretakers need simple, safe, and effective treatment options to ensure early intervention. Currently, diazepam and lorazepam are the most widely used medications for the emergent management of seizures in both adults and children [5], [6] and [7]. Diazepam must be given intravenously (IV) or rectally because absorption is slow and erratic if given via the intramuscular route [8] and [9]. Lorazepam may be administered via the IV, intramuscular, or transmucosal route [10] and [11]. Outside the hospital, where IV and intramuscular therapy may be difficult or impossible, transmucosal rectal diazepam has emerged as the primary treatment option for breakthrough seizures. Unfortunately, compared with the IV formulation, rectal diazepam has a slower onset of action and is less effective at controlling seizures [8], [12], [13], [14] and [15]. Rectal drug administration is also less socially acceptable than other routes, making medication compliance an issue [16], [17] and [18]. Finally, because of patent protection, the commercially available rectal diazepam product (Diastat-Xcel pharmaceuticals, San Diego, Calif) is considerably more expensive than generic formulations of other commonly used benzodiazepines, making affordability difficult for some families (see Table 1).

Table 1.

Average wholesale prices for benzodiazepines commonly used to treat seizures Medication Diastat Diazepam Midazolam Lorazepam

Packaging 10 mg (twin pack—2 doses) 5 mg/mL (2-mL vial) 5 mg/mL (2-mL vial) 2 mg/mL (1-mL vial)

AWP $117.43 per dose $2.53 $3.20 $6.43

AWP, average wholesale price.

Transmucosal delivery of generic benzodiazepines via the nasal mucosa offers an attractive and cost-effective alternative in the out-of-hospital setting. Midazolam and lorazepam easily cross the nasal mucosa and the blood brain barrier, resulting in a rapid rise in both the plasma and the cerebrospinal fluid concentrations [11], [13] and [19]. Numerous studies now demonstrate the efficacy and safety of intranasal benzodiazepines for seizure treatment, both within the hospital, prehospital, extended care, and home settings [15], [16], [17], [18], [20], [21], [22], [23], [24] and [25]. The following discussion will review the concept of intranasal medication delivery and the literature that supports hospital and home-based management of seizures with intranasal benzodiazepines.

2. Discussion

Transmucosal intranasal benzodiazepine delivery for the treatment of breakthrough seizures offers several advantages over transmucosal rectal delivery. First of all, intranasal benzodiazepine delivery is easily understood and mastered by the lay public and does not carry the social taboos associated with rectal drug delivery [16], [17], [18] and [25]. Secondly, the nasal mucosa provides a large (180 cm2), highly vascular absorptive surface sitting adjacent to the brain [26]. This vascular plexus and the adjacent olfactory mucosa provide direct routes for benzodiazepine absorption into the blood stream and the cerebral spinal fluid [27] and [28]. In fact, within a few minutes of delivery, serum levels of intranasal midazolam are comparable with injectable levels [13]. In contrast, rectal administration of benzodiazepines results in substantially lower blood levels than IV administration [8] and [12]. The result is higher blood levels, faster onset of action, and more effective seizure control with intranasal than with rectally administered benzodiazepines [8], [12], [13], [14] and [15].

However, to achieve optimal results using intranasal benzodiazepine delivery, it is important to use highly concentrated medications delivered as a thin layer over the mucosa. Too much medication will run out of the nose or down the back of the throat, rendering it ineffective. Therefore, volumes more than about 1/2 mL per nostril are not optimally absorbed [29]. Absorption can be further enhanced if half the medication is placed into each nostril, cutting the volume per nostril in half while doubling the surface area available for absorption. The method chosen to deliver the medication to the nasal mucosa is also important. Covering a large mucosal surface area with a thin layer of medication will result in better drug absorption than administration of large droplets to a small surface area [27]. Nasal medication bioavailability increases as the drug delivery system is changed from a drop form to a spray form to an atomized form [28] and [30].

Three randomized controlled trials and 1 prehospital observational trial exist, comparing rectal diazepam to either buccal (oral transmucosal) or intranasal midazolam [15], [24], [31] and [32]. Scott et al [32] conducted a randomized controlled trial comparing buccal midazolam to rectal diazepam in epileptic students in an extended care school. A school nurse administered medication to all students who suffered continuous seizures for more than 5-minutes. Patients with persistent seizures for an additional 10 minutes were treated at the on-call physician's discretion. Oral transmucosal midazolam was effective in 75% of cases (30 of 40 seizures), whereas rectal diazepam was effective in 59% (23/39) (P = non significant). There were no adverse cardiorespiratory effects in either group. Although these differences did not achieve statistical significance, the trend toward a better outcome along with the more socially acceptable delivery of oral transmucosal medication led the school to change its preferred treatment to the oral transmucosal route. Camfield et al [31] found similar efficacy in their randomized trail comparing these 2 routes and drew identical conclusions—oral transmucosal midazolam was preferred over rectal diazepam because of ease of use and social acceptability. The third randomized controlled trial, conducted by Fisgin et al, compared intranasal (rather than buccal) transmucosal midazolam to rectal diazepam [15]. In this study, midazolam aborted 20 (87%) of 23 seizures and rectal diazepam 13 (60%) of 22 seizures (P < .05). These results were statistically significant in favor of the intranasal route when compared with the rectal route. Again, as in previous studies, no clinically important adverse events were identified in the 2 groups. The final study was conducted in a prehospital ambulance setting [24]. In this study, the entire emergency medical system converted from rectal diazepam to intranasal midazolam for treatment of pediatric seizures. The authors compared effectiveness and complication data before and after the change. The rates of prehospital seizure control (100% vs 78%), need for need for emergent intubation (0% vs 33%), and need for hospital admission (40% vs 89%) were all substantially less in the intranasal midazolam group compared with the rectal diazepam group. All these authors conclude that transmucosal midazolam is more convenient, easier to use, just as safe, and is more socially acceptable than rectal diazepam. Furthermore, when given via the intranasal route, midazolam is more effective than rectal diazepam.

The above evidence clearly suggests that intranasal midazolam is superior to rectal midazolam for seizure therapy in children. However, IV benzodiazepines are first-line therapy in most hospitals—how does intranasal midazolam compare to IV benzodiazepines? Two randomized controlled trials comparing intranasal midazolam to IV diazepam answer this question [22] and [23]. Lahat et al [22] compared intranasal midazolam to IV diazepam in children seizing 10 minutes or longer. Patients were randomized to receive diazepam, 0.3mg/kg IV, or midazolam 0.2 mg/kg intranasally. Nasal midazolam stopped 23 (88%) of 26, whereas 24 (92%) of 26 were controlled with IV diazepam (P = non significant). The mean time from patient arrival to seizure cessation was 6.1 minutes with midazolam and 8.0 minutes with diazepam. The authors conclude that intranasal midazolam was as safe and effective as IV diazepam, but the overall time to cessation of seizures after arrival at the hospital was faster with intranasal midazolam because of the time required to establish an IV line in the diazepam group. A similar study was conducted by Mahmoudian and Zadeh [23]. These authors compared the efficacy of intranasal midazolam (0.2 mg/kg) to IV diazepam (0.2 mg/kg) in 70 patients (ages 2 to 15 years) presenting to the emergency department with seizure activity. Both methods were equally effective, and no adverse effects occurred in either group. These authors conclude that nasal midazolam should be used not only in medical centers but also in general practitioners' offices as well as at home by families of seizure-prone children after appropriate instruction.

Perhaps the greatest benefit of intranasal midazolam will be for the treatment of seizures in the prehospital, home or extended care setting. Wilson et al [17] sent intranasal midazolam home with families of children suffering epilepsy and found that 33 (83%) of 40 who used it found it effective and 83% (20/24) preferred using transmucosal midazolam to rectal diazepam. Harbord et al [18] reported experience using intranasal midazolam for home treatment of 54 seizures in 22 children. These authors found it to be 89% effective, with no evidence of respiratory compromise. Ninety percent of families found no difficulty with nasal medication administration. Of the 15 parents with previous rectal diazepam experience, 13 thought intranasal delivery was easier and 14 preferred it to the rectal route. Jeannet et al [25] used intranasal midazolam both on the medical wards and as home therapy. Their experience with 26 children suffering 125 seizures note a 98% effectiveness in less than 10 minutes, with no serious adverse effects. When compared with rectal diazepam, they report that the intranasal route was both easier to use and that postictal recovery was faster. Scheepers et al [16] report their experience with intranasal medication delivery in an extended care facility caring for adolescents and adults with severe epileptic disorders. Of 84 uses, they found this route to be effective in 79 (94%). In the 5 instances when it was not effective, 3 of the 5 doses were delivered intraorally rather than intranasally.

All these reports confirm that intranasal midazolam is safe and effective for treating seizures in the hospital, prehospital, and outpatient settings. Compared with the current “standard” of rectal diazepam, intranasal midazolam is preferred because of its superior efficacy, ease of use, reduced postictal period, and more dignified route of administration. These findings all suggest that intranasal midazolam should replace rectal diazepam as the preferred method for treating prolonged seizures in patients without IV access in place.

In conclusion, intranasal midazolam offers a simple, safe, and effective way to treat prolonged seizures. This therapy is proven to effectively terminate and control most acute seizures. It is as effective as IV diazepam and more effective than rectal diazepam. Parents, caregivers, paramedics, nurses, and physicians can easily learn intranasal midazolam delivery. It is as safe as traditional rectal and IV delivery methods, and it is more dignified than rectal diazepam. Emergency physicians who manage epileptic children should consider intranasal midazolam as viable method to control breakthrough seizures at home, in the prehospital setting, and in the emergency department.

References

[1] M.V. Johnston, Seizures in childhood. In: R.E. Behrman, Editor, Nelson textbook of pediatrics, W.B. Saunders, Philadelphia (2004), pp. 1994–2009.

[2] D.H. Lowenstein, Status epilepticus: an overview of the clinical problem, Epilepsia 40 (1999) (Suppl 1), pp. S3–S8. Abstract-EMBASE | Abstract-Elsevier BIOBASE

[3] B.K. Alldredge, A.M. Gelb and S.M. Isaacs et al., A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med 345 (2001), pp. 631–637. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef

[4] S. Bassins, T.L. Smith and T.P. Bleck, Clinical review: status epilepticus, Crit Care 6 (2002), pp. 137–142.

[5] R.J. DeLorenzo, W.A. Hauser and A.R. Towne et al., A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia, Neurology 46 (1996), pp. 1029–1035. Abstract-EMBASE | Abstract-MEDLINE

[6] D.L. Gilbert, P.S. Gartside and T.A. Glauser, Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis, J Child Neurol 14 (1999), pp. 602–609. Abstract-EMBASE | Abstract-MEDLINE

[7] T. Pang and L.J. Hirsch, Treatment of convulsive and nonconvulsive status epilepticus, Curr Treatm Opt Neurol 7 (2005), pp. 247–259. Abstract-EMBASE

[8] I. Magnussen, H.R. Oxlund, K.E. Alsbirk and E. Arnold, Absorption of diazepam in man following rectal and parenteral administration, Acta Pharmacol Toxicol (Copenh) 45 (1979), pp. 87–90. Abstract-EMBASE | Abstract-MEDLINE

[9] O.R. Hung, J.B. Dyck, J. Varvel, S.L. Shafer and D.R. Stanski, Comparative absorption kinetics of intramuscular midazolam and diazepam, Can J Anaesth 43 (1996), pp. 450–455. Abstract-EMBASE | Abstract-MEDLINE

[10] J.Y. Yager and S.S. Seshia, Sublingual lorazepam in childhood serial seizures, Am J Dis Child 142 (1988), pp. 931–932. Abstract-MEDLINE | Abstract-EMBASE

[11] D.P. Wermeling, J.L. Miller, S.M. Archer, J.M. Manaligod and A.C. Rudy, Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration, J Clin Pharmacol 41 (2001), pp. 1225–1231. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef

[12] S. Dhillon, J. Oxley and A. Richens, Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients, Br J Clin Pharmacol 13 (1982), pp. 427–432. Abstract-EMBASE | Abstract-MEDLINE

[13] P.D. Knoester, D.M. Jonker and R.T. Van Der Hoeven et al., Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers, Br J Clin Pharmacol 53 (2002), pp. 501–507. Abstract-Elsevier BIOBASE | Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef

[14] C. Remy, N. Jourdil, D. Villemain, P. Favel and P. Genton, Intrarectal diazepam in epileptic adults, Epilepsia 33 (1992), pp. 353–358. Abstract-MEDLINE | Abstract-EMBASE | Full Text via CrossRef

[15] T. Fisgin, Y. Gurer and T. Tezic et al., Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol 17 (2002), pp. 123–126.

[16] M. Scheepers, B. Scheepers, M. Clarke, S. Comish and M. Ibitoye, Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy?, Seizure 9 (2000), pp. 417–422. Abstract | Abstract + References | PDF (939 K)

[17] M.T. Wilson, S. Macleod and M.E. O'Regan, Nasal/buccal midazolam use in the community, Arch Dis Child 89 (2004), pp. 50–51. Abstract-MEDLINE | Full Text via CrossRef

[18] M.G. Harbord, N.E. Kyrkou, M.R. Kyrkou, D. Kay and K.P. Coulthard, Use of intranasal midazolam to treat acute seizures in paediatric community settings, J Paediatr Child Health 40 (2004), pp. 556–558. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef

[19] J.M. Malinovsky, C. Lejus and F. Servin et al., Plasma concentrations of midazolam after i.v., nasal or rectal administration in children, Br J Anaesth 70 (1993), pp. 617–620. Abstract-EMBASE | Abstract-MEDLINE

[20] T. Fisgin, Y. Gurer and N. Senbil et al., Nasal midazolam effects on childhood acute seizures, J Child Neurol 15 (2000), pp. 833–835.

[21] N.O. Kutlu, C. Yakinci, M. Dogrul and Y. Durmaz, Intranasal midazolam for prolonged convulsive seizures, Brain Dev 22 (2000), pp. 359–361. SummaryPlus | Full Text + Links | PDF (68 K)

[22] E. Lahat, M. Goldman, J. Barr, T. Bistritzer and M. Berkovitch, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ 321 (2000), pp. 83–86. Abstract-EMBASE | Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Full Text via CrossRef

[23] T. Mahmoudian and M.M. Zadeh, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav 5 (2004), pp. 253–255. SummaryPlus | Full Text + Links | PDF (98 K)

[24] M. Holsti, B.L. Sill, S.D. Firth, S.M. Joyce, F. Filloux and R.A. Furnival, Prehospital intranasal versed for pediatric seizures American Academy of Pediatrics National Meeting, San Francisco (2004) [Abstract presentation].

[25] P.Y. Jeannet, E. Roulet, M. Maeder-Ingvar, M. Gehri, A. Jutzi and T. Deonna, Home and hospital treatment of acute seizures in children with nasal midazolam, Eur J Paediatr Neurol 3 (1999), pp. 73–77. Abstract | PDF (430 K)

[26] T.H. Stanley, Anesthesia for the 21st century, BUMC Proceedings 13 (2000), pp. 7–10. Abstract-MEDLINE

[27] Y.W. Chien, K.S.E. Su and S.F. Chang, Chapter 1: anatomy and physiology of the nose. Nasal systemic drug delivery, Dekker, New York (1989), pp. 1–26.

[28] R.J. Henry, N. Ruano, D. Casto and R.H. Wolf, A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration, Pediatr Dent 20 (1998), pp. 321–326. Abstract-MEDLINE

[29] O. Dale, R. Hjortkjaer and E.D. Kharasch, Nasal administration of opioids for pain management in adults, Acta Anaesthesiol Scand 46 (2002), pp. 759–770. Abstract-EMBASE | Abstract-MEDLINE | Full Text via CrossRef

[30] N. Mygind and S. Vesterhauge, Aerosol distribution in the nose, Rhinology 16 (1978), pp. 79–88. Abstract-MEDLINE | Abstract-EMBASE

[31] P.R. Camfield, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, J Pediatr 135 (1999), pp. 398–399. Abstract-MEDLINE

[32] R.C. Scott, F.M. Besag and B.G. Neville, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet 353 (1999), pp. 623–626. SummaryPlus | Full Text + Links | PDF (101 K)

Ace844 · July 22, 2006

( Annals of Emergency Medicine

Volume 48 @ Issue 1 , July 2006, Pages 98-100 doi:10.1016/j.annemergmed.2006.03.003

Evidence-based emergency medicine/systematic review abstract

What Is the Preferred First-Line Therapy for Status Epilepticus?

Eddy S. Lang MDCM, CCFP(EM), CSPQa, EBEM Commentator Contact and James E. Andruchow MScb, EBEM Commentator Contact

aEmergency Department, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada

bDepartments of Medicine and Dentistry, McGill University, Montreal, Quebec, Canada.

Available online 27 April 2006.)

[Ann Emerg Med. 2006;58:98-100.]

Systematic review source

This is a systematic review abstract, a regular feature of the Annals’ Evidence-Based Emergency Medicine (EBEM) series. Each features an abstract of a systematic review from the Cochrane Database of Systematic Reviews and a commentary by an emergency physician knowledgeable in the subject area.

The source for this systematic review abstract is: Prasad K, Al-Roomi K, Krishnan PR, et al. Anticonvulsant therapy for status epilepticus. The Cochrane Database of Sytematic Reviews 2006, Issue 1. Art No.: CD 003723. DOI: 10.1002/14651858. CD003723.

The Annals’ EBEM editors assisted in the preparation of the abstract of this Cochrane systematic review, as well as selection of the Evidence-Based Medicine Teaching Points.

Objective

The objective of this systematic review was to compare selected anticonvulsant therapies against each other or placebo for treatment of status epilepticus in terms of effectiveness and safety. Furthermore, the review attempted to identify reasons for disagreements in the literature about optimal anticonvulsant therapy, and to highlight areas for further research.

Data sources

The authors searched for randomized controlled trials from several electronic databases, including the Cochrane Epilepsy Group Specialized Register (July 2005), Cochrane Central Database of Controlled Trials (CENTRAL) (Issue 2, 2005), MEDLINE (1966 to August 2004), and EMBASE (1966 to January 2003).

Study selection

Studies were selected if they were randomized controlled trials using random or quasirandom treatment allocation and included patients with several stages of status epilepticus: premonitory (period during which seizures became increasingly frequent or severe but did not meet the definition of status epilepticus), early (the first 30 minutes of seizure activity), established (either more than 30 minutes of continuous seizure activity or 2 or more seizures without recovery of full consciousness between the seizures), or refractory (seizure activity uncontrolled for 1 to 2 hours despite first-line treatment). Selected studies compared anticonvulsant drugs against placebo or another anticonvulsant and examined the outcome of “treatment failure,” defined primarily as the noncessation of seizure activity.

Data extraction and analysis

Two reviewers independently selected published trials for inclusion and methodologic quality; disagreements were adjudicated by a third reviewer. Data on the number of participants with a given outcome in each treatment arm were independently extracted and verified by 2 reviewers. The authors initially proposed to study risk of treatment failure as the primary outcome and to conduct separate analyses for each of several stages of status epilepticus, including premonitory, early, established, and refractory status epilepticus; however, this was not possible owing to limitations of the data, and these groups were combined for analysis. Heterogeneity among trials was examined with the χ2 test, and where no heterogeneity was evident, trials were combined using a fixed-effects model to provide a summary estimate of effect.

Main results

Eleven studies with analyzable data containing 2,017 participants were included in the review. Five of the 11 trials studied patients with premonitory status, 1 each with established and refractory status, 2 with mixed status, and 2 with the stage poorly defined. Seven of these studies included only adult patients, 4 only children. Fourteen different therapeutic comparisons were made in these trials, but only 3 of these were replicated in multiple studies to permit meta-analysis.

All comparisons of the intravenously administered benzodiazepines diazepam and lorazepam against placebo significantly favored the intervention arms. The comparisons of lorazepam intravenously versus phenytoin intravenously, lorazepam intravenously versus diazepam intravenously, and an examination of diazepam intrarectal gel efficacy are of particular interest and will be presented in detail.

Lorazepam intravenously was superior to phenytoin intravenously in a single study with 198 participants, with lower risk for noncessation of seizures (relative risk [RR] 0.62; 95% confidence interval [CI] 0.45 to 0.86). According to 3 trials with 289 participants, lorazepam intravenously was more effective than diazepam intravenously for decreasing the risk of noncessation of seizures (RR 0.64; 95% CI 0.45 to 0.90) and continuation of status epilepticus requiring a different drug or general anesthesia (RR 0.63; 95% CI 0.45 to 0.88); however, lorazepam did not significantly reduce the requirement for ventilatory support (RR 0.73; 95% CI 0.36 to 1.49) or the number of adverse effects (risk difference [RD] −0.03; 95% CI −0.10 to 0.03). Furthermore, there was no statistically significant difference in deaths between the groups according to data available from 2 of the studies with 203 patients (RD 0.02; 95% CI −0.04 to 0.08). Diazepam intrarectal gel was superior to placebo gel according to 2 studies with a total of 165 participants, demonstrating lower risk for noncessation of seizures (RR 0.43; 95% CI 0.30 to 0.62).

Conclusions

The authors conclude that lorazepam is superior to either diazepam or phenytoin for cessation of seizures, and compared to diazepam carries a lower risk of continuation of status epilepticus requiring the use of a different drug or general anesthesia. Lorazepam and diazepam are both better than placebo for the same outcomes, and diazepam intrarectal gel is useful in premonitory status.

Cochrane Systematic Review Author Contact

Kameshwar Prasad, DM, MSc

Neurosciences Center

All India Institute of Medical Sciences

New Delhi, India

E-mail drkameshwarprasad@yahoo.co.in

Commentary: Clinical implication

Status epilepticus is defined as a period of continuous motor seizure activity lasting 30 minutes or more or 2 or more consecutive seizures without a return to full consciousness between the seizures. Overall, seizure disorders are common in the emergency department (ED); however, status epilepticus is an infrequently encountered condition. Its importance lies in the fact that it is a dangerous disease, with high morbidity and mortality. First-line therapy for status epilepticus is usually a benzodiazepine, many of which are commonly available in EDs, including diazepam (Valium), lorazepam (Ativan), and midazolam (Versed). Benzodiazepine administration should be followed by phenytoin whose long-acting anticonvulsant properties prevent recurrence and thus play an integral role in the management of status epilepticus. Finally, in patients without a known seizure disorder, search for the causative insult (eg, bleeding, trauma, other medications, infections) is necessary.

Because of the rapidity with which severe injury or death can occur in status epilepticus, using optimal anticonvulsant therapy is essential to minimizing adverse outcomes such as cerebral injury, cardiac arrhythmias, aspiration, and rhabdomyolysis. Unfortunately, current emergency medicine textbooks and guidelines for treatment of status epilepticus either do not specify a preferred first-line agent 1 and 2 or present limited justification for their choice.3 This systematic review presents new evidence and highlights the need to update our resources with current evidence-based information.

This Cochrane review collected the best available evidence on the use of a variety of interventions for the treatment of status epilepticus. Overall, the review covers the topic broadly; however, it fails to identify sufficiently similar comparisons to draw useful conclusions to many questions. The meta-analysis evidence presented in this review suggests that lorazepam is more effective than diazepam for first-line treatment of status epilepticus, perhaps in part because of its more favorable pharmacokinetics, including a longer redistribution half-life than diazepam.4 The longer duration of clinical efficacy also facilitates the transition to antiepileptic medications such as phenytoin for long-term seizure control. Better control of status epilepticus results in not only improved patient outcomes but also considerable savings to the health care system, with less costly and invasive treatment requirements, such as airway control and general anesthesia. Given that lorazepam is only marginally more expensive than diazepam, lorazepam should be the preferred first-line agent for status epilepticus in the ED. Because diazepam intrarectal gel is also effective in controlling premonitory status epilepticus, with relative ease of use but high cost, it may be most useful in the out-of-hospital setting.

While the cessation of motor seizures is often used clinically to signify the termination of a status epilepticus episode, the absence of motor seizures does not preclude either nonconvulsive status epilepticus or subtle convulsive status epilepticus and concomitant ongoing cerebral injury. Thus, altered level of consciousness persisting after motor seizures have ceased should be treated with a high level of clinical suspicion in the ED and should be investigated further, ideally with emergency electroencephalogram.5

Take-home message

Lorazepam provides better control over status epilepticus than does either diazepam or phenytoin. Both intravenous lorazepam and diazepam are effective in controlling status epilepticus; diazepam intrarectal gel also can be used in premonitory status. Standardization of seizure terminology and clinical research protocols is necessary to facilitate more detailed analyses of the therapeutic options for status epilepticus.

EBEM Commentator Contact

Eddy S. Lang, MDCM, CCFP(EM) CSPQ

Emergency Department

SMBD Jewish General Hospital

Montreal, Quebec, Canada

E-mail eddylang@videotron.ca

EBEM teaching point

Broad versus narrow scope in systematic reviews. Systematic reviews may address questions that are either broad or narrow.6 Broad-based reviews might examine whether any of a variety of therapeutic options are useful in achieving a certain outcome, as was done in this review examining the efficacy of various anticonvulsants in control of status epilepticus. In contrast, reviews with a narrow scope address a specific question, often directly examining the effect of a particular therapy on a well-defined outcome. Both approaches have advantages and disadvantages; whereas broad questions tend to be more easily generalizable to multiple settings and populations, they often prove more time consuming and expensive to answer. Furthermore, results may be difficult to synthesize and interpret, and validity may be compromised, particularly when the results of large numbers of heterogeneous studies are combined. Narrow questions may provide better-defined answers but tend not to be as generalizable. The choice of whether to use a narrow or broad-based approach in a systematic review should depend on the nature and complexity of the problem being addressed, the available evidence to synthesize, and the availability of resources to address it.

References

1 In: J.A. Marx, R.S. Hockberger and R.M. Walls, Editors, Rosen’s Emergency Medicine Concepts and Clinical Practice (6th ed.), Mosby, St. Louis, MO (2005).

2 Working Group on Status Epilepticus, Treatment of convulsive status epilepticus recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus, JAMA 270 (1993), pp. 854–959.

3 In: J.E. Tintinalli, G.D. Kelen and J.S. Stapczynski, Editors, Emergency Medicine A Comprehensive Study Guide (6th ed.), McGraw-Hill, Medical Division, New York, NY (2004).

4 D.M. Treiman, Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus, Epilepsia 30 (1989), pp. S4–S10. Abstract-EMBASE

5 American College of Emergency Physicians Clinical Policies Committee and Clinical Policies Subcommittee on Seizures, Clinical policy critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures, Ann Emerg Med 43 (2004), pp. 605–625.

6 Higgins JPT, Green S, eds. Formulating the problem. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005], section 4. Available at: http://www.cochrane.org/resources/handbook/book.htm. Accessed May 31, 2005

Ace844 · July 22, 2006

(Journal of Emergency Medicine

Volume 31 @ Issue 2 , August 2006, Pages 157-163

doi:10.1016/j.jemermed.2005.09.012

Clinical communication

Alcohol-related seizures

Niels K. Rathlev MD⁎, , Andrew S. Ulrich MD⁎, Norman Delanty FRCPI† and Gail D’Onofrio MD, MS‡

†Department of Neurology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland

‡Section of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut

⁎Department of Emergency Medicine, Boston Medical Center and Boston, University School of Medicine, Boston, Massachusetts

Received 17 April 2004; revised 29 April 2005; accepted 8 September 2005. Available online 20 July 2006)

Abstract

Alcohol-related seizures are defined as adult-onset seizures that occur in the setting of chronic alcohol dependence. Alcohol withdrawal is the cause of seizures in a subgroup of these patients; however, concurrent risk factors including pre-existing epilepsy, structural brain lesions, and the use of illicit drugs contribute to the development of seizures in many patients. New onset or a new pattern of alcohol-related seizures, e.g., focal seizures or status epilepticus, should prompt a thorough diagnostic evaluation. This is not indicated if patients have previously completed a comprehensive evaluation and the pattern of current seizures is consistent with past events. Treatment is initially directed at aggressively terminating current seizure activity. This should be followed by prevention of recurrent alcohol-related seizures and progression to status epilepticus during the ensuing 6-h high-risk period. Our purpose is to present recommendations for the diagnostic evaluation, treatment and disposition of these patients based on the current literature.

Introduction

Alcohol-related seizures represent a diverse spectrum of disease that presents in adults with chronic alcohol dependence. In more than 50% of cases they occur as a result of concurrent risk factors such as pre-existing epilepsy, structural brain lesions related to stroke or trauma, and the use of illicit drugs. Alcohol withdrawal seizures are caused by sudden abstinence and should be considered a diagnosis of exclusion once other risk factors have been considered and ruled out. The development of alcohol-related seizures is a major predictor of adverse health outcomes as the mortality rate of these patients is approximately fourfold that of the population at large. This is primarily due to complications of chronic alcoholism and delirium tremens rather than a direct result of seizures or status epilepticus (1). Based on the current literature, we present recommendations for the diagnostic evaluation, treatment and disposition of patients with alcohol-related seizures that present to the Emergency Department (ED).

Clinical features

Alcohol-related seizures are typically brief, generalized tonic-clonic seizures that occur 6 to 48 h after the last drink. Multiple seizures occur in approximately 60% of patients without treatment and the interval between the first and the last seizure is typically less than 6 h. Alcohol-related seizures frequently present in the absence of other signs of alcohol withdrawal and sympathomimetic stimulation such as tachycardia, fever and hypertension (2). They also occur in chronically alcohol-dependent patients with high blood alcohol concentrations that exceed the legal limit of intoxication. In some cases these levels would be highly intoxicating to non-dependent patients (3). This scenario is thought to be caused by a significant decline in the blood alcohol concentration from a customarily even higher level.

Status epilepticus is an uncommon presentation of alcohol-related seizures accounting for less than 4% of cases (4). Conversely, alcohol withdrawal is responsible for 11% to 20% of all cases of status epilepticus; fortunately, seizures related to alcohol are generally associated with a favorable prognosis compared with other causes of status epilepticus (5). Focal brain lesions such as traumatic brain injury, stroke and intracranial mass lesions frequently cause partial rather than generalized seizures. Partial seizures recently have been reported to account for up to 51% of seizures in alcohol-dependent patients. The presence of both status epilepticus and partial seizures should prompt a careful evaluation for structural brain lesions and epilepsy (1).

Diagnosis

Approximately one-third of patients who are hospitalized for acute seizures report a recent history of heavy alcohol use (6). In spite of this, alcohol dependence is underestimated as a cause of generalized tonic-clonic seizures in adults, even when patients are evaluated by experienced clinicians. Twenty percent of patients who initially present with seizures of “unknown” etiology are retrospectively reclassified and diagnosed with alcohol-related seizures after evaluation of future convulsive episodes (7). Therefore, all patients presenting with seizures should be screened using a structured questionnaire for alcohol dependence when possible. The CAGE questionnaire is valuable as a practical instrument for identifying alcohol dependence in the ED setting, however, the role of this questionnaire in specifically diagnosing alcohol-related seizures has not been studied (8 and 9).

Reliable serum markers for alcohol-related seizures have yet to be discovered. Significantly higher mean levels of plasma homocysteine and lower levels of folate have been found in alcohol-dependent patients who develop new-onset seizures compared with individuals without seizures (10). Larger and methodologically sound studies must confirm these results before plasma homocysteine and folate levels can be adopted as clinical predictors of seizures in alcohol dependent patients.

Risk factors

Alcohol withdrawal is an important risk factor in the genesis of alcohol-related seizures in a subgroup of patients, although its clinical relevance has been questioned by some investigators (11). Additional risk factors appear to lower the seizure threshold sufficiently to precipitate convulsive episodes in more than 50% of alcohol-dependent patients (12). Several authors have studied the prevalence of these risk factors that include: 1) idiopathic generalized epilepsy, 2) traumatic brain injury, stroke and intracranial mass lesions, 3) illicit drug use, and rarely, 4) alcohol-associated metabolic disorders (3, 12 and 13). The results of the most recent of these studies are listed in Table 1 (3).

Table 1.

Concurrent Risk Factors in 130 Patients with Alcohol-Related Seizures Etiology # Patients % of Total

Alcohol withdrawal 55 42%

Traumatic brain injury 36 28%

Intracranial hemorrhage or contusion, depressed skull fracture, penetrating brain injury, > 30 min of unconsciousness or amnesia

Idiopathic generalized epilepsy 22 17%

Cerebrovascular accident 8 6%

Non-traumatic intracranial lesions 5 4%

Tumors, infection, gliosis

Toxic/metabolic conditions 4 3%

Cocaine abuse 2

Hypoglycemia (< 60 mg %) 1

Hypocalcemia (< 6.0 mEq/L) 1

Alcohol Withdrawal

The diagnosis of alcohol withdrawal seizures is made only after exclusion of other potential risk factors. They are categorized as acute symptomatic or situation-related seizures and occur in individuals who do not have epilepsy. Clinical and experimental observations suggest that partial or complete abstinence in chronically alcohol-dependent patients is a major prerequisite for seizures caused by alcohol withdrawal. Rathlev et al. and Hillbom separately reported an increased seizure frequency on Sundays and Mondays, 33% and 49.6%, respectively, following restricted access to alcohol on weekends (3 and 13). In contrast, Ng and associates concluded that seizures are the result of a direct toxic effect of rising levels of alcohol rather than withdrawal. Their conclusion must be viewed with skepticism because 84% of new-onset seizures in their series occurred during the “conventionally defined” withdrawal period, which is 6 to 48 h after the last drink (11).

Idiopathic Generalized Epilepsy

Idiopathic generalized epilepsy occurs on a genetic basis in otherwise normal individuals. Estimates are that the prevalence of epilepsy among alcoholics is at least three times that of the general population (14). Conversely, studies have correlated alcohol dependence with poor seizure control in patients with epilepsy (15). Several mechanisms have been suggested to explain this correlation, including a “stimulant” effect of alcohol, a withdrawal phenomenon, and decreased absorption and enhanced metabolism of antiepileptic drugs through hepatic enzyme induction. Altered sleep patterns and non-compliance with anticonvulsants may also contribute to poor seizure control. The pattern of epileptiform activity on electroencephalography has not been observed to differ between alcohol-dependent patients and controls in patients with epilepsy.

Structural Central Nervous System Lesions

Traumatic brain injury is associated with an increased risk of post-traumatic seizures depending on the severity of injury. Annegers et al. found that brain contusion associated with subdural hematoma is the strongest risk factor for post-traumatic seizures followed by skull fracture, age ≥ 65 years, and finally, loss of consciousness or amnesia for more than 1 day (16). Chronically alcohol-dependent individuals have an increased incidence of head trauma and susceptibility to brain injury as a result of falls, motor vehicle-related accidents, and assault (17). The incidence of cortical brain contusions is increased more than sixfold in patients with alcohol dependence compared to individuals without this affliction (18).

Several studies indicate that alcohol-dependent patients are predisposed to cerebrovascular lesions such as intracerebral and subarachnoid hemorrhage due to coagulopathy. Moreover, heavy consumption of alcohol and binge drinking increase both systolic and diastolic blood pressure; the resulting hypertension and alcohol-induced vasospasm are significant contributors to lacunar stroke and cerebral hemorrhage (19, 20, 21 and 22). Atrial fibrillation related to withdrawal and alcohol-induced cardiomyopathy are also potent risk factors for thromboembolic stroke.

The incidence of structural brain abnormalities in alcohol-dependent individuals with seizures far exceeds the rate in non-drinkers with epilepsy (23). A forensic autopsy study with neuropathology examination found structural brain lesions in 13 of 19 (68%) alcohol-dependent patients with recurrent seizures (18). Lesions potentially responsible for seizures included old cortical contusions in 11 (58%) cases and old cerebral infarcts in 2 (10%). The results suggest that structural brain lesions are underrepresented as a cause of seizures in clinical series that have studied the etiology of alcohol-related seizures (3 and 13). These series have reported an incidence of 36% to 40% of structural brain abnormalities related to trauma, stroke and non-traumatic mass lesions.

Toxic-Metabolic Disorders

Several Emergency Medicine studies note that patients with alcohol-related seizures rarely present with severe toxic-metabolic abnormalities that trigger the presenting seizure. Hypoglycemia is the most frequently encountered metabolic cause of seizures in general, however, it is found in less than 1% of adults who present to the ED with alcohol-related seizures (24 and 25). Alcohol substantially depletes liver glycogen, and chronically alcohol-dependent patients typically maintain poor nutritional support. Hyperventilation frequently accompanies alcohol withdrawal and the resultant respiratory alkalosis may produce hyperexcitability of the central nervous system and reduce the seizure threshold. Decreasing levels of magnesium and calcium during withdrawal also have been implicated as possible precipitants of seizures, however, measurably low serum levels of these cations are rarely found in the clinical setting (24 and 25).

Illicit use of cocaine, heroin, phencyclidine or amphetamines is a potential cause of seizures (26 and 27). Intoxication with stimulant drugs has been documented as an increasingly frequent cause of seizures although still accounting for only 0.0025% of all seizure admissions (28). Another study described current cocaine use by 2 of 75 patients with concurrent risk factors other than alcohol withdrawal (3). Seizures also can be precipitated by withdrawal from a variety of drugs such as benzodiazepines, barbiturates and narcotics.

Evaluation

Laboratory Testing

Patients presenting with new-onset alcohol-related seizures or a new pattern such as partial seizures or status epilepticus should undergo a thorough evaluation for concurrent risk factors. Although the recommendation is not supported by prospective evidence, it is likely that unsuspected risk factors will be discovered in many patients. The most important laboratory test is a serum glucose level based on the presented evidence. Rapid assessment of serum glucose is indicated initially in all patients with an altered mental status who present after a new-onset or recurrent alcohol-related seizure. However, it is unlikely to be low in patients with a normal mental status after a seizure, in part, because of hyperadrenergic stimulation.

The results of blood, urine or saliva toxicology screens are important if illicit drug use or overdose is considered. Blood levels should be obtained if the patient is currently taking anti-epileptic drugs. There is no current evidence to support further laboratory testing in these patients, assuming that they do not present with additional acute medical problems and rapidly return to baseline mental status. Assuming that the pattern of the presenting seizures is consistent with past events, repetition of the recommended work-up is not required if patients have been previously diagnosed with alcohol-related seizures after a comprehensive evaluation.

Computed Tomography

Computed tomography (CT) scan of the brain should be performed on all alcohol-dependent patients with a new-onset or partial seizure, status epilepticus, a prolonged postictal state, or significant head trauma as previously described (16, 29 and 30). Fortunately, life-threatening structural lesions are very unlikely in the absence of these features.

The presence of focal deficits on physical examination is not sensitive for intracranial lesions in patients with alcohol-related seizures. Earnest et al. obtained CT scans in 259 patients with a first generalized alcohol-related seizure without evidence of traumatic brain injury or severe toxic-metabolic disorder (31). Sixteen patients (6.2%) had clinically significant intracranial lesions including chronic subdural hematoma (4), subdural hygroma (4), vascular malformation (2), neurocycsticercosis (2), cerebral aneurysm (1), possible tumor (1), skull fracture with subarachnoid hemorrhage (1), and cerebral infarct (1). Clinical management was altered as a result of the study in 10 (3.9%) cases. The history and physical examination did not correlate with CT scan findings. Feussner et al. evaluated the usefulness of CT scan in 151 patients with a history of alcohol-related seizures and found that 15% revealed focal structural lesions including 11 with old strokes, 7 with subdural hematomas, 2 with hygromas, and 2 with intracranial hemorrhages. Of the 6 patients who required operative intervention, only 5 demonstrated focal deficits on physical examination. Abnormal CT scans were found in 30% of patients with focal deficits compared to 6% of patients with a non-focal neurological examination (32).

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the brain is the imaging method of choice in the assessment of seizures, however, the value of this modality in patients with alcohol-related seizures has not been determined (33). It is preferable to computed tomography because of superior soft tissue contrast and multi-planar imaging capability leading to a greater sensitivity and accuracy in diagnosing small mass lesions such as tumors and cerebrovascular lesions (34). It appears reasonable to reserve MRI for patients with negative CT scan who may be at higher risk for structural abnormalities because of status epilepticus or partial seizures.

Electroencephalography

Electroencephalography (EEG) in waking and sleeping states is used to support the diagnosis and classification of epilepsy in patients in whom the clinical history indicates a significant probability of epileptic seizures. Indications for EEG in patients with suspected alcohol-related seizures have not been established to date. Current recommendations are similar to the indications for MRI, i.e., partial seizures or status epilepticus. The EEG examination ideally should be performed 48 h or more after the initial seizure. Obtaining an EEG immediately after a seizure may yield misleading results and the study is therefore rarely indicated in the Emergency Department (35). A routine EEG is most likely normal in patients with alcohol-related seizures without epilepsy, but may demonstrate mild non-specific slowing and attenuation of the background amplitude (36, 37 and 38).

Treatment

Alcohol typically accounts for 50% of the caloric intake of alcohol-dependent individuals and therefore displaces normal nutrients such as folate, thiamine and other vitamins. In order to prevent Wernicke-Korsakoff syndrome, thiamine should be administered intramuscularly, intravenously, or orally to all patients undergoing treatment for alcohol withdrawal. Although thiamine has no effect in preventing seizures or delirium tremens, Wernicke’s encephalopathy may present subtly and elude careful evaluation by clinicians (18 and 39). Folate and multivitamins also should be administered to patients because they should be assumed to be clinically malnourished.

Benzodiazepines

There is significant evidence to suggest that benzodiazepines are effective in preventing both initial and recurrent seizures in alcohol-dependent individuals (40). They offer excellent anti-convulsant activity with minimal respiratory and cardiac depression. They exhibit cross-tolerance with alcohol, act at the GABA receptor site in place of alcohol, and reduce the signs and symptoms of the alcohol withdrawal syndrome. Benzodiazepines should be given not only for the treatment of active convulsions, but also for short-term prophylaxis within the 6- to 12-h window in which patients are at high risk for recurrent alcohol-related seizures. This is particularly true for patients who are at high risk because of a prior history of epilepsy, alcohol-related seizures, or multiple previous detoxifications (41). High doses of benzodiazepines equivalent to 60 mg of diazepam—administered orally in divided doses—is associated with a lower rate of seizures in the ED compared with lower doses (42).

All benzodiazepines appear to be equally efficacious in reducing the signs and symptoms of withdrawal. However, longer-acting agents such as chlordiazepoxide and diazepam may be more effective than shorter-acting drugs in preventing seizures. Longer-acting agents can, however, pose a risk of increased sedation in the elderly and in patients with advanced liver disease. Oxazepam and lorazepam are preferable in these cases because they do not undergo hepatic oxidation and have fewer active metabolites (43 and 44). Marx and colleagues randomized 831 patients admitted to a detoxification unit from the ED (45). Patients receiving chlorazepate developed significantly fewer seizures (0.7%) than patients receiving phenytoin (3.0%) or placebo (6.2%) during a 96-h observation period.

Lorazepam appears to be an ideal agent for the treatment of patients with alcohol-related seizures and should be given within the 6- to 12-h period when recurrent seizures typically occur. It has minimal depressant effects on respirations and the circulation and has a shorter half-life than diazepam with no active metabolites. It controls seizures longer than diazepam (12 to 24 h vs. 15 to 30 min, respectively) due to favorable pharmacokinetics (5). Therapeutic central nervous system concentrations persist for a significantly longer period of time because lorazepam is less lipid-soluble than diazepam; it is therefore redistributed into fatty tissues at a slower rate. Lorazepam has the additional advantage that it can be administered intramuscularly with good effect if intravenous access is not available. A prospective, randomized, controlled trial by D’Onofrio demonstrated lorazepam to be an extremely effective agent for the prevention of recurrent seizures in patients who present following an initial alcohol-related seizure (25). Among patients receiving lorazepam, 3% had a second seizure during a 6-h observation period, compared with 24% in the placebo group (p < 0.0001). Lorazepam should therefore be administered routinely upon presentation to the ED, unless contraindicated because of heavy sedation due to intoxication, head injury etc.

Anti-epileptic Drugs

In limited series, anti-epileptic drugs appear to be effective in preventing primary alcohol withdrawal seizures but do not confer additional benefit when combined with longer-acting benzodiazepines such as chlordiazepoxide or diazepam (40). Large, prospective trials demonstrating the efficacy and safety of antiepileptic drugs in alcohol-dependent patients have not been performed. Anti-epileptic drugs have not been shown to be effective and safe in preventing recurrent alcohol withdrawal seizures. Alldredge et al. and Rathlev et al. independently demonstrated a lack of efficacy of phenytoin compared with placebo in these patients (24 and 46). A randomized, controlled study from Finland also failed to demonstrate effectiveness of carbamazepine and valproic acid in this setting (47). The efficacy of the newer generation anticonvulsant drugs, e.g., gabapentin, lamotrigine and topiramate, has not been studied in controlled trials although they appear to be safe in this setting (48).

Patients with chronic alcohol dependence and epilepsy are often non-compliant with their drug regimen and are therefore at increased risk for further seizures. Hillbom and Hjelm-Jager reported that the sudden withdrawal of phenytoin may actually increase the frequency of seizures (49). The risks and benefits of anticonvulsant therapy must therefore be carefully considered in chronically non-compliant patients. Prescribing expensive medications with questionable efficacy and possible risks for chronically non-compliant patients is not warranted. Conversely, patients with a known structural brain lesion or an electroencephalogram indicating an epileptogenic abnormality should be placed on long-term anti-convulsant therapy (50 and 51).

Disposition

Discharge to a detoxification center is dependent on recovery of patients to baseline mental status and their ability to safely ambulate (52). Most patients with alcohol-related seizures that have been treated with appropriate doses of lorazepam, and in whom concurrent risk factors have been ruled out by history, physical examination and diagnostic testing, can be safely discharged after a 3-h period of observation (25). Patients are unlikely to develop further seizures if recurrent events do not develop within a 3-h window after initial benzodiazepine administration.

The focus of patient management should be on promoting primary prevention by encouraging patients to seek help in a structured detoxification program. The patient should be referred to a detoxification unit, and receive treatment with longer acting benzodiazepines to prevent further sequelae of alcohol withdrawal including recurrent seizures. The occurrence of a new-onset seizure should be viewed as a major adverse consequence of alcohol dependence, and presents an opportunity for the physician to assess the patient’s readiness for change and to successfully link them to a treatment center (53, 54 and 55).

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47 M. Hillbom, R. Tokola and V. Kuusela et al., Prevention of alcohol withdrawal seizures with carbamazepine and valproic acid, Alcohol 6 (1989), pp. 223–226. Abstract

48 A. Rustembegovic, E. Sofic and G. Kroyer, A pilot study of topiramate in the treatment of tonic-clonic seizures of alcohol withdrawal syndromes, Med Arh 56 (2002), pp. 211–212. Abstract-MEDLINE

49 Hillbom M, Hjelm-Jager M. Should alcohol withdrawal seizures be treated with antiepileptic drugs? Acta Neurol Scand 1984;15:69:39–42.

50 N.R. Temkin, S.S. Dikmen, A.J. Wilensky, J. Keihm, S. Chabal and H.R. Winn, A randomized double-blind study of phenytoin for the prevention of post-traumatic seizures, N Engl J Med 323 (1990), pp. 497–502. Abstract-MEDLINE | Abstract-EMBASE

51 W.A. Hauser, M. Ramirez-Lassepas and R. Rosenstein, Risk for seizures and epilepsy following cerebrovascular insults (abstract), Epilepsia 25 (1984), p. 666.

52 ACEP Clinical Policies Committee; Clinical Policies Subcommittee on Seizures, Clinical policy critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures, Ann Emerg Med 43 (2004), pp. 605–625.

53 E. Bernstein, J. Bernstein and S. Levenson, Project ASSERT an ED-based intervention to increase access to primary care, preventive services and the substance abuse treatment system, Ann Emerg Med 30 (1997), pp. 181–189. SummaryPlus | Full Text + Links | PDF (817 K)

54 G. D’Onofrio, E. Bernstein and S. Rollnick, Motivating patients for change a brief strategy for negotiation. In: E. Bernstein and J. Bernstein, Editors, Emergency medicine and the health of the public, Jones and Bartlett, Boston, MA (1996), pp. 51–62.

55 G. D’Onofrio, E. Bernstein and J. Bernstein et al., Patients with alcohol problems in the ED, Part 2 intervention and referral, Acad Emerg Med 5 (1998), pp. 1210–1217.

Clinical Communications (Adults) is coordinated by Ron Walls, MD, of Brigham and Women’s Hospital and Harvard University Medical School, Boston, Massachusetts.

Reprint Address: Niels K. Rathlev, MD, Department of Emergency Medicine, Boston Medical Center, One Boston Medical Center Place, Boston, MA 02118

Ace844 · July 24, 2006

Evaluation of the first seizure in adults

INTRODUCTION — A seizure is a sudden change in behavior that is the consequence of brain dysfunction.

Epileptic seizures result from electrical hypersynchronization of neuronal networks in the cerebral cortex. Epilepsy is characterized by recurrent epileptic seizures due to a genetically determined or acquired brain disorder [1]. Approximately 0.5 to 1 percent of the population has epilepsy.

Nonepileptic seizures (NES), are sudden changes in behavior that resemble epileptic seizures but are not associated with the typical neurophysiological changes that characterize epileptic seizures [2-4].

NES are subdivided into two major types: physiological and psychogenic. Physiological NES are caused by a sudden alteration of neuronal function due to metabolic derangement or hypoxemia. Causes of physiological NES include cardiac arrhythmias, syncope, and severe hypoglycemia. Psychogenic NES are thought to result from stressful psychological conflicts or major emotional trauma and are more challenging to recognize and diagnose than physiological NES, but rarely occur de novo in patients without a significant psychiatric history.

The pharmacological treatment of epileptic seizures is directed at restoring neuronal function to normal, while the treatment of NES is specific to the disorder that triggered the seizure. Thus, the primary goal in evaluating a patient's first seizure is to resolve whether the seizure resulted from a treatable systemic process or intrinsic dysfunction of the central nervous system and, if the latter, the nature of the underlying brain pathology. This evaluation will determine the likelihood that a patient will have additional seizures and assist in the decision whether to begin anticonvulsant therapy [5,6].

The differential diagnosis and clinical features of seizures and the diagnostic evaluation of the first seizure in adults are reviewed here. While convulsive and nonconvulsive status epilepticus may be the initial presentation of epilepsy, they are not specifically discussed because clinical recognition is straightforward [7]. (See "Status epilepticus in adults"). The treatment of chronic epilepsy is reviewed separately. (See "Overview of the management of epilepsy in adults").

ETIOLOGY

Epileptic seizures — Less than one-half of epilepsy cases have an identifiable cause. It is presumed that epilepsy in most, if not all, of these other patients is genetically determined. In the remainder of patients in whom an etiology can be determined, the causes of epileptic seizures include congenital brain malformations, inborn errors of metabolism, high fevers, head trauma, brain tumors, stroke, intracranial infection, cerebral degeneration, withdrawal states, and iatrogenic drug reactions [8]. (See "Post-traumatic seizures and epilepsy"). In the elderly, vascular, degenerative, and neoplastic etiologies are more common than in younger adults and children [9]. A higher proportion of epilepsy in children is due to congenital brain malformations than in other age groups. (See "Epilepsy syndromes in children").

These general principles were illustrated in a population-based cohort study of 1195 patients with newly diagnosed or suspected epileptic seizures, 564 of whom had definite epileptic seizures [10]. The proportions of males and females were similar, 25 percent were under the age of 15, and 24 percent were 60 years or older. The majority (62 percent) of epileptic seizures were idiopathic. In the remainder, the cause was vascular disease in 15 percent and tumor in 6 percent. The proportion with an identifiable cause was much higher in older patients; 49 percent were due to vascular disease and 11 percent to tumor.

Onset of seizures in late life may be a risk factor for stroke, possibly because covert cerebrovascular disease can often be the mechanism of new onset epilepsy in older patients. This point is illustrated by a study of 4,709 people with idiopathic epilepsy beginning at or after the age of 60 years, but no history of stroke [11]. Subjects were matched to the same number of controls with no history of epilepsy or stroke. In longitudinal follow-up, the epilepsy group had a significantly higher risk of stroke at any time point compared with controls (hazard ratio 2.9, 95% CI 2.45-3.41). This finding suggests that new onset of seizures in older patients should prompt evaluation and treatment for stroke risk factors.

Head injury accounts for a relatively small proportion of epilepsy overall. The risk to an individual who suffers head trauma varies widely from minimal risk in people who have a concussive head injury in which the loss of consciousness or amnesia is less than 30 minutes, to at least a 12-fold increased risk over 10 years in people who suffer trauma-induced prolonged amnesia, subdural hematoma, or brain contusion [12]. Antiepileptic drugs prevent seizures in the first week after head injury, but do not prevent the development of epilepsy [13]. (See "Post-traumatic seizures and epilepsy").

Physiological nonepileptic seizures — A number of medical disorders are known to cause physiological NES (show table 1).

Hyperthyroidism can cause seizures and can exacerbate seizures in patients with epilepsy.

Hypoglycemic seizures are most common in diabetic patients who take excessive amounts of insulin or oral hypoglycemics; islet cell tumors are much less common, but seizures may be the initial presentation. Prodromal symptoms of hypoglycemic seizures include diaphoresis, tachycardia, anxiety, and confusion.

Nonketotic hyperglycemia most commonly occurs in elderly diabetics and can cause focal motor seizures.

Precipitous falls in serum sodium concentrations can trigger generalized tonic-clonic seizures (see "Generalized seizures" below), usually in association with a prodrome of confusion and depressed level of consciousness. These convulsions are associated with a high risk of mortality and must be treated urgently. (See "Manifestations of hyponatremia and hypernatremia").

Hypocalcemia is a rare cause of seizures and most often occurs in neonates. In adults, hypocalcemia may occur after thyroid or parathyroid surgery or in association with renal failure, hypoparathyroidism, or pancreatitis. Typical prodromic symptoms and signs are mental status changes and tetany. Magnesium levels below 0.8 mEq/L may result in irritability, agitation, confusion, myoclonus, tetany, and convulsions, and may be accompanied by hypocalcemia. (See "Clinical manifestations of hypocalcemia").

Renal failure and uremia are often associated with seizures, particularly myoclonic seizures (see "Generalized seizures" below). Generalized tonic-clonic seizures occur in approximately 10 percent of patients with chronic renal failure, usually late in the course. Seizures may also occur in patients undergoing dialysis as part of the dialysis disequilibrium syndrome; associated symptoms are headache, nausea, muscle cramps, irritability, confusion, and depressed level of consciousness. (See "Seizures in patients undergoing hemodialysis").

Disorders of porphyrin metabolism may cause seizures. Acute intermittent porphyria (AIP) is due to a partial deficiency of porphobilinogen deaminase, which results in excess delta-aminolevulinic acid and porphobilinogen in the urine. Seizures occur in approximately 15 percent of AIP attacks and are usually generalized tonic-clonic seizures, although partial seizures may occur (see "Auras (simple partial seizures)" below and see "Complex partial seizures" below). Other symptoms of AIP include abdominal pain and behavioral changes. (See "Acute intermittent porphyria").

Cerebral anoxia as a complication of cardiac or respiratory arrest, carbon monoxide poisoning, drowning, or anesthetic complication can cause myoclonic and generalized tonic-clonic seizures. Cerebral anoxia due to syncope can result in very brief tonic and/or clonic movements without a prolonged postictal state, which is why syncope frequently results in an evaluation for seizures. (See "Evaluation of the patient with syncope", section on Distinction of syncope from seizures).

DIFFERENTIAL DIAGNOSIS — Several conditions must be differentiated from epileptic seizures.

REM behavior disorder — REM behavior disorder is a parasomnia that consists of sudden arousals from REM sleep immediately followed by complicated, often aggressive, behaviors for which the patient is amnestic. Diagnosis is clarified by overnight sleep testing (polysomnography). (See "Classification of sleep disorders", section on Parasomnias.)

Transient ischemic attack — Transient ischemic attacks (TIAs) may last seconds to minutes. They are generally characterized by "negative" symptoms and signs (such as weakness or visual loss) rather than the "positive" symptoms and signs (eg, jerking movements, stiffening, or visual illusions or hallucinations) that generally accompany seizures. Nevertheless, the postictal state may include lateralizing "negative" symptoms such as weakness; thus, a careful history of possible symptoms that preceded the "negative" symptoms is critical. (See "Differential diagnosis of brain ischemia").

Transient global amnesia — Transient global amnesia (TGA) is a syndrome characterized by the acute onset of severe anterograde amnesia accompanied by retrograde amnesia, without other cognitive or focal neurologic impairment. The amnesia resolves within 24 hours. Most patients are middle aged or older adults. Episodes are usually not recurrent, but some patients have infrequent attacks that recur over several years.

The etiology of TGA is uncertain [14]. Most TGA episodes are probably related to vasoconstriction or migraine, but some may be caused by transient ischemia or complex partial seizures. TGA can be associated with small focal abnormalities on diffusion-weighted MRI [15-19], but the significance of these remains unclear.

Migraine — Migraine auras such as visual illusions and basilar migraine symptoms, including altered consciousness, can mimic complex partial seizures. Furthermore, the headache that follows complex partial and generalized tonic-clonic seizures is migrainous in quality and duration. (See "Complex partial seizures" below and see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults").

CLINICAL FEATURES — The diagnostic evaluation of a first seizure begins with the history. An accurate description of the seizure may be difficult to obtain from the patient and witnesses; it is usually necessary to ask pointed questions about the circumstances leading up to the seizure, the ictal behaviors, and the postictal state. It is also worthwhile to inquire specifically whether the patient has had prior seizures, including febrile seizures in infancy, or other episodes that were not evaluated by a physician or that were labeled as something other than seizures.

Seizure precipitants or triggers — A key element in the history is whether a particular environmental or physiological precipitant or trigger immediately preceded the seizure. Some patients with epilepsy tend to have seizures under particular conditions, and their first seizure may provide a clue to their so-called seizure trigger. Triggers include (but are not limited to) strong emotions, intense exercise, loud music, and flashing lights. (See "Photic induced seizures" below). These triggers are often experienced immediately before the seizure.

Other physiological conditions such as fever, the menstrual period, lack of sleep, and stress can also precipitate seizures, probably by lowering seizure threshold rather than directly causing a seizure. As a result, the temporal relationship to the presenting seizure is often less clear. Triggers may also precipitate physiological NES; a cough, for example, can bring on a syncopal seizure.

However, the majority of patients with epilepsy have no identifiable or consistent trigger to their seizures. In addition, triggers are the sole cause of epileptic seizures in only a very small percentage of patients.

Photic induced seizures — Photosensitivity has received considerable attention as a seizure trigger. The light stimulation may come from a natural or artificial source, in particular television shows and video games. The most famous incident occurred in relation to a Pokemon cartoon aired in 1997 in Japan in which 685 children (from an estimated 7 million viewers) sought medical attention for neurologic symptoms; most (about 80 percent) were felt to be seizures [20,21]. Three-fourths of the children had not experienced seizures previously.

A review of photic-induced seizures made the following epidemiologic observations [21]:

Children are more susceptible to photic-induced seizures and photoparoxysmal EEG changes than adults; and photosensitivity may decline in individuals with photic-induced seizures.

A tendency for photic-induced seizures may be inherited.

Photoconvulsive seizures are usually generalized, but they may be partial.

Individuals may be sensitive to certain light triggers but not others.

Women appear more susceptible, but males dominate in reports of video game-induced seizures, probably because they play them more.

The stimuli that are most likely to induce seizures appear to be identifiable. Guidelines for restricting use of specific signals on television broadcasts exist in Japan and Great Britain, and a working group has developed draft consensus guidelines in the United States [22].

Seizure symptoms and signs — The next step in the history is to identify the symptoms and signs (observed behaviors) that occurred throughout the seizure.

Auras (simple partial seizures) — The symptoms that a patient experiences at the beginning of the seizure are referred to as the warning or aura. Auras are seizures that affect enough of the brain to cause symptoms, but not enough to interfere with consciousness. In the seizure classification system established by the International League Against Epilepsy, auras are called simple partial seizures (show table 2); "simple" means that consciousness is not impaired and "partial" means that only part of the cortex is disrupted by the seizure [23].

The symptoms of simple partial seizures vary from one patient to another and depend entirely on where the seizure originates in the brain, that is, the part of the cortex that is disrupted at the onset of the seizure. A seizure that begins in the occipital cortex may result in flashing lights, while a seizure that affects the motor cortex will result in rhythmic jerking movements of the face, arm, or leg on the side of the body opposite to the involved cortex (Jacksonian seizure).

Auras that commonly occur in patients with epilepsy are shown in the table (show table 3). These symptoms can also be experienced under other circumstances, but do not typically precede physiological NES. Thus, the occurrence of an aura supports the diagnosis of an epileptic seizure.

When a patient's first seizure was not preceded by a simple partial seizure, it is more difficult to distinguish whether it was an epileptic seizure or a NES. Many epileptic patients do not have a warning when their seizures start. Instead, they abruptly lose consciousness, which they may describe as blacking out, when the part of the cortex that controls memory is disrupted by the seizure. However, this process is not specific for epileptic seizures and therefore does not allow differentiation from NES.

Complex partial seizures — The classification system for epileptic seizures includes several seizure types that are characterized by an abrupt loss of consciousness: complex partial seizures ("complex" means that consciousness and awareness of the surroundings are lost), absence seizures, and generalized tonic-clonic seizures (also known as convulsions; "tonic" refers to muscle stiffening and "clonic" refers to muscle jerking) (show table 2).

Complex partial seizures (previously called temporal lobe seizures or psychomotor seizures) are the most common type of seizure in epileptic adults. During the seizure patients appear to be awake but are not in contact with others in their environment and do not respond normally to instructions or questions. They often seem to stare into space and either remain motionless or engage in repetitive behaviors, called automatisms, such as facial grimacing, gesturing, chewing, lip smacking, snapping fingers, repeating words or phrases, walking, running, or undressing. Patients may become hostile or aggressive if physically restrained during complex partial seizures.

Complex partial seizures typically last less than three minutes and may be immediately preceded by a simple partial seizure. Afterward, the patient enters the postictal phase, often characterized by somnolence, confusion, and headache for up to several hours (show table 4). The patient has no memory of what took place during the seizure other than, perhaps, the aura.

The behaviors that typify complex partial seizures are not specific for epileptic seizures and may be observed in association with NES.

Generalized seizures — In contrast to partial seizures, generalized seizures originate virtually in all the regions of the cortex. Absence seizures and generalized tonic-clonic seizures are types of generalized seizures. Other subtypes of generalized seizures are clonic, myoclonic, tonic, and atonic seizures.

Absence seizures usually occur during childhood and typically last between 5 and 10 seconds. They frequently occur in clusters and may take place dozens or even hundreds of times a day. Absence seizures cause sudden staring with impaired consciousness. If an absence seizure lasts for 10 seconds or more, there may also be eye blinking and lip smacking. Absence seizures are discussed in greater detail separately. (See "Epilepsy syndromes in children", section on Absence seizures).

A generalized tonic-clonic seizure (also called grand mal seizure, major motor seizure, or convulsion) is the most dramatic type of seizure (show table 5). It begins with an abrupt loss of consciousness, often in association with a scream or shriek. All of the muscles of the arms and legs as well as the chest and back then become stiff. The patient may begin to appear cyanotic during this tonic phase. After approximately one minute, the muscles begin to jerk and twitch for an additional one to two minutes. During this clonic phase the tongue can be bitten, and frothy and bloody sputum may be seen coming out of the mouth. The postictal phase begins once the twitching movements end. The patient is initially in a deep sleep, breathing deeply, and then gradually wakes up, often complaining of a headache.

Clonic seizures cause rhythmical jerking muscle contractions that usually involve the arms, neck, and face.

Myoclonic seizures consist of sudden, brief muscle contractions that may occur singly or in clusters and that can affect any group of muscles, although typically the arms are affected. Consciousness is usually not impaired.

Tonic seizures cause sudden muscle stiffening, often associated with impaired consciousness and falling to the ground.

Atonic seizures (also known as drop seizures or drop attacks) produce the opposite effect of tonic seizures — a sudden loss of control of the muscles, particularly of the legs, that results in collapsing to the ground and possible injuries.

The behaviors that typify absence seizures and generalized tonic-clonic seizures are not specific for epileptic seizures and may be observed in association with NES.

Other aspects of the patient history

Medication history — There are a number of medications that have been associated with iatrogenic seizures [8,24]. Partial-onset seizures are less likely to be drug-induced than generalized tonic-clonic seizures.

Past medical history — There are a number of risk factors for epileptic seizures that should be addressed, including head injury, stroke, Alzheimer's disease, history of intracranial infection, and alcohol or drug abuse.

Family history — A positive family history of seizures is highly suggestive that the patient has epilepsy. In particular, absence seizures and myoclonic seizures may be inherited. Occasionally, a family member does not have seizures but has an abnormal electroencephalogram.

Physical and neurologic examination — The physical examination is generally unrevealing in patients with epileptic seizures, but is important when central nervous system infection or hemorrhage are diagnostic possibilities. The neurologic examination should evaluate for lateralizing abnormalities, such as weakness, hyperreflexia, or a positive Babinski sign, that may point to a contralateral structural brain lesion.

DIAGNOSTIC STUDIES

Laboratory screening — Laboratory evaluations that are appropriate for the evaluation of a first seizure include glucose, calcium, magnesium, hematology studies, renal function tests, and toxicology screens. Tests for porphyria may be considered under appropriate clinical circumstances. Some laboratory abnormalities such as metabolic acidosis and leukocytosis may occur as a result of the seizure; thus, abnormal test results detected immediately after the seizure has occurred should be repeated.

Prolactin — Serum prolactin assessment has limited utility as a diagnostic test for epileptic seizures [25]. The serum prolactin concentration may rise shortly after generalized tonic-clonic seizures and some partial seizures. Typically, a level is drawn 10 to 20 minutes after the event and compared with a baseline level drawn six hours later. Criteria for abnormality are not well established; many investigators use twice the baseline level.

A systematic review made the following conclusions regarding prolactin as a diagnostic test for epileptic seizures [26]:

Pooled sensitivity was higher for generalized tonic-clonic seizures than for partial complex seizures (60 versus 46 percent).

An elevated serum prolactin level can be useful in differentiating generalized tonic-clonic and partial complex seizures from psychogenic seizures in adults and older children. The positive predictive value is greater than 93 percent, if the pretest probability is 50 percent or higher.

Because of low sensitivity, a normal prolactin level is insufficient to exclude epileptic seizures or support a psychogenic diagnosis.

Some studies suggest that prolactin rises after syncope. Prolactin levels cannot be used to differentiate seizure from syncope.

Insufficient data preclude conclusions regarding the utility of prolactin levels after simple partial seizures, repetitive seizures, status epilepticus, and in neonates.

Lumbar puncture — A lumbar puncture is essential if the clinical presentation is suggestive of an acute infectious process that involves the central nervous system or the patient has a history of cancer that is known to metastasize to the meninges. In other circumstances the test is not likely to be helpful and may be misleading since a prolonged seizure itself can cause cerebrospinal fluid pleocytosis. Lumbar puncture should only be performed after a space occupying brain lesion has been excluded by appropriate neuroimaging studies.

Electroencephalography — The electroencephalogram (EEG) is an essential study in the diagnostic evaluation of epileptic seizures. If abnormal, the EEG may substantiate the diagnosis of epileptic seizures and indicate whether a patient may have generalized or partial seizures. Obtaining the EEG in the sleep-deprived state and using provocative measures during the test, such as hyperventilation and intermittent photic stimulation, increase the yield [27]. An abnormal EEG that confirms the clinical diagnosis of epilepsy substantially increases the likelihood that the patient will experience a second seizure over the next two years [28].

However, a normal EEG does not rule out epilepsy, and a positive EEG may be nonspecific. As an example, certain types of EEG abnormalities are seen in patients with migraine headaches or in association with medications.

Neuroimaging — A neuroimaging study should be done to exclude a structural brain abnormality if the patient's first seizure was clearly not a physiological NES. Brain magnetic resonance imaging (MRI) is preferred over computed tomography (CT) to identify specific lesions such as cortical dysplasias, infarcts, or tumors. Nevertheless, a brain CT scan is suitable to exclude a mass lesion, hemorrhage, or large stroke under emergency situations or if an MRI is unavailable or contraindicated (eg, in patients with pacemakers, non-compatible aneurysm clips, or severe claustrophobia).

The value of neuroimaging in the evaluation of adults with a first seizure was demonstrated in a retrospective review of 148 patients studied within 30 days of the seizure [29]. The cause of seizure was established in 71 patients (48 percent); a structural lesion was identified by CT in 55 (37 percent) and 16 (11 percent) had metabolic seizures. CT findings agreed with the results of neurologic examination in 82 percent of cases. However, structural lesions (including three tumors) were found by CT in 14 patients (15 percent) with nonfocal findings and in 12 (22 percent) patients with generalized EEG abnormalities.

In young to middle-aged adults, common MRI findings are mesial temporal sclerosis, sequelae of head injury, congenital anomalies, brain tumors, and vascular lesions. In the elderly, MRIs often reveal strokes, cerebral degeneration, or neoplasms. However, up to 50 percent of patients, regardless of age, have normal neuroimaging studies. The utility of brain MRI in children presenting with a seizure is discussed separately. (See "Clinical and laboratory diagnosis of seizures in infants and children", section on Neuroimaging).

WHEN TO START ANTIEPILEPTIC THERAPY — The decision to initiate therapy with antiepileptic drugs is often difficult. This topic is discussed separately. (See "Overview of the management of epilepsy in adults", section Antiepileptic drug therapy).

PSYCHOSOCIAL CONSIDERATIONS — Newly diagnosed patients with epilepsy may suffer a number of losses, including loss of independence, employment, insurance, ability to drive, and self-esteem. As the treatment plan is formulated, these psychosocial issues should be explored with patients so that appropriate referrals for additional help and counseling can be initiated.

Driving — States vary widely in driver licensing requirements for patients with epilepsy [30]. This topic is discussed in more detail elsewhere. (See "Driving restrictions for patients with seizures and epilepsy").

HOSPITALIZATION — Hospitalization may be required for patients who have a first seizure associated with a prolonged postictal state or incomplete recovery. Other indications for hospitalization include status epilepticus, the presence of a systemic illness that may require treatment, a history of head trauma, or questions regarding compliance.

REFERRAL — Many primary care physicians do not feel comfortable with the initial evaluation and management of patients with seizures and refer them to neurologists. All patients in whom the diagnosis is in question should be referred to a neurologist. Other indications for referral include focal findings on the neurologic examination or EEG, or a history suggestive of a focal seizure. Some experts believe that all patients with suspected seizures should be referred to a specialist [31].

CONCLUSIONS — The primary objectives of the medical evaluation of the first seizure are to establish whether it resulted from a correctable systemic process, and if not, whether the patient is at risk for developing further unprovoked seizures. A careful history, physical and neurologic examinations, and laboratory evaluation are usually helpful in achieving these objectives and determining the appropriate therapeutic approach. Referral to a specialist is indicated for most persons suspected of having a seizure, especially if focal features are present on examination or testing.

REFERENCES

1. Chang, BS, Lowenstein, DH. Epilepsy. N Engl J Med 2003; 349:1257.

2. Vossler, DG. Nonepileptic seizures of physiologic origin. J Epilepsy 1995; 8:1.

3. Alper, K, Devinsky, O, Perrine, K, et al. Psychiatric classification of nonconversion nonepileptic seizures. Arch Neurol 1995; 52:199.

4. Bortz, JJ. Nonepileptic seizures: issues in differential diagnosis and treatment. CNS Spectrums 1997; 2:20.

5. Berg, AT, Shinnar, S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology 1991; 41:965.

6. Camfield, PR, Camfield, CS, Dooley, JM, et al. Epilepsy after a first unprovoked seizure in childhood. Neurology 1985; 35:1657.

7. Willmore, LJ. Epilepsy emergencies: the first seizure and status epilepticus. Neurology 1998; 51:S34.

8. Schachter, SC. Iatrogenic seizures. Neurol Clin 1998; 16:157.

9. Schold, C, Yarnell, PR, Earnest, MP. Origin of seizures in elderly patients. JAMA 1977; 238:1177.

10. Sander, JW, Hart, YM, Johnson, AL, Shorvon, SD. National General Practice Study of Epilepsy: newly diagnosed epileptic seizures in a general population. Lancet 1990; 336:1267.

11. Cleary, P, Shorvon, S, Tallis, R. Late-onset seizures as a predictor of subsequent stroke. Lancet 2004; 363:1184.

12. Annegers, JF, Hauser, WA, Coan, SP, Rocca, WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998; 338:20.

13. Temkin, NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 2001; 42:515.

14. Caplan, LR. Transient global amnesia. In: Handbook of Clinical Neurology, vol 1 (46), Clinical Neuropsychology, Frederiks, JAM (Ed), Vinken, PJ, Bruyn, GW, Klawans (Eds), Elsevier, Amsterdam, 1985. p.205.

15. Woolfenden, AR, O'Brien, MW, Schwartzberg, RE, et al. Diffusion-weighted MRI in transient global amnesia precipitated by cerebral angiography. Stroke 1997; 28:2311.

16. Strupp, M, Bruning, R, Wu, RH, et al. Diffusion-weighted MRI in transient global amnesia: elevated signal intensity in the left mesial temporal lobe in 7 of 10 patients. Ann Neurol 1998; 43:164.

17. Ay, H, Furie, KL, Yamada, K, Koroshetz, WJ. Diffusion-weighted MRI characterizes the ischemic lesion in transient global amnesia. Neurology 1998; 51:901.

18. Sedlaczek, O, Hirsch, JG, Grips, E, et al. Detection of delayed focal MR changes in the lateral hippocampus in transient global amnesia. Neurology 2004; 62:2165.

19. Huber, R, Aschoff, AJ, Ludolph, AC, Riepe, MW. Transient Global Amnesia. Evidence against vascular ischemic etiology from diffusion weighted imaging. J Neurol 2002; 249:1520.

20. Takada, H, Aso, K, Watanabe, K, et al. Epileptic seizures induced by animated cartoon, "Pocket Monster". Epilepsia 1999; 40:997.

21. Fisher, RS, Harding, G, Erba, G, et al. Photic- and pattern-induced seizures: a review for the Epilepsy Foundation of America Working Group. Epilepsia 2005; 46:1426.

22. Harding, G, Wilkins, AJ, Erba, G, et al. Photic- and pattern-induced seizures: expert consensus of the Epilepsy Foundation of America Working Group. Epilepsia 2005; 46:1423.

23. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989; 30:389.

24. Dallos, V, Heathfield, K. Iatrogenic epilepsy due to antidepressant drugs. Br Med J 1969; 4:80.

25. Shukla, G, Bhatia, M, Vivekanandhan, S, et al. Serum prolactin levels for differentiation of nonepileptic versus true seizures: limited utility. Epilepsy Behav 2004; 5:517.

26. Chen, DK, So, YT, Fisher, RS. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65:668.

27. Shinnar, S, Kang, H, Berg, AT, et al. EEG abnormalities in children with a first unprovoked seizure. Epilepsia 1994; 35:471.

28. van Donselaar, CA, Schimsheimer, RJ, Geerts, AT, Declerck, AC. Value of the electroencephalogram in adult patients with untreated idiopathic first seizures. Arch Neurol 1992; 49:231.

29. Ramirez-Lassepas, M, Cipolle, RJ, Morillo, LR, Gumnit, RJ. Value of computed tomographic scan in the evaluation of adult patients after their first seizure. Ann Neurol 1984; 15:536.

30. Krauss, GL, Ampaw, L, Krumholz, A. Individual state driving restrictions for people with epilepsy in the US. Neurology 2001; 57:1780.

31. National Institute for Clinical Excellence (UK). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE Clinical Guideline 20, Oct. 2004. www.nice.org.uk/page.aspx?o=229249 (Accessed 3/7/05).

Ace844 · July 24, 2006

Status epilepticus in adults

INTRODUCTION — Although exact definitions vary, the term status epilepticus generally refers to the occurrence of a single unremitting seizure with a duration longer than 5 to 30 minutes or frequent clinical seizures without an interictal return to the baseline clinical state [1-3].

The diagnostic evaluation and clinical management of status epilepticus will be discussed here. The management of chronic epilepsy, the actions of antiepileptic drugs, and the management of status epilepticus in children are discussed separately. (See "Overview of the management of epilepsy in adults", see "Pharmacology of antiepileptic drugs"and see "Management of status epilepticus in children").

EPIDEMIOLOGY — It is estimated that there are 100,000 to 200,000 episodes of status epilepticus in the United States annually [4].

Refractory status epilepticus, defined as ongoing seizures following first- and second-line drug therapy, was noted in nearly 30 [5] to 43 [6] percent of patients with status epilepticus. Although not associated with increased mortality, refractory status epilepticus was linked to prolonged hospitalization and poorer functional outcomes. Encephalitis was associated significantly more often with refractory than with nonrefractory status epilepticus (22 versus 4 percent, respectively). In contrast, inadequate serum levels of antiepileptic drugs (AEDs) were associated significantly more often with nonrefractory than with refractory status epilepticus (28 versus 0 percent, respectively). Also, generalized tonic-clonic status was less likely to be refractory than nonconvulsive or focal motor status.

ETIOLOGY — Optimal management of status epilepticus requires identification and correction, if possible, of any predisposing factors that are present. Virtually any acute or chronic brain injury, as well as a number of toxic-metabolic insults, can cause status epilepticus [1,7]. Some of the more common predisposing factors include:

Antiepileptic drug noncompliance or discontinuation

Withdrawal syndromes associated with the discontinuation of alcohol, barbiturates, baclofen, or benzodiazepines (particularly alprazolam)

Acute structural injury (eg, encephalitis, tumor, stroke, head trauma, subarachnoid hemorrhage, cerebral anoxia or hypoxia)

Remote or longstanding structural injury (eg, prior head injury, cerebral palsy, previous neurosurgery, perinatal cerebral ischemia, arteriovenous malformations)

Metabolic abnormalities (eg, hypoglycemia, hepatic encephalopathy, uremia, pyridoxine deficiency, hyponatremia, hyperglycemia, hypocalcemia, hypomagnesemia)

Use of, or overdose with drugs that lower the seizure threshold (eg, theophylline, imipenem, high dose penicillin G, quinolone antibiotics, metronidazole, isoniazid, tricyclic antidepressants (especially bupropion), lithium, clozapine, flumazenil, cyclosporine, lidocaine, bupivacaine, metrizamide, and, to a lesser extent, phenothiazines)

Chronic epilepsy; status epilepticus may represent part of a patient's underlying epileptic syndrome (as with the Landau-Kleffner syndrome or Rasmussen's encephalitis), or may be associated with any of the generalized epilepsies

COMPLICATIONS AND OUTCOME — The mortality rate for adults who present with a first episode of status epilepticus is roughly 20 percent [4,8]. Estimates vary widely, mainly as a function of the underlying etiology and whether status epilepticus following cerebral anoxia is included in the study [1,9,10]. The mortality for status epilepticus after anoxia ranges from 69 to 81 percent [4,7,11]. Older age and high initial APACHE-II scores (a prognostic scoring system for ICU patients based on underlying disease, chronic conditions, and physiologic variables) are also independent risk factors for mortality [12]. Many of the other underlying causes of status epilepticus (see "Etiology" above) are associated with significant morbidity and mortality, even in the absence of seizures. In one series, 89 percent of deaths in patients with status epilepticus were attributed to the underlying etiology [13]. Another study suggested that acute symptomatic status is associated with a six-fold increased risk of mortality from status epilepticus [14].

The mortality of status epilepticus is in part due to the metabolic stress of repeated muscular convulsions. Rhabdomyolysis, lactic acidosis, aspiration pneumonitis, neurogenic pulmonary edema, and respiratory failure may complicate convulsions [1]. In addition, cardiac injury due to massive release of catecholamines may also contribute to injury [15,16] (See "Cardiac complications of stroke", section on neurogenic cardiac damage).

In addition, neuronal death can occur under certain circumstances after as little as 30 to 60 minutes of continuous seizure activity [17-19]. The pathologic hallmark of this phenomenon, cortical laminar necrosis, may also be seen on brain MRI as a persistant, high intensity lesion on T1-weighted images, which follows the gyral anatomy of the cerebral cortex [20]. Clinically, this effect manifests in increasing neurologic morbitidty with increasing seizure duration, even after the effects of etiology are eliminated [18,21]. Consequently, survivors of status epilepticus are at significant risk for recurrent seizures, and up to 10 percent may be left with disabling neurologic deficits [14].

DIAGNOSIS — The diagnosis of status epilepticus is often straightforward, but may be more complicated when symptoms are continuous and affect focal cognitive functions like language. The diagnosis of status epilepticus rests primarily upon the neurologic examination and the electroencephalogram (EEG).

Neurologic examination — Although the diagnosis of tonic-clonic status epilepticus may be obvious, a neurologic examination can be critical in making the diagnosis in more complex cases. Particularly important are assessment of the level of consciousness, observations for automatic movements or myoclonus, and any asymmetric features on examination that may indicate a focal structural lesion. (See "The detailed neurologic examination in adults" and see "Stupor and coma in adults", section on the Neurologic examination).

Electroencephalogram — The EEG is an extremely valuable tool in evaluating the patient with suspected status epilepticus. An EEG that reveals continuous seizure activity is diagnostic of status epilepticus. However, there are some limitations to the use of the EEG in this context [22]:

Clear ictal activity may not be seen during simple partial status epilepticus

Some ictal EEG patterns are difficult to recognize or are controversial

An EEG obtained over a short period of time and between seizures can miss intermittent ictal activity

Many cases of status epilepticus can be diagnosed on the basis of the neurologic examination alone, but EEG data are invaluable in diagnosing complex cases. (See "Clinical neurophysiology").

Certain EEG patterns in unresponsive patients are diagnostic of status epilepticus, including patterns that show temporal evolution. The meaning of other patterns, such as periodic lateralized epileptiform discharges (PLEDS), remains controversial, although aggressive pharmacologic treatment in a patient whose EEG shows only PLEDS without evolution and whose examination reveals no clinical seizures should generally be avoided [23]. Serial EEG recordings may be helpful if the initial study is not diagnostic.

Single photon emission computed tomography — Single photon emission computed tomography (SPECT) may demonstrate areas of increased perfusion during status epilepticus that can persist for weeks after the termination of seizures [24]. SPECT may be helpful in diagnosing status epilepticus when the EEG is equivocal. However, good studies of sensitivity and specificity are not available, and results should be interpreted in conjunction with clinical and EEG findings.

Magnetic resonance imaging — Magnetic resonance imaging (MRI) is the best tool to reveal the structural lesions that may trigger status epilepticus, but MRI is not a first-line test for diagnosing status epilepticus. However, MRI may reveal areas of increased signal intensity on FLAIR, T2-, or diffusion-weighted images in the presence of status epilepticus [25,26]. These findings are believed to represent seizure-induced cellular edema and are seen in cortical and limbic structures, particularly the hippocampus [27]. They may persist for days to weeks, especially if seizures are prolonged, and either ultimately resolve or evolve into focal atrophy and sclerosis. These lesions are nonspecific and can be associated with many other processes.

CLASSIFICATION — Classifying the type of status epilepticus is important because it is a major factor in determining morbidity and, therefore, the aggressiveness of treatment that is required; generalized tonic-clonic or partial-complex status epilepticus poses the greatest risk. The three most common forms of status epilepticus are:

Simple partial — Simple partial status epilepticus is characterized by continuous or repeated focal motor seizures (eg, twitching of one thumb), focal sensory symptoms (eg, the sensation of flashing lights in one visual field), or cognitive symptoms (eg, aphasia) without impaired consciousness.

Complex partial — Complex partial status epilepticus is characterized by continuous or repeated episodes of focal motor, sensory, or cognitive symptoms with impaired consciousness, and should be considered in the differential diagnosis of acute confusional states [28]. Other symptoms, such as automatisms and behavioral disturbances, may also occur.

Generalized tonic-clonic — Generalized tonic-clonic status epilepticus is always associated with impaired consciousness. Tonic-clonic seizures may be the initial manifestation of status epilepticus, or may represent secondary generalization from other seizure types.

Less common varieties — In addition to the three major types of status epilepticus listed above, there are a number of less common but important forms to recognize:

Absence — Absence (petit mal) status epilepticus is characterized by altered awareness, but not necessarily unconsciousness. Patients are typically confused or stuporous, and there may be associated myoclonus, eye blinking, perseveration, altered motor performance, language difficulty, or other symptoms. Absence status epilepticus typically occurs in patients with chronic epilepsy and frequently requires EEG for confirmation.

Myoclonic — Myoclonic status epilepticus is characterized by frequent myoclonic jerks in the setting of altered mental status. This typically occurs in patients with one of the generalized epilepsies, such as juvenile myoclonic epilepsy. The term has also been applied by some authors to the myoclonus seen in the patient who has experienced global cerebral ischemia. However, this myoclonus should not be considered in the same category as myoclonic status epilepticus unless EEG recordings demonstrate actual seizure activity and not simply a burst-suppression pattern. Overall, patients with myoclonus and altered consciousness are far more likely to be suffering from a metabolic encephalopathy (particularly uremic or hepatic encephalopathy) than from true myoclonic status epilepticus.

Psychogenic — Although relatively rare, psychogenic status epilepticus should be considered in situations where there are bilateral motor movements with preserved consciousness. An EEG recording during one of the patient's typical clinical events can help establish this diagnosis, although the EEG may also appear relatively normal during simple partial status epilepticus. (See "Factitious disorder and Munchausen syndrome").

Although prolactin levels drawn shortly after the onset of a seizure may help differentiate epileptic and non-epileptic events, prolactin levels normalize during prolonged seizures and so are not helpful in the diagnosis of status epilepticus [29].

PHARMACOLOGIC AGENTS — There are four main categories of drugs used to treat status epilepticus: benzodiazepines, phenytoin (or fosphenytoin), barbiturates, and propofol [2]. Other treatments with drugs such as lidocaine, paraldehyde (which is no longer available in the United States for intravenous infusion), chloral hydrate, ketamine, carbamazepine, or etomidate are less efficacious or less well studied and should not be considered part of the routine management of status epilepticus. Similarly, general anesthesia with isoflurane or other inhalational agents may be temporarily effective in stopping seizures but is used only in extreme circumstances because of logistical problems. Other agents such as chlormethiazole are used in other countries but are not available in the United States [30].

Benzodiazepines — Benzodiazepines remain the first-line treatment for status epilepticus because they can rapidly control seizures [31]. A number of studies have addressed the different uses and pharmacology of the three most commonly used benzodiazepines for status epilepticus: diazepam, lorazepam, and midazolam. All are thought to increase chloride conductance in central nervous system GABA(A) receptors and thus decrease neuronal excitability [32].

Diazepam — Diazepam has a high lipid solubility and therefore an ability to rapidly cross the blood-brain barrier; it is highly effective in rapidly terminating seizures when administered at doses of 0.1 to 0.3 mg/kg intravenously. An affect upon seizure activity can be seen as early as 10 to 20 seconds after administration, and cerebrospinal fluid (CSF) concentrations reach half of their maximum value in three minutes. However, because of subsequent redistribution of the drug into adipose tissue, the duration of diazepam's acute anticonvulsant effect is typically <20 minutes. Initial termination of seizure activity with intravenous diazepam is seen in 50 to 80 percent of patients [33], but if no other medication is provided, there is a 50 percent chance of seizure recurrence within the next two hours [34,35].

Nonetheless, diazepam remains the drug of first choice in many settings because it is stable in liquid form for long periods at room temperature. Therefore, diazepam is available in resuscitation kits in premixed form, while lorazepam, midazolam, and phenytoin are not. A rectal gel formulation of diazepam is also marketed and provides rapid delivery when intravenous access is problematic.

Lorazepam — Although lorazepam is as effective as diazepam in terminating seizures, the time from its injection to its maximum effect against seizures is as long as two minutes. The clinical advantage of lorazepam is that the effective duration of action against seizures is as long as four to six hours because of its less pronounced redistribution into adipose tissue. Effective initial intravenous doses of lorazepam are 0.02 to 0.2 mg/kg.

One study randomized 570 patients with a verified diagnosis of status epilepticus to one of four initial regimens [33]: lorazepam (0.1 mg/kg), phenytoin (18 mg/kg), diazepam (0.15 mg/mL) plus phenytoin (18 mg/kg), or phenobarbital (15 mg/kg). In the subgroup of 384 patients with overt generalized convulsive status epilepticus, treatment with lorazepam alone was most effective in terminating seizures within 20 minutes and maintaining a seizure-free state in the first 60 minutes after treatment (65 percent versus 58 percent with phenobarbital, 56 percent with diazepam plus phenytoin, and 44 percent with phenytoin alone). This observation is supported by a Cochrane review of 11 studies encompassing 2017 patients [36]. No significant differences in the success rates of the different regimens were observed in the 134 patients with subtle generalized convulsive status epilepticus, and overall there were no significant differences in seizure recurrence during the 12-hour study period, outcome at 30 days, or in the incidence of adverse events.

Midazolam — Like lorazepam and diazepam, midazolam is very effective in acutely terminating seizures (frequently in less than one minute), but it has a short half-life in the central nervous system. The advantage of midazolam over the other two benzodiazepines is that its use as a continuous infusion for refractory status epilepticus has been more thoroughly investigated and is associated with minimal cardiovascular side effects [32]. Effective initial intravenous doses of midazolam are a 0.2 mg/kg bolus, followed by continuous infusion at rates of 0.75 to 10 µg/kg per minute.

A continuous midazolam infusion is probably less effective than high dose barbiturates or propofol for the treatment of refractory status epilepticus, although high quality studies directly comparing these treatments have not been performed. Nasally administered midazolam may be useful in the rapid termination of seizures when IV access is difficult [37], but additional studies are needed before this can be recommended.

Clonazepam — Clonazepam has been used to treat status epilepticus outside the United States in settings where intravenous formulations are available. It has effects similar to those of other benzodiazepines, with a rapidity of onset that is intermediate between that of lorazepam and that of diazepam. Its duration of activity is more prolonged than that of diazepam.

Phenytoin — Phenytoin is one of the most commonly used treatments for status epilepticus, despite the trial described above which showed that initial treatment of generalized convulsive status epilepticus with lorazepam alone was more effective than treatment with diazepam and phenytoin [33]. The principal advantage of phenytoin derives from its efficacy in preventing the recurrence of status epilepticus for extended periods of time.

Phenytoin is generally infused at a rate of up to 50 mg/minute to a total dose of 20 mg/kg, but it is critical to modify the infusion rate in the presence of hypotension or other adverse cardiovascular events. The risks of hypotension and cardiac arrhythmias increase with higher infusion rates, partly due to the propylene glycol used to solubilize phenytoin. In addition, the risks of local pain and injury (including venous thrombosis and the purple glove syndrome) increase with more rapid rates of infusion. Cardiac monitoring during the initial infusion is mandatory because bradyarrhythmias or tachyarrhythmias may occur.

Fosphenytoin — Fosphenytoin is a pro-drug of phenytoin that is hydrolyzed into phenytoin by serum phosphatases. Fosphenytoin is highly water soluble and therefore unlikely to precipitate during intravenous administration. The risk of local irritation at the site of infusion is significantly reduced compared with phenytoin; fosphenytoin can therefore be infused much more rapidly (up to 150 mg/minute versus 50 mg/minute with phenytoin). In addition, the increased water solubility of fosphenytoin makes intramuscular (IM) administration possible if intravenous (IV) access cannot be obtained. However, IM administration will yield less predictable levels and a longer time to onset of effect than IV administration.

Since propylene glycol is not required to solubilize fosphenytoin, the cardiovascular side effects of fosphenytoin may be less frequent and severe than those of phenytoin. However, at least two studies have suggested that the incidence of adverse hemodynamic effects with fosphenytoin and phenytoin infusions is similar [38,39].

Since fosphenytoin is converted on a 1:1 molar basis to phenytoin, the dosing of fosphenytoin in terms of moles is identical. However, the molecular weight of fosphenytoin is greater than that of phenytoin; hence, a greater weight of fosphenytoin must be given in order to yield the same concentration of phenytoin. To eliminate this problem, the manufacturer recommends prescribing of fosphenytoin as milligrams of phenytoin equivalent (PE). Orders for fosphenytoin should be written in terms of PEs; as an example, 20 mg/kg PE load at a rate of 100 to 150 mg PE/minute. Cardiac monitoring is required during the infusion of fosphenytoin or phenytoin.

Barbiturates — Barbiturates are similar to benzodiazepines in that they also bind to the GABA(A) receptor, amplifying the actions of GABA by extending GABA-mediated chloride channel openings [40]. This process permits an increasing flow of chloride ions across the membrane, causing neuronal hyperpolarization (eg, membrane inhibition to depolarization). Phenobarbital and pentobarbital are the most useful barbiturates in the treatment of status epilepticus.

Phenobarbital — Phenobarbital is an excellent anticonvulsant, especially in the acute stage of managing seizures. Various studies have shown a rate of seizure control of approximately 60 percent when phenobarbital is used alone; this rate is similar to that seen with lorazepam alone or the combination of phenytoin and diazepam [33,41]. Despite its efficacy, phenobarbital is generally not used as a first-line treatment in adults because it carries a higher risk of hypoventilation and hypotension than benzodiazepines or phenytoin.

Initial doses of 20 mg/kg infused at a rate of 30 to 50 mg/minute are generally used, but slower infusion rates should be used in the elderly. Careful monitoring of respiratory and cardiac status is mandatory. It is often necessary to intubate patients in order to provide a secure airway and minimize the risk of aspiration if phenobarbital is administered following benzodiazepines. The risk of prolonged sedation with phenobarbital is greater than with the other anticonvulsants because of its half-life of 87 to 100 hours.

Pentobarbital — Pentobarbital is used primarily in the treatment of refractory status epilepticus, typically with a loading dose of 10 mg/kg infused at a rate of up to 100 mg/minute [42]. The ultimate infusion rate is determined by the amount of drug required to terminate status epilepticus, but can be limited by hypotension due to the drug's adverse inotropic and vasodilatory effects. Vasopressors are almost universally required during high dose pentobarbital infusions, and pulmonary artery catheterization may be required to optimize volume status and facilitate vasopressor management. (See "Use of vasopressors and inotropes" and see "Swan-Ganz catheterization: Indications and complications").

Thiopental — Some centers use thiopental instead of pentobarbital for refractory status epilepticus, but there are a number of problems with this approach [30]. Animal studies suggest that thiopental carries a higher incidence of adverse cardiovascular effects than pentobarbital. The half-life of thiopental is shorter than that of pentobarbital, but this is counterbalanced by the fact that thiopental is degraded to active metabolites (including pentobarbital), which accumulate with longer term infusions. Thiopental may also have immunosuppressive effects on neutrophil function and mucociliary clearance [43,44].

An uncontrolled series of 10 consecutive adults presenting with status epilepticus noted that high-dose thiopental therapy effectively terminated clinical and electrophysiological evidence of seizures [45]. However, therapy was associated with systemic hypotension; each patient required fluid resuscitation with an average of 2.6 L of crystalloid in the first 24 hours. High-dose thiopental resulted in delayed recovery from anesthesia, and six patients developed S. aureus pneumonia, resulting in prolonged intubation.

Propofol — Propofol is a hindered phenolic compound with anticonvulsant properties. The drug is unrelated to any of the currently used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents. Hypotension and respiratory depression may complicate its use.

Experience with propofol in the treatment of status epilepticus is limited, but promising results have been reported in several small trials [18,46,47]. As an example, one study compared the results of treatment with propofol or high dose barbiturates in 16 patients with refractory status epilepticus [48]. Termination of seizures was significantly faster among successfully treated patients in the propofol group (mean 3 versus 123 minutes), but there was a nonsignificant trend toward higher overall success rates in barbiturate-treated patients (82 versus 63 percent).

Valproic acid — The use of intravenous (IV) valproic acid (Depacon) in the treatment of status epilepticus has been limited in part because the United States Food and Drug Administration (FDA) approved it only for slow infusion rates (up to 20 mg/min). However, accumulating evidence suggests that more rapid infusion rates and higher intravenous loading doses of valproate are safe and well tolerated. (See "Pharmacology of antiepileptic drugs", section on Valproate).

The limited available data suggest that valproate may be useful in treating acute status epilepticus [49-51], but questions remain about the relative effectiveness of IV valproate compared with other antiepileptic drugs (AEDs) that are first-line agents for treating status epilepticus. In addition, the risk of hyperammonemic encephalopathy due to valproate, may pose diagnostic challenges in the postictal setting [52]. (See "Valproic acid intoxication"). Further clinical trial data are needed to define the role of IV valproate in this setting.

TREATMENT — Any patient with possible status epilepticus requires rapid evaluation and treatment [53]. There are many possible pharmacologic approaches to status epilepticus; successful approaches to management have been developed empirically, since there are few controlled trials comparing different regimens [2,3]. Although there are differences in efficacy and side effect profile among effective agents, it is important to become familiar with and primarily use one reasonable treatment method.

We divide the initial management into three phases: assessment/supportive treatment, initial pharmacologic therapy, and secondary pharmacotherapy (if required) for the treatment of refractory seizures.

Assessment and support — A rapid neurologic examination should be performed to provide a preliminary classification of the type of status epilepticus and its probable etiology. The patient should also undergo a rapid general evaluation, with particular attention to respiratory and circulatory status, and supportive therapy (eg, oxygen, mechanical ventilation) should be instituted as needed.

During this time, intravenous catheters should be placed and blood obtained for electrolyte, serum glucose, and toxicology studies, a complete blood count, and a rapid "finger-stick" glucose. Measurement of arterial blood gases is often valuable and may suggest a need for intubation and mechanical ventilatory support. Cardiac monitoring, frequent measurement of blood pressure, and pulse oximetry should be instituted. These tasks may require one to four minutes and may overlap with the next phase of treatment.

Initial pharmacologic therapy — Lorazepam 0.02 to 0.03 mg/kg should be administered intravenously and approximately one minute allowed to assess its effect. Diazepam 0.1 mg/kg IV or midazolam 0.05 mg/kg IV may be substituted if lorazepam is not available. If seizures continue at this point, additional doses of lorazepam (up to a cumulative dose of 0.1 mg/kg) should be infused at a maximum rate of 2 mg/minute, and a second intravenous catheter placed in order to begin a concomitant phenytoin (or fosphenytoin) loading infusion. Even if seizures terminate after the initial lorazepam dose, therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures.

Phenytoin and any of the benzodiazepines are incompatible and will precipitate if infused through the same intravenous line. A phenytoin infusion of 20 mg/kg (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) should be started at 25 to 50 mg/min (or 100 mg PE/minute for fosphenytoin) and reduced if significant adverse effects of the infusion are seen. This phase of treatment usually lasts approximately 30 minutes.

Treatment of refractory seizures — Status epilepticus that is refractory to first line anticonvulsants indicates a grave prognosis and requires management in an intensive care setting. After failure of the first line therapy discussed above, the next step is to consider infusion of another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and up to another 0.05 mg/kg of lorazepam if the patient is stable. Metabolic derangements from initial laboratory studies should be appropriately treated.

Further measures are required if seizures continue, but whereas there is reasonable agreement upon treatment up to this point, the optimal therapy of refractory status epilepticus is less well defined. Regardless of the specifics of pharmacologic therapy, it is critical to provide adequate ventilatory and hemodynamic support. Patients with refractory seizures should be endotracheally intubated, and continuous electroencephalogram (EEG) recordings are desirable [54].

The primary drugs used for refractory status epilepticus are phenobarbital, pentobarbital, midazolam, and propofol. There is no consensus about which should be used first. A systematic review of drug therapy for refractory status epilepticus assessed data on 193 patients from 28 trials in an attempt to clarify this issue [54]. Overall mortality was 48 percent, but there was no association between drug selection and the risk of death. Pentobarbital was more effective than either propofol or midazolam in preventing breakthrough seizures (12 versus 42 percent), but was associated with a significantly increased incidence of hypotension, defined as a systolic blood pressure below 100 mmHg (77 versus 34 percent). In contrast, another study of 107 patients failed to show an influence of the therapy used on the outcome of refractory status [55].

Further pharmacologic therapy at this point is based primarily upon the patient's hemodynamic stability and the risk for prolonged mechanical ventilation.

Hemodynamically stable patients — Treatment with high-dose barbiturates (pentobarbital or phenobarbital) remains common in this setting because of the greatest experience with its use [42]. However, propofol is gaining some acceptance in this setting for patients who are already intubated because response to therapy is very rapid, allowing a rapid change to another regimen if propofol infusion is unsuccessful. Continuous EEG monitoring should be instituted, if possible, along with continuous pulse oximetry and blood pressure monitoring via an arterial catheter. Vasopressors should be available at the bedside. (See "Use of vasopressors and inotropes").

An initial dose of 20 mg/kg of phenobarbital should be infused at a maximum rate of 100 mg/minute. If seizure activity continues, a dose of 10 mg/kg of pentobarbital should be infused while careful attention is paid to the EEG and hemodynamic status. Additional doses of pentobarbital at rates up to 100 mg/min should be infused until seizures stop and the EEG shows a burst-suppression pattern. The primary advantage of the burst-suppression endpoint is that it is easily recognizable, but achieving a burst-suppression pattern is not always necessary [55].

Almost all patients at this point will require vasopressor support (typically phenylephrine or dopamine), as well as crystalloid infusions. The mortality rate associated with barbiturate coma is high because of adverse hemodynamic effects and the severity of the underlying neurologic process, and reaches 80 percent in patients over 70.

If seizures are terminated with pentobarbital, then an infusion at 1 to 4 mg/kg per hour should be maintained for 24 hours and tapered over the following 24 hours. Some physicians may prolong the duration of high-dose therapy if frequent focal epileptiform discharges remain on the EEG after treatment. During this time, high therapeutic phenytoin and/or phenobarbital concentrations must be maintained.

Hemodynamically unstable patients — Treatment with barbiturates or propofol may significantly worsen the hemodynamics of unstable patients. Therefore, one option is to proceed with a midazolam infusion because it is the best-tolerated treatment in this setting [3,32]. Generally, therapy is initiated with a 0.2 mg/kg bolus, followed by a continuous infusion of 0.05 to 0.5 mg/kg per hour. If this is unsuccessful within 45 to 60 minutes, a propofol or pentobarbital infusion should be started.

Patients at high risk for respiratory failure — Patients who are at high risk for prolonged mechanical ventilation (eg, those with severe COPD, severe debilitation, or cancer) should be treated with propofol in an attempt to minimize the duration of sedation [48]. Pressors should be ready at the bedside, and blood pressure and EEG monitored closely while propofol infusion is initiated at 1 to 2 mg/kg per hour. This infusion should be titrated over the next 20 to 60 minutes to maintain a seizure-free state and burst suppression on the EEG. Infusion rates up to 10 to 12 mg/kg/hour may be required.

If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of 5 percent per hour. This prevents rebound seizures that commonly occur with abrupt propofol discontinuation. It is critical that high therapeutic levels of at least one anticonvulsant (phenytoin levels >25 mg/L [99 µmol/L] or phenobarbital levels >30 mg/L [129 µmol/L]) are obtained prior to tapering the propofol in order to reduce the risk of seizure recurrence.

Treatment with propofol should generally be considered unsuccessful if it does not terminate seizure activity within 45 to 60 minutes. In this case, a high dose barbiturate infusion should be considered. Propofol infusions for refractory status epilepticus are relatively new in comparison with midazolam or high dose barbiturates. However, as clinical experience with propofol sedation in the intensive care setting grows, this agent is increasingly used in patients with refractory status persisting after intubation. It remains critical that propofol be employed cautiously and by individuals familiar with its use in this context.

Malignant status epilepticus — The term "malignant" status epilepticus has been introduced to refer to status epilepticus that either fails to respond to the therapies discussed above or recurs quickly on tapering these medications [56]. It has been reported that as many as 20 percent of patients with refractory status epilepticus evolve into malignant status epilepticus, a transition that is associated with a very poor prognosis.

Out-of-hospital treatment — Treatment of status epilepticus out of hospital by paramedics appears to be safe and effective. This was illustrated in a randomized, double-blind study of 205 patients with status epilepticus, of whom 66 received lorazepam, 68 received diazepam, and 71 received placebo [57]. Status epilepticus had been terminated on arrival to the emergency department in more patients treated with lorazepam and diazepam than placebo (59, 43, and 21 percent, respectively). Active treatment also reduced the rates of respiratory or circulatory complications (10.6, 10.3, and 22.5 percent, respectively).

SUMMARY AND RECOMMENDATIONS — Status epilepticus refers to the occurrence of a single unremitting seizure with a duration longer than 5 to 30 minutes or frequent clinical seizures without an interictal return to the baseline clinical state.

Etiologies include noncompliance with antiepileptic drug (AED) treatment, drug or alcohol withdrawal syndromes, acute brain injury or infection, and metabolic disturbances, among others. (See "Etiology" above).

The prognosis depends most strongly on the underlying etiology; however, there is some evidence that status epilepticus is independently associated with mortality and neurologic sequelae. (See "Complications and outcome" above).

The diagnosis of status epilepticus can be difficult. A careful neurologic examination and EEG studies are important in situations where there is any uncertainty. (See "Diagnosis" above).

The initial assessment and treatment of a patient in status epilepticus should proceed relatively simultaneously. Hemodynamic and respiratory monitoring are also required in order to avoid side effects of therapy. (See "Assessment and support" above).

We recommend lorazepam 0.02 to 0.03 mg/kg IV as the initial treatment for status epilepticus (Grade 1A). A loading dose of phenytoin or fosphenytoin should follow to maintain anti-seizure effect (Grade 1B). (See "Initial pharmacologic therapy" above).

There are many possible approaches to the treatment of status epilepticus. One possible approach is summarized in the accompanying protocol (Grade 2C). (See "Treatment of refractory seizures" above). Clinicians should employ those medication regimens with which they and the care team are familiar in order to avoid unintended complications of therapy.

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18. Payne, TA, Bleck, TP. Status epilepticus. Crit Care Clin 1997; 13:17.

19. Chapman, MG, Smith, M, Hirsch, NP. Status epilepticus. Anaesthesia 2001; 56:648.

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31. Treiman, DM. Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus. Epilepsia 1989; 30(suppl 2):s4.

32. Kumar, A, Bleck, TP. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 1992; 20:483.

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42. Yaffe, K, Lowenstein, DH. Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology 1993; 43:895.

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Ace844 · July 24, 2006

Pharmacology of antiepileptic drugs

INTRODUCTION — The rapid increase in the cellular theories of epileptogenesis and the recent availability of second-generation antiepileptic drugs (felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide) have resulted in the development of correlations between the in vitro cellular action of antiepileptic drugs (AEDs) and the types of human seizures against which they are most effective [1]. As an example, both carbamazepine and phenytoin inhibit voltage-dependent neuronal sodium channels; this action is predictive of efficacy against tonic seizures. Growing understanding of these correlations has led to the current era of AED development and highlights the importance of understanding the basic mechanisms of AEDs [2,3].

With the exception of felbamate, second generation AEDs (eg, gabapentin, lamotrigine, topiramate, levetiracetam, oxcarbazepine, zonisamide) have a number of potential advantages over older AEDs (eg, phenobarbital, phenytoin, carbamazepine, valproate). These include generally lower side-effect rates, little or no need for serum monitoring, once or twice daily dosing for some, and fewer drug interactions. However, these drugs are not a panacea. The National Institute for Clinical Excellence (UK) practice guidance evaluated newer AEDs (excluding zonisamide and felbamate) and made the following observations [4,5]:

Monotherapy data in newly diagnosed epilepsy patients do not show significant differences in effectiveness between older and newer AEDs.

Insufficient evidence exists to support the claim that newer AEDs are generally associated with an improved quality of life.

There is a high degree of uncertainty about the costs and benefits associated with individual drugs.

Freedom from seizures, the desired outcome, is infrequently achieved with combination therapy in patients who have failed monotherapy; insufficient evidence exists to determine whether any of the newer AEDs is superior to other AEDs in providing long-term freedom from seizures.

The pharmacology of AEDs is reviewed here. Their use in a treatment plan for patients with seizures is discussed separately. (See "Overview of the management of epilepsy in adults").

DRUGS THAT BLOCK VOLTAGE-DEPENDENT SODIUM CHANNELS — Depolarization of neuronal membranes (such as by excitatory neurotransmitters at postsynaptic receptor sites) produces an influx of sodium ions from the extracellular space into the neuron through sodium channels along the neuronal membrane. As the cell membrane depolarizes, this influx further increases the number of open sodium channels in the cell membrane, further increasing the incoming current of sodium ions. Thus, these sodium channels are termed voltage-dependent.

The sodium channels are termed resting or closed when the cell is at resting membrane potential. During the process of depolarization, the sodium channels are activated or open. After activation, they are inactivated (closed) or refractory. Sodium channels cannot be further activated by depolarization during the refractory state. Thus, the membrane potential starts to repolarize and the sodium channels eventually resume the resting or closed state.

The inactivated period is usually brief enough to allow for rapid, high-frequency action potentials. Blocking voltage-dependent sodium channels (eg, with tetrodotoxin from the puffer fish), or extending their inactivated state (eg, with certain AEDs), prevents neurons from firing rapidly, although single action potentials are unaffected. This inhibition also can prevent post-tetanic potentiation, a phenomenon consisting of an unusually large response of a postsynaptic neuron to an incoming single action potential after previous exposure to rapid, high-frequency (tetanic) incoming stimulation. Neurons that undergo post-tetanic potentiation may be responsible for spreading abnormal electrical responses after being exposed to intermittently rapid firing neurons. This action may correlate with the rapid spread of epileptic activity from a circumscribed seizure focus to other cortical areas.

Carbamazepine — Carbamazepine (CBZ) has been used to treat partial and generalized seizures since being introduced in Switzerland and the United Kingdom over 35 years ago. It is also effective for the treatment of affective illnesses such as bipolar disorder and chronic pain syndromes such as trigeminal neuralgia [6,7].

Carbamazepine is approximately 70 percent protein bound. It is metabolized in the liver by the cytochrome P-450 (CYP) system, an inducible enzyme. The main metabolite, carbamazepine epoxide, has anticonvulsant activity and can be measured in the serum.

Carbamazepine binds to voltage-dependent sodium channels, probably after they change from the activated to the inactivated state. This binding extends the inactivated phase and inhibits the generation of rapid action potentials when the cell is experiencing incoming depolarizing trains [8]. The effectiveness of CBZ in inhibiting action potentials by extending the inactivated phase of sodium channel function increases with the rate of neuronal firing.

Carbamazepine is used for the initial therapy of primary generalized tonic-clonic seizures and for partial seizures, with or without secondary generalization (show table 1). The usual initial starting dose is 2 to 3 mg/kg per day given twice, three, or four times daily; the dose is increased every five days to 10 mg/kg daily. Generally, three times daily dosing is recommended. However, if patients experience side effects two to four hours after a dose, then the total daily dosage could be redistributed over four doses. Further increases up to 15 to 20 mg/kg per day may be necessary after two to three months because of hepatic autoinduction of the cytochrome P-450 enzyme.

Extended-release formulations allow for twice daily dosing with more stable blood levels. Two open-label studies found that switching from immediate-release to extended-release formulation decreased side effects [9,10]. The larger of these two studies (453 patients) also showed improved seizure control [9].

Serum CBZ levels should be measured initially at three, six, and nine weeks, with a goal level of 4 to 12 mcg/mL. Frequent levels are needed early in therapy due to autoinduction, which results in decreased serum concentrations. Serum levels subsequently should be checked at least every two months until successive determinations are constant, more frequently if CBZ dosages or concomitant antiepileptic drug doses are changed. A number of drugs can influence the serum concentration of carbamazepine (show table 2 and show table 3).

Common systemic side effects of carbamazepine include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, and fluid retention (show table 4A-4B). Men with localization-related epilepsy taking carbamazepine have higher rates of sexual dysfunction and low testosterone levels [11]. Carbamazepine has been associated with the Stevens-Johnson syndrome and toxic epidermal necrolysis, particularly during the first eight weeks of therapy [12]. Neurotoxic side effects include drowsiness, dizziness, blurred or double vision, lethargy, and headache. Hyponatremia related to carbamazepine and oxcarbazepine is discussed separately. (See "Hyponatremia" below).

Leukopenia occurs in approximately 12 percent of children and 7 percent of adults with CBZ treatment [13]. It may be transient or persistent and does not usually require immediate discontinuation of CBZ therapy [14,15]. The onset is typically within the first three months of treatment. Patients who have a low or low-normal white blood cell (WBC) or neutrophil count before CBZ treatment may be at higher risk for developing CBZ-induced leukopenia or neutropenia.

Aplastic anemia (pancytopenia) is a rare, idiosyncratic, non-dose-related side effect that is most likely to occur within the first three or four months after initiating CBZ therapy [14]. Daily laboratory checks would be necessary to monitor for aplastic anemia, agranulocytosis, and thrombocytopenia because of their rapid onset [13], and such frequent monitoring is neither practical nor necessary for most patients taking CBZ. A more suitable approach is to monitor for aplastic anemia by informing patients and physicians to carefully watch for signs and symptoms [13]. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis").

Some experts recommend monitoring WBC counts of high-risk patients during the first three months of CBZ treatment, with the monitoring frequency determined by results of each laboratory value. White blood cell counts less than 3000/microliter or neutrophil counts below 1000/microliter warrant either a decrease in CBZ dose with frequent WBC monitoring, or CBZ discontinuation [13].

Phenytoin — Phenytoin was introduced nearly 60 years ago for use in epilepsy and is still widely prescribed for partial and generalized seizures [16]. Similar to carbamazepine, it blocks voltage-dependent neuronal sodium channels [17]. Other effects of phenytoin include diminishing synaptic transmission, limiting fluctuation of neuronal ionic gradients via sodium-potassium ATPase, and affecting second messenger systems by inhibiting calcium-calmodulin protein phosphorylation [18,19]. The first step in the metabolism of phenytoin, which takes place in the liver, involves arene oxidase, which has nonlinear kinetics.

In addition to partial and generalized seizures, phenytoin is a second line agent for patients with mixed seizures (myoclonic and tonic-clonic) (show table 1). It is administered orally or intravenously; the latter, or the prodrug fosphenytoin, can be used in patients who are having active seizures. The initial oral dose is 15 mg/kg in three divided doses, followed by a maintenance dose of 5 mg/kg daily in one or two divided doses. Initial blood levels should be obtained two to three weeks after the first dose with a goal concentration of 10 to 20 mcg/mL in patients with normal renal function. In the presence of low serum albumin or other highly protein bound drugs (such as valproate), free levels should be followed with a goal of 1 to 2 mcg/mL.

After an oral or intravenous loading dose, the initial phenytoin blood level can be drawn several hours after the conclusion of the loading dose. The results can be used to guide the determination of the maintenance dose or the need for additional loading. Given the long half-life of phenytoin, serum levels should always be checked within five to seven days following any change (increase or decrease) in the daily dose in order to determine the steady-state serum concentration at the new maintenance dose.

Like all AEDs, phenytoin dosing should be guided primarily by effect (ie, seizure control) and tolerability. Most, but not all, patients who have normal renal function and serum albumin levels can achieve seizure freedom without side effects with a serum phenytoin concentration of 10 to 20 mcg/mL.

A number of drugs can influence the serum concentration of phenytoin (show table 2 and show table 3). Renal failure impairs the protein-binding of phenytoin; the pharmacologically active free concentration may increase relative to the total concentration.

Commercially available brand and generic phenytoin products may differ in phenytoin content and other formulation characteristics that can affect bioavailability [20]. These differences may occasionally result in an increase [21] or decrease [22-24] in serum phenytoin levels, which in turn might adversely affect seizure control or cause toxicity when patients are switched from one preparation to another. Therefore, more frequent serum levels and heightened clinical vigilance may be warranted when substituting phenytoin formulations in patients with difficult-to-control seizures or those prone to side effects, particularly in light of phenytoin's nonlinear kinetics and relatively narrow therapeutic window.

The major systemic side effects of phenytoin are gingival hypertrophy, body hair increase, rash, and lymphadenopathy (show table 4A-4B). Like carbamazepine, phenytoin has been associated with the Stevens-Johnson syndrome and toxic epidermal necrolysis, particularly during the first eight weeks of therapy [12]. Age-related sexual dysfunction and low testosterone levels are more common in men taking phenytoin than in controls [11]. Neurotoxic side effects include confusion, slurred speech, double vision, ataxia, and neuropathy (with long-term use).

Lamotrigine — The cellular mechanism of action of lamotrigine (LTG) is not completely understood; in rodent brain preparations, LTG blocks the repetitive firing of neurons by inactivating voltage-dependent sodium channels (show table 1). However, there is some evidence that LTG, unlike carbamazepine and phenytoin, may selectively influence neurons that synthesize glutamate and aspartate, since it diminishes the release of these excitatory neurotransmitters [25]. These findings suggest that the anticonvulsant effect of LTG may relate to actions on synaptic as well as membrane functions.

Lamotrigine is efficacious for the treatment of partial seizures in adults and children (show table 1) [26-28]. It also has demonstrated efficacy as adjunctive therapy in primary generalized tonic clonic seizures [29].

Guidelines issued by the American Academy of Neurology (AAN) state that LTG can be used as initial therapy in patients with newly diagnosed partial epilepsy and idiopathic generalized epilepsy, as well as mixed seizure disorders [26]. Lamotrigine may also be used for the treatment of newly diagnosed absence seizures in children [26]. However, LTG is not approved by the US Food and Drug Administration (FDA) for these indications.

Lamotrigine is quickly and totally absorbed when given orally, and plasma concentrations have an apparent linear relationship to dose. The drug is approximately 55 percent bound to plasma proteins, and the liver metabolizes LTG to inactive glucuronide conjugates excreted in the urine. Serum concentrations of LTG are not influenced by interactions with most non-AEDs. However, drug levels are markedly increased by an interaction with valproate, which inhibits glucuronidation, the main metabolic pathway of LTG (show table 3). Levels are decreased in the presence of enzyme-inducing drugs (including phenytoin, carbamazepine, and to a lesser extent oxcarbazepine) [30]. This interaction leads to two different dosing schemes:

For patients taking an AED that induces hepatic enzymes (eg, carbamazepine, phenytoin, or mysoline), the initial dose is 25 mg twice daily, titrated upward by 5 mg increments every one to two weeks as needed.

For patients taking valproate, the initial dose is 12.5 to 25 mg every other day, with increases of 25 mg every two weeks as needed to a maximum of 300 to 500 mg per day.

Levels of LTG can also be influenced by concomitant oral contraceptive agents that decrease levels. This can result in increased concentrations during the "placebo" week used with many preparations, with decreases when the active drug is resumed. This effect appears to be limited to contraceptives containing ethinyl estradiol; progesterone only compounds have not been found to alter LTG levels [31].

Therapeutic serum levels of LTG have not been definitively established. However, data from 811 patients who took LTG as monotherapy or adjunctive therapy revealed a significant correlation between LTG serum concentrations and clinical toxicity [32]. Toxicity was defined as any side effect that required a dose decrease or discontinuation of LTG. The following observations were made.

Toxicity increased with increasing serum LTG levels; 7 percent of patients developed toxicity at <5.0 mcg/mL compared with 59 percent at >20 mcg/mL.

Toxicity was uncommon at the most frequently encountered serum concentrations (<10 microgram/mL).

To put this in perspective, the highest LTG level encountered in any of the major LTG clinical trials was 8.8 mcg/mL, and most patients in those trials had LTG levels in the low single digits (1.53 to 3.60 mcg/mL) [32]. Thus, the authors of this study suggest an initial target range of 1.5 to 10 mcg/mL for LTG therapy, while noting that efficacy may increase at higher levels for patients with refractory seizures.

Several studies suggest that LTG clearance increases by about 65 percent in pregnant women with epilepsy, which may lead to an increase in seizures [33,34]. Because of this, frequent monitoring of LTG serum levels and appropriate dose adjustments are advised during the period of withdrawal from oral contraceptives, during pregnancy, and after delivery. Serum monitoring before, during, and after pregnancy can help to guide dosing to avoid a significant decrease during pregnancy or an overshoot due to rebound of levels after delivery.

Lamotrigine is excreted in breast milk and may lead to significant serum levels in breast fed infants [35].

Systemic side effects of LTG include rash and nausea (show table 4A-4B). A benign rash may develop in up to 10 percent of patients during the initial one to two months of therapy and necessitates discontinuation of the drug. Patients who have previously had a rash with another AED are more likely to experience rash with LTG [36]. The risk of developing a life-threatening rash such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema is approximately 1 in 1000 adults; this risk is increased dramatically in children, leading to the recommendation that the drug not be used in patients under the age of 16 years.

Neurotoxic side effects are predominantly dizziness and somnolence. In rare cases, lamotrigine has exacerbated or initiated myoclonus and even myoclonic status in juvenile myoclonic and other idiopathic generalized epilepsies [37]. This disappears with withdrawal of the medication and sometimes with lowering the dose. The risk of this side effect is low, and lamotrigine is still considered a treatment option in these patients.

Oxcarbazepine — Oxcarbazepine is a compound with a similar chemical structure to carbamazepine and likely a similar mechanism of action (show table 1) [38]. The efficacy of oxcarbazepine is comparable to carbamazepine and other first line therapies for partial and secondarily generalized tonic clonic seizures (show table 1) [26,27,38-40]. However, it is considerably more expensive than the older drugs [41].

Oxcarbazepine is almost completely absorbed regardless of food intake. Serum concentrations of its active metabolite, 10-monohydroxy metabolite (MHD), reach a peak in four to six hours, with a half-life of 8 to 10 hours [38]. The half-life does not change significantly with chronic administration due to a lack of autoinduction. The concentration of this metabolite decreases during pregnancy and increases after delivery [42]. This, with the observation that oxcarbazepine monotherapy was associated with increased seizures in one large pregnancy registry, supports close clinical monitoring during pregnancy and after delivery [43]. There are little other published data on this drug in pregnancy.

Metabolism of oxcarbazepine occurs in the liver, but only minimally affects the cytochrome P450 system [38]. This represents a major advantage over carbamazepine, particularly in patients who require polytherapy. Monotherapy in adults begins with 300 to 600 mg/day, increasing to a dose of 900 to 3000 mg/day in two or three divided doses. In infants and young children, one study showed that higher maintenance doses (60 mg/kg per day) were significantly more effective then lower doses (10 mg/kg per day) when used as adjunctive therapy for partial seizures [44].

The most common side effects of oxcarbazepine are sedation, headache, dizziness, rash, vertigo, ataxia, nausea, hyponatremia, and diplopia (show table 4A-4B) [38].

Rare but serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been associated with oxcarbazepine use in both children and adults; the median time of onset for reported cases was 19 days [45]. These reports prompted the manufacturer and US FDA to issue revised labeling with an updated WARNINGS section in April 2005. In addition, rare multiorgan hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days; range 4 to 60 days) to the initiation of oxcarbazepine therapy in both children and adults.

Hyponatremia — Hyponatremia associated with oxcarbazepine and carbamazepine is due at least in part to increased responsiveness of collecting tubules to antidiuretic hormone, and it is considered to be one of the forms of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). (See "Causes of the SIADH", section on Drugs).

The incidence of hyponatremia associated with oxcarbazepine therapy may be higher than that seen with carbamazepine [46,47]. The following observations have been made about the incidence of this complication:

Hyponatremia occurred in 23 percent of patients in a postmarketing study, but only 1 percent of patients discontinued oxcarbazepine because of hyponatremia [48]. Hyponatremia may be less common in children than in adults [49,50].

Serum sodium values below 125 meq/L emerged during the first months in 3 percent of patients treated with oxcarbazepine in clinical trials [51]. A cross-sectional analysis of an epilepsy patient database found a prevalence of 12.4 percent for sodium levels less than 128 meq/L among patients taking oxcarbazepine [47].

Elderly patients, particularly those on concomitant natriuretic drugs, are significantly more likely to develop hyponatremia [47,52].

Hyponatremia typically develops gradually in the first few months of therapy, which may explain why most patients are asymptomatic [53].

Evidence for a dose relationship between oxcarbazepine and hyponatremia is conflicting [47,54,55].

Although symptoms attributable to hyponatremia are to some degree related to the severity of the abnormality, the rate of onset is of primary importance. Acute hyponatremia can cause cerebral edema, which can lead to encephalopathy and seizures. Because of a cerebral adaptation, the degree of cerebral edema is less with chronic hyponatremia, and most patients seem to be asymptomatic. (See "Manifestations of hyponatremia and hypernatremia").

Oxcarbazepine-related hyponatremia tends to be mild, asymptomatic, and reversible [48,53], and overall tolerability of oxcarbazepine appears to be better than that of carbamazepine. There is no need to measure the serum sodium concentration at baseline or during oxcarbazepine or carbamazepine therapy unless the patient has some other predisposing factor such as renal failure or a central nervous system lesion that itself causes the syndrome of inappropriate ADH secretion, or the patient has suggestive symptoms [53]. (See "Causes of hyponatremia").

Cessation of oxcarbazepine therapy because of hyponatremia is uncommon, being required in only 1 percent of patients in a postmarketing study. For patients with mild to moderate asymptomatic hyponatremia, the oxcarbazepine can be continued and, if deemed necessary, water restriction and a high salt intake can be initiated in an attempt to raise the serum sodium concentration. (See "Treatment of hyponatremia: SIADH and reset osmostat").

Zonisamide — Zonisamide is a sulfonamide derivative that is chemically and structurally unrelated to other anticonvulsants [56]. Its primary mechanism of action appears to be related to blockage of voltage dependent sodium and T-type calcium channels (show table 1) [57].

Zonisamide is a broad spectrum agent that has been proven effective in randomized, controlled trials as add-on therapy for both partial and generalized seizures (show table 1) [26,27,58-60]. Zonisamide also appears to be effective for myoclonic epilepsy [61,62]. The recommended initial daily dose is 100 to 200 mg per day in two divided doses. Because of its long half-life, once a day dosing is often effective. The dose is increased at two week intervals to a target maintenance dose of 400 to 600 mg per day, although higher doses may be necessary in some patients.

The most commonly reported side effects of zonisamide are somnolence, ataxia, anorexia, confusion, abnormal thinking, nervousness, fatigue, and dizziness (show table 4A-4B) [58,59]. Most of these are self-limited, and the likelihood of adverse effects can be reduced by gradually titrating the dose over 4 to 8 weeks [63].

Zonisamide is a weak carbonic anhydrase inhibitor. Nephrolithiasis was reported in 3.7 percent of patients in an early clinical trial [64], but later studies found a much lower risk [3]. (See "Nephrolithiasis in renal tubular acidosis", section on Carbonic anhydrase inhibitors).

DRUGS THAT AFFECT CALCIUM CURRENTS — There are three types of calcium channels in neurons, each of which is distinguished by its rate of reactivation and voltage dependency. Low-threshold T-type calcium currents inactivate quickly and have been described in experimental preparations of thalamic relay neurons. These neurons probably are an integral component of the thalamocortical circuits associated with absence seizures, a subtype of generalized seizures associated with brief episodes of staring and a characteristic 3-per-second spike and wave pattern on the electroencephalogram (EEG) [65].

Ethosuximide — Ethosuximide is effective for the treatment of absence seizures; it has no activity against generalized tonic-clonic or partial seizures (show table 1). Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized (show table 1) [66]. The metabolite of trimethadione, another AED for absence seizures, acts similarly.

The recommended dose of ethosuximide is 20 to 40 mg/day in one to three divided doses. Blood levels should be checked initially after one to three weeks, with a goal therapeutic concentration of 40 to 100 mcg/mL. There are no significant reactions reported with other drugs. The major side effects include nausea, vomiting, sleep disturbance, drowsiness, and hyperactivity (show table 4A-4B).

DRUGS THAT AFFECT GABA METABOLISM — Gamma-aminobutyric acid (GABA) is a neurotransmitter that is widely distributed throughout the central nervous system and exerts postsynaptic inhibition. The GABA(A) receptor complex has binding sites for GABA, benzodiazepines, and phenobarbital. Picrotoxin and other similar proconvulsants bind to the GABA(A) receptor and block chloride channels, thereby preventing postsynaptic inhibition. Thus, reduced GABAergic tone is viewed as epileptogenic, while increasing GABAergic tone generally has an anticonvulsant effect [67-69].

Synthesis of GABA is dependent upon the enzyme glutamic acid decarboxylase (GAD), which requires pyridoxine as a coenzyme. Pyridoxine deficient infants lack the capacity to synthesize GABA normally and are prone to seizures. The metabolism of GABA to succinate occurs in presynaptic neurons and glia by means of the mitochondrial enzyme GABA transaminase (GABA-T).

Over the past two decades, AEDs have been designed to increase the supply of GABA by lowering GABA metabolism by GABA-T, reducing the reuptake of GABA into neurons and glia, or increasing the production of GABA by GAD. Other AEDs have been designed to imitate the action of GABA, while still others improve endogenous GABA-mediated inhibition (show table 1).

Phenobarbital — Phenobarbital is among the oldest AEDs still in use. It is effective for the treatment of generalized and partial seizures (show table 1). However, its clinical utility is limited by its sedating effect (show table 4A-4B).

Phenobarbital binds to the GABA(A) receptor, improving the effect of GABA by extending GABA-mediated chloride channel openings [70]. This process permits an increasing flow of chloride ions across the membrane, causing neuronal hyperpolarization (eg, membrane inhibition to depolarization). Benzodiazepines also bind to the GABA(A) receptor and facilitate the attachment of GABA to its binding site on the receptor. The inhibitory action of endogenous GABA is magnified because benzodiazepines increase the occurrence of chloride channel openings.

The oral dose of phenobarbital is 1 to 5 mg/kg per day; it may also be administered intravenously. Serum phenobarbital concentrations should be checked three to four weeks after the initial dose, with a goal therapeutic level of 10 to 40 mcg/mL. A number of drugs can influence the serum concentration of phenobarbital (show table 2 and show table 3).

Tiagabine — Tiagabine is a second generation AED that is indicated as adjunctive treatment for partial seizures (show table 1) [26,27,71]. It is a potent enhancer of GABA action via specific inhibition of GABA reuptake into presynaptic neurons and glia in vitro (show table 1) [72]. Thus it decreases the elimination of GABA from the synaptic space, making endogenously produced GABA more available for post-synaptic inhibitory effects.

The initial dose of tiagabine is 4 to 8 mg/day. It can be titrated in adults at weekly increments of 4 to 8 mg/day until there is a clinical response, or up to 56 mg/day in divided doses. There are no established therapeutic serum levels. Tiagabine has no significant drug interactions. Major side effects include dizziness, lack of energy, somnolence, nausea, nervousness, tremor, difficulty concentrating, and abdominal pain (show table 4A-4B).

There is concern that tiagabine has a potential proconvulsive effect. In February 2005, the FDA added a warning label regarding more than 30 reports of seizures, including seven cases of status epilepticus, which were associated with off-label use of tiagabine for patients without epilepsy [73,74]. This issue is not resolved. Tiagabine has been associated with nonconvulsive status epilepticus in patients being treated for localization-related epilepsy in a number of case reports, but this was not observed in randomized, controlled clinical trials or in long-term safety studies [75]. In a retrospective review of patients with localization-related epilepsy, 7.8 percent of 90 tiagabine-treated patients developed nonconvulsive status epilepticus compared with 2.7 percent of the 1165 patients not receiving tiagabine [76]. The frequency of generalized convulsive status epilepticus was not increased. The apparent discrepancy between the risk in seizure and nonseizure patients may be explainable [77]:

Tiagabine was developed and is approved for use as an adjunctive treatment for epilepsy. Virtually all patients treated with tiagabine in clinical trials were taking at least one hepatic-enzyme inducing AED, which decreased the concentration of tiagabine; it is likely that patients without epilepsy have increased concentrations of tiagabine.

Another potential contributor is the fact that patients taking tiagabine for off-label indications (psychiatric disease and pain) are also on other medications that potentially lower seizure threshold.

Vigabatrin — Vigabatrin is an irreversible inhibitor of GABA-transaminase that raises the concentration of GABA in the central nervous system [78]. It is effective as an add-on agent in patients with refractory partial seizures [59,79]. It is also useful as monotherapy [80], although probably less effective that carbamazepine for this purpose [81,82].

Vigabatrin is not available in the United States. It is licensed in Canada and in many countries of Europe and Asia.

As many as 30 to 50 percent of patients with long-term exposure to vigabatrin have developed irreversible concentric visual field loss of varying severity that is often asymptomatic [83-87]. In one cohort,this adverse effect was not related to daily dose, duration of exposure, or cumulative dose of vigabatrin [88]. Vigabatrin treatment in laboratory rats is associated with irreversible injury of cone photoreceptors [89]. These findings indicate that vigabatrin should be reserved for patients with partial epilepsy that is refractory to other drugs. Visual field testing should be performed before starting therapy and repeated every six months [90].

Other frequent adverse events with vigabatrin include drowsiness, fatigue, headache, and dizziness [81]. Depression and weight gain also have been reported.

Benzodiazepines — Benzodiazepines enhance GABA inhibition by increasing the frequency of GABA-mediated chloride channel openings. Clonazepam is most often used as an adjunctive therapy for myoclonic and atonic seizures. Clorazepate, diazepam, and lorazepam are effective for those seizure types as well as for partial and generalized tonic-clonic seizures.

The starting dose of clonazepam in adults is 0.5 to 1.0 mg/day with weekly increments of 0.5 to 1.0 mg/day as needed. Lorazepam and diazepam (especially rectal diazepam) are usually used as PRN medications for acute repetitive seizures or status epilepticus.

As a class, the benzodiazepines may be associated with the development of tolerance, limiting their usefulness in the chronic treatment of epilepsy [91]. Side effects include sedation, irritability, ataxia, and depression. Sudden discontinuation of benzodiazepines may lead to withdrawal seizures.

DRUGS WITH MULTIPLE MECHANISMS OF ACTION — A number of antiepileptic drugs (AEDs) have multiple mechanisms by which they prevent seizures.

Valproate — Valproate (valproic acid) is a broad-spectrum AED used alone and in combination for the treatment of generalized and partial seizures (show table 1). It has multiple cellular mechanisms of action consistent with its broad clinical effectiveness [92-94]. Valproate seems to suppress high frequency, repetitive neuronal firing by blocking voltage-dependent sodium channels, but at sites different than carbamazepine and phenytoin.

Valproate increases brain gamma-aminobutyric acid (GABA) concentrations at clinically relevant doses, although the basis of this effect is debated. Valproate does not seem to have any direct effects on the GABA-alpha receptor, but GABA release may be enhanced by a presynaptic effect of valproate on GABA-beta receptors. Inhibition of nerve terminal GABA transaminase (GABA-T) probably also increases presynaptic GABA levels. Furthermore, valproate may increase GABA synthesis by activating glutamic acid decarboxylase (GAD). Finally, valproate acts against T-type calcium currents, although this action is weaker than that observed with ethosuximide.

Valproate is tightly protein-bound. It is metabolized in the liver by means of several processes involving oxidation and conjugation. The initial dose is 15 mg/kg per day in three divided doses; it may be increased by 5 to 10 mg/kg per day every week as needed. A serum level should be checked one to two weeks after the initial dose; therapeutic concentrations are usually in the 50 to 150 mcg/mL range. A number of drugs affect the serum level of valproate (show table 2 and show table 3).

Valproic acid is available in several formulations, listed here with the corresponding US brand name:

Valproic acid capsule, as Depakene

Valproic acid syrup, as Depakene

Divalproex sodium capsule sprinkles, as Depakote Sprinkle

Delayed release divalproex sodium tablet, as Depakote

Extended release divalproex sodium tablet, as Depakote ER

Valproate sodium injection solution, as Depacon

Valproate can be delivered by both oral and intravenous (IV) routes. Current prescribing information recommends slow administration of IV valproate (Depacon) over 60 minutes at a rate of 20 mg/minute, or more rapid infusion of single doses up to 15 mg/kg over 5 to 10 minutes at 1.5 to 3 mg/kg per minute. Accumulating evidence suggests that IV valproate can be safely infused at rates up to 6 mg/kg per minute in adults without adverse effects on blood pressure or heart rate [95-98]. Rapid IV loading may be desirable as a way to achieve serum concentrations >100 mcg/mL quickly.

Side effects of valproate include weight gain and obesity [99], nausea, vomiting, hair loss, easy bruising, and tremor (show table 4A-4B). In the United States between 1978 and 1998, there were 37 fatalities due to hepatic failure attributed to valproate use. Among those receiving monotherapy, the calculated rate of fatality was 1 per 37,000 [100]. The rate was much higher for children under the age of two years and for children receiving polytherapy. There were no liver-related fatalities reported in patients over the age of 10 years who were receiving monotherapy. Liver function tests should be periodically monitored in patients on valproate.

Valproate-related hyperammonemic encephalopathy (VHE) causes lethargy, increased seizures, and rarely coma and death. VHE can occur without abnormalities of liver function tests or elevated serum valproate levels. (See "Valproic acid intoxication", section on VHE).

Felbamate — The mechanism of action of felbamate is not well understood. It blocks the channel at the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor and augments GABA function in rat hippocampal neuronal cultures [101]. It is almost totally absorbed by the gastrointestinal tract, approximately 30 percent bound to plasma protein, and metabolized by the hepatic cytochrome P-450 system.

Felbamate can be used to treat partial seizures; Felbamate can also be used to treat the Lennox-Gastaut syndrome, a mixed seizure disorder of childhood onset associated with multiple seizure types, slow spike-wave electroencephalograms, mental retardation, and resistance to standard AEDs [102,103]. However, felbamate has been associated with fatal aplastic anemia and hepatic failure (show table 4A-4B). Aplastic anemia may not occur for several months after the start of therapy, may not be reliably detected by routine testing, and may continue to be a risk for patients even after cessation of the drug. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis").

Therapeutic blood levels of felbamate have not been established, but patients should have baseline laboratory testing including a complete blood count and liver enzymes. These tests should continue to be monitored every one to two months, and monitoring of the blood counts should continue following cessation of therapy.

Felbamate is not recommended for first-line therapy of seizures because of the potential for serious adverse reactions; use of this drug is mostly confined to cases of Lennox-Gastaut syndrome [104]. The manufacturer recommends that written consent be obtained prior to beginning therapy.

Topiramate — Topiramate also has multiple mechanisms of action. It blocks voltage-dependent sodium channels, enhances the activity of GABA at a nonbenzodiazepine site on GABA(A) receptors, and antagonizes an NMDA–glutamate receptor. It also weakly inhibits carbonic anhydrase in the central nervous system [105].

Topiramate is effective as adjunctive therapy for the treatment of adults and children with partial seizures, and may have efficacy for other seizure types (show table 1) [26,27,106,107].

AAN guidelines state that topiramate may be used as initial therapy for newly diagnosed partial and mixed seizure disorders [27]; the guidelines also state that topiramate may be used as monotherapy for refractory generalized tonic-clonic convulsions and partial seizures in adults and children [106]. However, topiramate is not approved by the US Food and Drug administration (FDA) for initial therapy or monotherapy; it is approved for adjunct therapy of partial and primary generalized tonic-clonic seizures.

The starting dose of topiramate is 50 mg/day for one week, titrated at weekly increments of 50 mg to an effective dose. The recommended total daily dose for adjunctive therapy is 200 mg twice daily. Therapeutic levels have not been established. Topiramate's clearance is increased twofold by enzyme-inducing agents (eg, phenytoin, carbamazepine), requiring twofold increased dosages in this setting. Topiramate may increase phenytoin concentration, but there do not appear to be any clinically significant interactions with valproate (show table 3).

Weight loss is a common dose-related side effect. In a double-blind placebo-controlled trial of topiramate added to existing AEDs in 264 patients, topiramate was associated with a 2.0 kg mean decrease in weight at three months [108]. A smaller, uncontrolled trial found that at one year weight loss occurred in 86 percent with a mean cumulative weight loss of 5.9 kg [109]. Weight loss is associated with fat loss and correlates with reduced caloric intake.

Impaired cognition is a reported side effect in a minority of patients taking topiramate, but it is a common reason for discontinuation of therapy [108]. Studies suggest that this may be a more common phenomenon than patient complaints would suggest:

In a small, randomized controlled trial of healthy adult volunteers, topiramate monotherapy (target dose 400 mg/day) was associated with significantly impaired test performance on a variety of cognitive measures, including language, compared with baseline [110].

A similar trial in healthy adults showed that the cognitive impairments in topiramate are broad in spectrum [111]. Patients on topiramate scored worse on 38 out of 41 cognitive variables compared with nondrug controls, and all subjects taking topiramate suffered impairment of more than one standard deviation on more than 25 percent of the cognitive variables measured.

In a double-blind, randomized cross-over study comparing topiramate and lamotrigine in 29 healthy adults, topiramate but not lamotrigine was associated with slowed responses and errors on tasks of working memory [112].

Other side effects of topiramate include paresthesias, headache, fatigue, dizziness, depression, and mood problems (show table 4A-4B). The incidence of most side effects decrease with continued dosing; weight loss and paresthesia are the exceptions [108]. Despite reports of a high frequency of somnolence when topiramate was used as add-on therapy in patients with epilepsy [113], monotherapy with topiramate 200 mg/day does not appear to impair daytime vigilance in adult patients [114].

Topiramate has been associated with decreased sweating leading to heat intolerance and hyperthermia, particularly in children; there have also been case reports of decreased sweating in adults [115]. Acute myopia and secondary angle glaucoma, characterized by the acute onset of decreased visual acuity and/or ocular pain, also have been reported with topiramate therapy (23 cases out of approximately 825,000 users), typically within one month of initiating treatment [116].

Metabolic acidosis may result from renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase, which can cause both proximal and distal acidification defects. The following observations have been made [117,118]:

Metabolic acidosis is common, occurring in 32 to 44 percent of adults and 67 percent of children.

It is dose-related and usually mild with an average decrease in serum bicarbonate of 4 meq/L at daily doses of topiramate 400 mg in adults and 6 mg/kg per day in children. However, reductions in serum bicarbonate of as much as 10 meq/L have been described.

It is most likely to occur early in treatment.

The main clinical manifestation of metabolic acidosis is tachypnea, although calcium phosphate nephrolithiasis can occur [119], presumably via a mechanism similar to that seen with other carbonic anhydrase inhibitors such as acetazolamide [120,121] and perhaps zonisamide [3]. It is not known if the risk of nephrolithiasis is increased when two carbonic anhydrase inhibitors are used concurrently. (See "Nephrolithiasis in renal tubular acidosis", section on Carbonic anhydrase inhibitors).

Measuring serum bicarbonate at baseline and periodically (for example, every two to four months) is recommended. Gradual dose reduction or cessation of topiramate (after tapering) is advised if significant metabolic acidosis develops. Alkali treatment may be helpful if topiramate is continued in patients with symptoms or more marked acidosis [117]. (See "Treatment of type 1 and type 2 renal tubular acidosis").

Pregabalin — Pregabalin has multiple mechanisms of action. It binds to the alpha2-delta subunit of voltage-gated calcium channels and modulates calcium currents [122,123]. Pregabalin also modulates the release of several neurotransmitters including glutamate, noradrenaline, and substance P. The net result of pregabalin's action appears to be inhibition of neuronal excitability [124].

Pregabalin was approved by the European Medicines Agency (EMEA) in July 2004 as adjunctive therapy for partial seizures and for the treatment of peripheral neuropathic pain. Pregabalin has also received FDA approval for the adjunctive treatment of partial seizures in adults. and for neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia [125].

Pregabalin is chemically related to gabapentin [126]. It is renally excreted virtually unchanged, and it is not hepatically metabolized [124,127]. Pregabalin does not induce or inhibit the cytochrome P450 system. In addition, it does not bind to plasma proteins. Thus, pregabalin does not have significant interactions with other AEDs and is not expected to have pharmacokinetic interactions with other drugs [128].

Pregabalin exhibits linear pharmacokinetics, has a time to maximal plasma drug concentration (Tmax) of about one hour and a plasma half-life (T1/2) of about six hours [127]. Experimental data suggest that the pharmacodynamic half-life (ie, anticonvulsant effect) of pregabalin is longer than the six-hour pharmacokinetic half-life [129]. The Tmax may be delayed to about three hours if the drug is taken with food, but total absorption is not affected by food. Steady state is achieved within 24 to 48 hours.

Pregabalin is effective for the adjunctive treatment of partial seizures as demonstrated in randomized controlled trials [130,131]. In a study that tested pregabalin at the highest anticipated total daily dose of 600 mg, 313 patients with medically refractory partial seizures were randomly assigned to 12 weeks of treatment with pregabalin (either 300 mg twice daily or 200 mg three times daily) or placebo [131]. Both pregabalin regimens were significantly more effective in reducing the frequency of partial-onset seizures than placebo (43 and 53 percent reductions versus a 1 percent increase).

The starting dose of pregabalin for the treatment of partial seizures is 150 mg daily given with or without food in either two or three divided doses [132]. Pregabalin may be increased to a daily dose of 300 mg after one week and to a maximum daily dose of 600 mg after an additional week, based on patient response and tolerability.

The most common side effects with pregabalin in the studies cited above were dizziness, somnolence, and ataxia (show table 4A-4B) [130,131]. Other side effects include weight gain, peripheral edema, blurred or double vision, asthenia, and abnormal thinking (most often impaired concentration). Pregabalin may also cause euphoria and is classified as a schedule V controlled substance. New onset myoclonus has been reported in patients taking pregabalin for epilepsy [133].

DRUGS WITH UNKNOWN MECHANISM OF ACTION — The precise mechanism of action for gabapentin and levetiracetam is unknown.

Gabapentin — Gabapentin was designed to cross the blood-brain barrier and mimic the physiologic effects of GABA, but it binds to a previously unknown receptor rather than to any of the known GABA receptors.

Gabapentin is used as add-on therapy for refractory partial seizures (show table 1) [27]. The AAN guidelines state that gabapentin may also be used as initial monotherapy in newly diagnosed partial epilepsy [26], although it is not approved by the US Food and Drug administration (FDA) for this indication.

Gabapentin is absorbed by means of amino acid transport systems in the gut [134]. The drug does not bind to plasma protein and is not metabolized; it is excreted entirely in the urine, corresponding with the creatinine clearance [135].

The initial dose of gabapentin is 300 mg the first day, 300 mg twice daily the second day, 300 mg three times a day on the third day, and then increased as needed to 1800 mg/day in three divided doses. A rapid initiation schedule, with a starting dose of 900 mg/day, also appears to be well tolerated [136]. There are no established therapeutic serum levels.

A major advantage of gabapentin is that it has no significant drug interactions, making it ideal for use in combination with other AEDs. However, it should be taken at least two hours after the use of antacids since concurrent administration decreases the bioavailability of gabapentin. The major side effect is sedation (show table 4A-4B); it appears to have fewer adverse cognitive effects than carbamazepine [137]. Gabapentin has not been approved in the United States for use in children.

In studies of six women taking gabapentin during pregnancy, there was evidence of active transplacental transport and accumulation of the drug in the fetus [138]. Gabapentin is also transferred to breast milk. In this limited series, no adverse consequences of gabapentin on the newborn were seen.

Levetiracetam — Levetiracetam (LEV) is a broad spectrum AED that has been found effective and is approved for use as add-on therapy for adults with refractory partial seizures (show table 1) [26,27,139,140]. It also appears to be effective as monotherapy in patients with partial seizures [141], and as add-on therapy for patients with generalized seizures [142]. The mechanism of action for levetiracetam is unknown.

Levetiracetam is an attractive AED for several reasons [56]:

Metabolism is independent of the cytochrome P450 (CYP) system, so that the elimination half-life of levetiracetam is unaffected by concomitant metabolism of other anticonvulsants.

Levetiracetam does not act as an inducer of the CYP system; thus, there is little potential for pharmacokinetic interactions with other drugs, such as oral contraceptives, or immunosuppressant drugs commonly used in organ transplantation [143].

Levetiracetam does not require a titration period, and it appears to have a very rapid onset of action as demonstrated by a significant increase in the proportion of patients who achieved seizure-free status on the first day of LEV 500 mg twice daily treatment compared with placebo [144].

The drug is relatively well tolerated. The most common adverse events include fatigue, somnolence, dizziness, and infection (upper respiratory). Most of these are mild to moderate in intensity and most often occur during the initial titration phase (show table 4A-4B).

In a postmarketing surveillance study of 373 patients at a single epilepsy center, both the efficacy of levetiracetam and cumulative probability of 74 percent for remaining on levetiracetam at 12 months compared favorably with published data for vigabatrin, lamotrigine, and topiramate [145]. This was corroborated in a larger, multicenter study in which a 58 percent three-year retention rate was estimated [146]. Sedation was the most common side effect of levetiracetam, occurring in 38 patients (10.7 percent), but mood disturbance was not rare (17 patients or 4.8 percent), and was more likely to lead to discontinuation [145]. Psychiatric adverse effects led to discontinuation in an additional nine patients (2.5 percent), including behavioral disturbance in eight and psychosis in one.

Treatment of levetiracetam is initiated at 500 mg twice daily. It is titrated by 1000 mg every two weeks, as needed for seizure control, to a maximum dose of 4000 mg daily.

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86.

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