14 Convulsive and Nonconvulsive Status Epilepticus

Status epilepticus (SE) has been defined as continuous or repetitive seizure activity without full or complete recovery of consciousness between attacks. For epidemiological and research purposes, this has usually meant seizures that last at least 30 minutes. However, as SE became recognized as a medical emergency because of its potential for causing systemic and neuronal injury, a more practical, clinically oriented definition became necessary.1 More recently, authors have suggested that seizures lasting more than 5 to 10 minutes should be considered SE because very few single seizures persist this long. For practical purposes, SE should be diagnosed if a seizure persists for more than 5 minutes; if two or more seizures occur without recovery of consciousness in between; or in any patient who is still seizing when brought to the emergency room.

Classification

There are as many types of SE as there are different types of seizures. Operationally, SE is most usefully considered to be either convulsive (CSE) or nonconvulsive (NCSE), based primarily on the presence or absence of observable muscle jerking. Further classification of NCSE is of limited value, and in any event there is no consensus. Many authors subdivide both CSE and NCSE into generalized or partial (localized) onset based on the presence of historical, clinical, or imaging evidence of focal brain lesions. In practice, however, it is often not possible to differentiate between the two, even with electroencephalographic (EEG) monitoring. NCSE of generalized onset has also been termed absence status or spike-wave stupor, and NCSE of partial onset, with or without bilateral spread, is referred to as complex partial SE.

Epidemiology

Convulsive Status Epilepticus

CSE occurs 50,000 to 250,000 times per year in the United States. It is most common in infants, young children, and the elderly.^2,3 More than half the patients who present with SE have never had a previous seizure. Approximately 15% of patients newly diagnosed with epilepsy have SE as their first seizure episode. About 0.5% to 1.0% of patients with epilepsy will experience SE each year, and 10% to 20% of patients with epilepsy will experience SE at least once in their lifetime.^2,4 SE is most likely to occur in those with remote symptomatic epilepsy and in children with static or progressive encephalopathies.

Nonconvulsive Status Epilepticus

Although previously thought to be rare, nonconvulsive seizures (NCSzs) and NCSE are recognized with increasing frequency, especially with the advent of continuous EEG (CEEG) monitoring in intensive care units (ICUs). In critically ill patients, the great majority of seizures are nonconvulsive and can only be recognized with EEG monitoring.⁵ NCSE has been found in 25% to 35% of patients undergoing continuous EEG monitoring in neurological/neurosurgical ICUs.^6,7 In a study of 63 patients with nontraumatic intracerebral hemorrhage, 28% had seizures, most of which were nonconvulsive; half of these qualified as NCSE.⁸ Seizures correlated with increased mass effect and shift on computed tomographic (CT) scans, even after controlling for hemorrhage size, and a trend toward worse prognosis. Although seizures were most common in patients with lobar hemorrhages (34%), seizures also occurred with deep subcortical hemorrhages (21%). NCSzs and NCSE are also seen in patients with traumatic brain injury, subarachnoid hemorrhage, brain tumors, and following CSE. After seemingly successful treatment of CSE, 20% of patients will still have ictal discharges on EEG.⁹

Without EEG monitoring, the full spectrum of seizure activity cannot be appreciated. The possibility of NCSzs should be considered in any neurosurgical patient with impaired mental status. As a result, prolonged EEG monitoring is useful in any patient with unexplained impairment of mental status, fluctuating mental status, slow awakening after CSE, or prolonged alteration in consciousness following an uncomplicated neurosurgical procedure. Routine EEGs, which are typically recorded for 30 to 60 minutes, are inadequate for this purpose because they will detect seizures in only about half the patients who are found to have NCSzs on continuous EEG monitoring.^5,7 For noncomatose patients, a 24-hour EEG will detect >90% of subclinical seizures, but 48 hours or more are sometimes needed in comatose patients.⁵

Compiled from Hauser WA. Status epilepticus: epidemiologic considerations. Neurology 1990;40(5, Suppl 2:9–13; DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol 1995;12:316-325; Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43(3 Pt 1):483-488; Claassen J, Lokin JK, Fitzsimmons BF, Mendelsohn FA, Mayer SA. Predictors of functional disability and mortality after status epilepticus. Neurology 2002;58:139-142.
* Some of these can cause status epilepticus on their own, but all have the potential to exacerbate seizures and subsequent neuronal injury.
†Treat with pyridoxine (vitamin B6).

Etiologies for SE are listed in Table 14-1A,B. In at least half of patients, an acute cause can be identified (e.g., brain tumor, head trauma, stroke). When metabolic abnormalities are the presumed cause, correcting them is more effective in controlling seizures than routine use of antiepileptic drugs.

Dangers of Status Epilepticus

There can no longer be any question that SE carries a significant risk of permanent brain damage.^10–12 Data from both animals and humans have shown convincingly that prolonged seizures can cause permanent neuronal injury. With ongoing seizure activity, physiological demands surpass the capabilities of cerebral compensatory mechanisms, resulting in hypoxia, cellular metabolic failure, and cell death.^13–16 Loss of cerebral autoregulation further amplifies these effects. There is excessive autonomic stimulation, and cardiorespiratory functions progressively fail.

There are several pathophysiological mechanisms that lead to neuronal injury and cell death in SE. Most important are increased neuronal metabolic demand and excitatory neurotransmitter toxicity caused by NMDA- and non-NMDA glutamate receptor-mediated calcium entry. Neuronal damage is further aggravated by adverse systemic factors, especially hypoxia, hypotension, fever, hypo- and hyperglycemia, and other metabolic abnormalities. Although neuronal injury can be clearly demonstrated after 60 minutes of SE, it probably occurs much earlier in the presence of these ubiquitous exacerbating factors. Other systemic consequences of SE are listed in Table 14-2.

Evidence that seizures, including those that are nonconvulsive, cause clinically relevant neuronal injury include the following: (1) SE after stroke is associated with higher mortality, independent of stroke size and location¹⁵; (2) In NCSE, seizure duration and delay to diagnosis are independent predictors of outcome after controlling for etiology¹⁷; (3) There are multiple case reports of prolonged NCSE alone causing permanent neurological deficits, including cognitive abnormalities, memory loss, and motor and sensory dysfunction¹⁸; (4) Neuron-specific enolase (NSE), a marker of neuronal injury, is highest in patients with acute brain injury plus seizures, and seizures alone (without any other cause for acute brain injury) result in increased NSE levels¹⁹; (5) In patients with intracerebral hemorrhage, NCSzs are associated with greater mass effect and midline shift.⁸

Recognizing Nonconvulsive Status Epilepticus

NCSE can present in many ways (Table 14-3), including coma or lack of awakening after surgery or following treatment of CSE. As with CSE, it is important to make the diagnosis quickly because nearly all forms of SE become increasingly refractory to treatment the longer they continue, and the likelihood of a good outcome is inversely related to duration of seizure activity.

Hormigo et al²⁰ recently reported eight patients with cancer and NCSE. They found that NCSE itself, in the absence of brain or meningeal metastases, can cause reversible enhancing cortical abnormalities on magnetic resonance imaging (MRI). Other reports have emphasized that seizures/NCSE can cause focal areas of bright signal on MRI diffusion-weighted imaging (DWI) that mimic infarcts.^21,22

Source: Data partly extracted and expanded from Kaplan PW. Nonconvulsive status epilepticus in the emergency room. Epilepsia 1996;37:643–650.
*Alphabetical and not all inclusive.
Bolded items are the most common (but nonspecific) clinical findings in intensive care unit patients with nonconvulsive status epilepticus.

Table 14-4 presents a sample treatment protocols for SE in adults.

General Principles

Rapid treatment is of paramount importance in the treatment of SE; therapeutic interventions are most effective when initiated early. Controlled animal experiments have demonstrated that the efficacy of benzodiazepines, phenytoin, and barbiturates decreases significantly with increasing seizure duration.^23,24 In humans, first-line medications control SE in 80% of patients when initiated within 30 minutes, but only in 40% if started 2 hours after onset.^25,26 For practical purposes, treatment should be started after 5 minutes of continuous seizure activity.

Patients should not be pharmacologically paralyzed unless the EEG is being recorded continuously. Fever, hypotension, hypoxia, hypo- and hyperglycemia, and other metabolic abnormalities must be treated simultaneously.

When intravenous (IV) access is not available immediately, rectal diazepam or nasal, buccal, or intramuscular (IM) midazolam should be administered; the IV preparations can be given by these routes if site-specific formulations are not available. All of these options have been shown to be effective in controlling seizures rapidly. For example, in a randomized study of prolonged febrile seizures, intranasal midazolam terminated seizures more quickly than IV diazepam (6 vs 8 minutes with nonoverlapping confidence intervals), probably due to more rapid administration.²⁷ Therefore, whenever obtaining IV access would delay AED administration, diazepam should be given rectally (0.2 to 0.5 mg/kg for SE; usually 20 mg for an adult), or midazolam should be given nasally, buccally, or IM (0.2 to 0.3 mg/kg; usually 10 mg for an adult).

ABG, arterial blood gas; AED, antiepileptic drug; CIV, continuous intravenous; ABC’s, stabilize airway, breathing, and circulation; ASAP, as soon as possible; CBC, complete blood count; D50, 50% dextrose; EEG, electroencephalogram; EKG, electrocardiographic; IM, intramuscular; IV, intravenous; LFTs, liver function tests; PR, per diem.
* The IV solution of diazepam can be given rectally if Diastat (Valeant Pharmaceuticals International, Aliso Viejo, CA) rectal valium gel is not available; the IV solution of midazolam can be given by any of these routes.

If a patient stops seizing clinically but does not wake up promptly, there is a high probability of ongoing subclinical seizures or continuing electrographic SE. DeLorenzo et al found subclinical electrographic seizure activity in 48% of patients after control of CSE, including 14% in NCSE.28 In the Veterans Affairs (VA) Status Epilepticus Cooperative study, 20% of CSE patients whose clinical seizures stopped after treatment were still seizing on EEG.⁹

Randomized Controlled Trials

Only a few prospective randomized trials have been conducted comparing treatment strategies for SE. The most important of these is the VA Status Epilepticus Cooperative study⁹ that compared lorazepam alone to diazepam plus phenytoin, phenobarbital alone, and phenytoin alone (all IV). Lorazepam was most effective (65%, vs 58% for phenobarbital, 56% for diazepam plus phenytoin, and 44% for phenytoin alone). Complications were equivalent across groups. There have not been any randomized controlled trials for second-line therapy or for SE refractory to first- and second-line treatments.

Treatment Steps (see Table 14-4)

Based on findings of the VA study, most epileptologists today use IV lorazepam (0.1 mg/kg) as the drug of first choice. Although second-line options have not been evaluated prospectively, phenytoin or fosphenytoin is usually recommended. Once patients fail to respond to two AEDs, seizure activity is often very difficult to control. Of the 38% of patients in the VA Cooperative study with “overt” SE and the 82% of patients with “subtle” SE that continued to seize after receiving two AEDs, seizures were controlled by a third agent in only 2% and 5% of cases. Even more disappointing was the finding that once lorazepam failed, very few patients(~5%) responded to phenytoin as a second-line agent. For this reason, some experts advocate moving directly to anesthetic drips after lorazepam has failed.

All medications are administered IV unless otherwise specified (see Table 14-4 for doses).

Noncontinuous Benzodiazepines

Lorazepam: time to stop SE: 3 to 10 minutes; duration of effect: 12 to 24 hours; elimination half-life: 14 hours; duration of sedation: several hours; side effects: occasional respiratory depression. Diazepam: time to stop SE: 1 to 5 minutes; duration of effect: 15 to 30 minutes; elimination half-life: 30 hours; duration of sedation: 15 to 60 minutes; side effects: occasional respiratory depression.

Phenytoin/Fosphenytoin

Fosphenytoin: maximum bolus rate: 150 mg/min (3x the rate of phenytoin). Intramuscular administration is safe and well tolerated with low therapeutic levels reached in 30 minutes, peak levels in 2 hours. This is too slow for CSE. Side effects: hypotension (5 to 15%, rate dependent), rare arrhythmias, rare respiratory depression or decreased consciousness, transient pruritus (in up to 50% of awake patients, but not an allergic reaction; often in the groin; possibly due to phosphate load). Wait 2 hours after a load to check a phenytoin level to allow complete conversion to phenytoin. During and after SE, we recommend that the unbound (free) phenytoin level be maintained at 1.5 to 2.5 μg/mL, which is equivalent to a total phenytoin level of 15 to 25 when protein binding is normal. This is rarely the case, however, in critically ill patients. Unbound phenytoin levels can become very high in patients with low albumin or who are being given other highly protein bound drugs such as benzodiazepines or valproate. High phenytoin levels can impair mental status, occasionally cause myoclonus, and possibly exacerbate seizures.

Intravenous fosphenytoin is preferred to IV phenytoin due to its water solubility and normal pH, which allow more rapid administration with less irritation of veins, no risk of necrosis with extravasation, less hypotension during administration, and compatibility with all IV fluids. It is rapidly dephosphorylated in the bloodstream to phenytoin, with a conversion half-life of 10 to 15 minutes, reaching therapeutic free phenytoin levels slightly faster than with IV phenytoin. Cardiac complications can still occur with fosphenytoin (due to its conversion to phenytoin). Phenytoin is effectively still being loaded for more than 15 minutes after the end of the infusion.

Phenytoin

Do not mix with glucose/dextrose. Do not give in small peripheral veins or IM. Maximum rate: 50 mg/min.

Phenobarbital

Maximum rate: 75 to 100 mg/min. Half-life: 72 hours. Side effects: respiratory depression (need to intubate) and prolonged sedation. Recommended serum levels for SE: 30 to 45 μg/mL initially; may need higher levels.

Refractory Status Epilepticus

Though differing to some degree, most authors define refractory SE as generalized convulsive or nonconvulsive SE that continues clinically or electrographically despite adequate first- and second-line therapy. Failure to treat aggressively early on increases the likelihood of developing refractory SE. When benzodiazepines and phenytoin/ fosphenytoin have failed, traditional treatment algorithms recommend loading with phenobarbital or starting continuous IV pentobarbital. Like others today, however, we usually prefer to go directly to rapid-acting intravenous drips (either midazolam or propofol) once a patient has failed first- and second-line drugs rather than to phenobarbital or pentobarbital. IV valproate may also be useful, especially in cases of NCSE.

Valproate (Intravenous)

Several small case series suggest good efficacy for IV valproate (Depacon, Abbott Laboratories, North Chicago, IL) in the treatment of different types of SE, including partial onset, nonconvulsive, absence, and myoclonic SE^29–33; however, it is not approved by the U.S. Food and Drug Administration (FDA) for use in SE. Loading dose: 20 mg/kg. In the presence of acute illness and enzyme-inducing drugs such as phenytoin, phenobarbital, and carbamazepine, higher doses of 40 to 60 mg/kg are needed. Maximum bolus rate: 5 to 6 mg/ kg/min²⁹ (NB: it is only approved at a bolus rate of up to 3 mg/kg/min for a total loading dose of up to 15 mg/kg). Intravenous valproate is generally well tolerated in critically ill patients.³⁰ There is minimal sedation. It may thus be possible to avoid intubation, and it is particularly useful in patients with refractory SE in whom intubation is to be avoided. Hypotension is rare but has been reported.³⁴ Recommended serum levels for SE: 70 to 140 μg/mL. Valproate is highly protein bound. If it is given concurrently with phenytoin, it is important to follow unbound drug levels, especially of phenytoin, to avoid toxicity.

All AEDs given by continuous IV infusion require CEEG monitoring.

Pentobarbital

Traditionally titrated to suppression-burst on EEG. Halflife: 15 to 60 hours. Side effects: prolonged coma (usually days after infusion stopped), hypotension (pressors are almost always required), myocardial depression, immune suppression, ileus.

Midazolam

Half life: 1.5 to 3.5 hours initially; with prolonged use, there may be tolerance, tachyphylaxis, and significant prolongation of half-life, up to days.35 Time to stop SE: usually well under 1 hour. Duration of effect: minutes to hours. Duration of sedation: minutes to hours (and possibly days if prolonged use). Side effects: occasional hypotension.

Propofol

(Gamma-Aminobutyric Acid A Agonist) Time to stop SE: usually <10 minutes. Duration of sedation: 5 to 10 minutes. Side effects: large lipid load (3000 cal/d) requiring adjustment of caloric intake; occasional pancreatitis; multiorgan failure with refractory acidosis and vascular collapse with prolonged use, probably more common in children³⁶; for this reason, prolonged or high-dose propofol is not recommended for children with SE. A large series of 27 adults with 31 episodes of refractory SE receiving propofol was recently published by Rossetti et al.³⁷ Mortality and morbidity were quite low in this series: only 22% died, and there were no sequelae in two thirds of the episodes in which patients survived. Mean propofol infusion rate was 4.8 mg/kg/hr (range 2.1 to 13; goal was suppression-burst); median duration of treatment was 3 days (range 1 to 9). Patients were maintained on IV clonazepam as well. Based on this study and the anecdotal experience of other centers, we conclude that propofol can be safe and effective when used short term in adults, especially in combination with IV benzodiazepines. However, we suggest avoiding doses of >5 mg/kg/hr for >18 to 24 hours and monitoring pH, CPC, triglycerides and lipase with prolonged use. Patients who may be particularly prone to refractory acidosis are also taking carbonic anhydrase inhibitors.

Use of Adjunctive Medications via Nasogastric Tube

AEDs that are only available in an oral form can be given via nasogastric tube or PEG in SE patients, including levetiracetam, topiramate, gabapentin, oxcarbazepine, and carbamazepine. These medications may be helpful for preventing breakthrough and withdrawal seizures, particularly as AEDs administered by continuous infusion are being tapered. There is preliminary evidence suggesting that topiramate³⁸ and levetiracetam³⁹ may have neuroprotective or antiepileptogenic properties as well.

Outcome and Prognosis

Mortality

Mortality in SE in various series has been 17% to 23%.^40,41 Important predictors of mortality include older age, acute symptomatic etiology, and duration of SE.^{13,17,26,40,41} In a meta-analysis of 1686 episodes of SE, 89% of deaths were attributed to the underlying cause of SE.¹³

Morbidity

Approximately 10% of patients who survive SE are left with disabling neurological deficits.²⁶ In a recent study, functional deterioration was observed in 23% of nonfatal SE episodes.⁴⁰ Predictors of disability were acute symptomatic seizures and length of hospitalization. EEG findings of NCSE, ictal discharges, and periodic discharges have been associated with poor outcome and mortality after GCSE, even after controlling for etiology.^42,43

Nonconvulsive Status Epilepticus

There is conflicting data on the morbidity and mortality associated with NCSE, but prognosis has been poor when NCSE occurs in the setting of acute brain disease such as stroke and metabolic disturbances.^44,47,48 Shneker and Fountain⁴² recently reported outcomes in a series of 100 patients with NCSE. Death occurred in 18%. Worse outcome was associated with an acute symptomatic etiology (27% mortality) and severe mental status impairment (39%). In a study of NCSE in ICU patients, Young et al¹⁷ found that seizure duration was the single major predictor of mortality on multivariate analysis: if duration was <10 hours, 60% returned home and 10% died; if duration was >20 hours, none returned home and 85% died.

Refractory Status Epilepticus

Outcome in refractory SE is extremely poor: mortality is almost 50% and only a minority of patients return to their premorbid functional baseline.^44,47,48 As with SE in general, mortality in refractory SE is associated with older age, etiology (especially poor with anoxic injury and subarachnoid hemorrhage), long seizure duration, and high Acute Physiology and Chronic Health Evaluation-2 (APACHE-2) scale scores.^17,37,45

Conclusion

SE is a neurological emergency. Rapid diagnosis and effective treatment are key to obtaining the best outcomes. Standardizing and distributing written treatment protocols (an example is shown in Table 14-4) facilitate coordinated management and likely improve outcomes. If a patient does not awaken rapidly after CSE, EEG recording is indicated to determine if NCSE is present. The underlying etiology for SE and factors that can exacerbate neuronal injury should be addressed promptly as well, including fever, hypoxia, and metabolic abnormalities.

NCSE is being recognized more commonly, especially in patients with acute brain injuries or procedures. How best to treat NCSzs, including how aggressively, is currently unclear. Technology is now available to study cerebral blood flow, brain tissue oxygen, brain metabolism and energy status, intracranial pressure, EEG, neuronal injury markers, and other parameters in these patients in detail. Research in these areas is progressing rapidly. In combination with research into neuroprotection and antiepileptogenesis, these advances will continue to improve our ability to recognize, treat, and prevent SE more effectively.

1. Lowenstein DH, Bleck T, Macdonald RL. It’s time to revise the definition of status epilepticus. Epilepsia 1999;40:120–122

2. Hauser WA. Status epilepticus: epidemiologic considerations. Neurology 1990;40(5, Suppl 2):9–13

3. DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol 1995;12:316–325

4. Hauser WA. Status epilepticus: frequency, etiology, and neurological sequelae. Adv Neurol 1983;34:3–14

5. Claassen J, Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004;62:1743–1748

6. Jordan KG. Continuous EEG monitoring in the neuroscience intensive care unit and emergency department. J Clin Neurophysiol 1999;16:14–39

7. Pandian JD, Cascino GD, So EL, Manno E, Fulgham JR. Digital video-electroencephalographic monitoring in the neurological-neurosurgical intensive care unit: clinical features and outcome. Arch Neurol 2004;61:1090–1094

8. Vespa PM, O’Phelan K, Shah M, et al. Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome. Neurology 2003;60:1441–1446

9. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–798

10. Delorenzo RJ, Sun DA, Deshpande LS. Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintenance of epilepsy. Pharmacol Ther 2005;105:229–266

11. Fountain NB. Cellular damage and the neuropathology of status epilepticus. In: Drislane F, ed. Status Epilepticus: A Clinical Perspective. Totowa, NJ: Humana Press; 2005:181–193

12. Duncan JS. Seizure-induced neuronal injury: human data. Neurology 2002;59(9, Suppl 5):S15–S20

13. Shorvon S. Prognosis and outcome of status epilepticus. In: Shorvon S, ed. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge: Cambridge University Press; 1999:293–312

14. Wasterlain CG, Fujikawa DG, Penix L, Sankar R. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34(Suppl 1):S37–S53

15. Waterhouse EJ, Vaughan JK, Barnes TY, et al. Synergistic effect of status epilepticus and ischemic brain injury on mortality. Epilepsy Res 1998;29:175–183

16. Shorvon SD. Handbook of Epilepsy Treatment. Oxford; Malden, MA: Blackwell Science; 2000

17. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology 1996;47:83–89

18. Krumholz A, Sung GY, Fisher RS, Barry E, Bergey GK, Grattan LM. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology 1995;45:1499–1504

19. DeGiorgio CM, Correale JD, Gott PS, et al. Serum neuron-specific enolase in human status epilepticus. Neurology 1995;45:1134–1137

20. Hormigo A, Liberato B, Lis E, DeAngelis LM. Nonconvulsive status epilepticus in patients with cancer: imaging abnormalities. Arch Neurol 2004;61:362–365

21. Lansberg MG, O’Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW. MRI abnormalities associated with partial status epilepticus. Neurology 1999;52:1021–1027

22. Kim JA, Chung JI, Yoon PH, et al. Transient MR signal changes in patients with generalized tonicoclonic seizure or status epilepticus: periictal diffusion-weighted imaging. AJNR Am J Neuroradiol 2001;22:1149–1160

23. Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res 1998;814:179–185

24. Mazarati AM, Wasterlain CG. N-methyl-D-aspartate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat. Neurosci Lett 1999;265:187–190

25. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43(3 Pt 1):483–488

26. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998 Apr 2;338:970–976

27. Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ 2000;321:83–86

28. DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39:833–840

29. Limdi NA, Faught E. The safety of rapid valproic acid infusion. Epilepsia 2000;41:1342–1345

30. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000;55:722–724

31. Peters CN, Pohlmann-Eden B. Intravenous valproate as an innovative therapy in seizure emergency eituations including status epilepticus-experience in 102 adult patients. Seizure. 2005;14:164–169

32. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology. 2006 Jul 25;67:340–342

33. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure 2007 Jul 6 (Epub ahead of print)

34. White JR, Santos CS. Intravenous valproate associated with significant hypotension in the treatment of status epilepticus. J Child Neurol 1999;14:822–823

35. Naritoku DK, Sinha S. Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology 2000;54:1366–1368

36. Hanna JP, Ramundo ML. Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology 1998;50:301–303

37. Rossetti AO, Reichhart MD, Schaller MD, Despland PA, Bogous-slavsky J. Propofol treatment of refractory status epilepticus: a study of 31 episodes. Epilepsia 2004;45:757–763

38. Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res 1999;837:263–269

39. Klitgaard H. Levetiracetam: the preclinical profile of a new class of antiepileptic drugs? Epilepsia 2001;42(Suppl 4):13–18

40. Claassen J, Lokin JK, Fitzsimmons BF, Mendelsohn FA, Mayer SA. Predictors of functional disability and mortality after status epilepticus. Neurology 2002;58:139–142

41. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus. Epilepsia 2001;42:1031–1035

42. Jaitly R, Sgro JA, Towne AR, Ko D, DeLorenzo RJ. Prognostic value of EEG monitoring after status epilepticus: a prospective adult study. J Clin Neurophysiol 1997;14:326–334

43. Vespa PM, Nuwer MR, Nenov V, et al. Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J Neurosurg 1999;91:750–760

44. Claassen J, Hirsch LJ, Emerson RG, Bates JE, Thompson TB, Mayer SA. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001;57:1036–1042

45. Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003;61:1066–1073

46. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146–153

47. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205–210

48. Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34