Status Epilepticus. G. Bryan Young, MD, FRCPC. Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada

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1 1 Status Epilepticus G. Bryan Young, MD, FRCPC Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada Contact information: Dr. G. B. Young, Room B10-106, University Hospital, 339 Windermere Road, London, ON N6A 5A5; phone: (519) ; fax (519) ;

2 2 Objectives: After this session the attendee should: 1. be able to give a classification of status epilepticus. 2. know the definition of refractory status epilepticus and the pathophysiological implications for management. 3. understand the proposed mechanisms for brain damage in convulsive and some types of nonconvulsive status epilepticus. 4. have a clear management plan for status epilepticus.

3 3 Conflict of Interest Statement Dr. Young received a frozen yogurt from a very pleasant woman who worked for a company in a booth in the exhibit hall two years ago, but he cannot recall the company name. He also took a very nice pen (with a highlighter on one end), which he still uses, from one of the booths last year, but again the name of the company cannot be remembered. There are no other potential conflicts of interest.

4 4 In this review, I shall concentrate on the detection and management of status epilepticus. Investigation and management of the underlying cause (etiology) of the seizures as well as general supportive measures are dealt with in more comprehensive reviews (Shorvon et al., 2008; Kahled and Hirsch, 2008). Definition of Status Epilepticus: The original definition of status epilepticus was A condition characterized by an epileptic seizure which is so frequently repeated or so prolonged as to create a fixed and lasting epileptic condition (Gastaut et al. 1962). Although this definition is imprecise, it reveals the concept that the normal turn-off mechanisms of the brain have failed and that the seizures have taken control. The duration criterion was formalized by the International League Against Epilepsy and the Epilepsy Foundation of America (1993), which stipulates duration of at least 30 minutes. This is supported by studies on animals that showed neuronal death occurred after 30 minutes of continuous convulsive seizure activity, even in absence of physiologic compromise (baboons were paralysed and intubated, with glycemia normalized). Also, DeLorenzo and colleagues have shown that to 43% of patients will spontaneously stop seizing between 10 and 29 minutes and only 7% cease if they seize more than 30 minutes. Thus, there is still a solid rationale for considering status epilepticus as requiring 30 minutes. On the other hand a video EEG study of 120 patients with convulsive seizures that only 1 lasted more than 5 minutes. This led to the proposal that for practical purposes seizures lasting more than 5 minutes are unusually long lasting and probably warrant emergency treatment to stop them.

5 5 Imbedded within the definition of status epilepticus is the issue of what is a seizure. Since we cannot tell reliably clinically when nonconvulsive seizures are present, an electrographic definition is necessary. The following table provides useful criteria for seizures on scalp EEGs (Young et al, 1996): Table 1 Primary Criteria for Seizure 1. Repetitive generalized or focal spikes, sharp waves, spike and wave at >3/second 2. Repetitive generalized or focal spikes, sharp waves, spike and wave at <3/second and secondary criterion #4. 3. Sequential rhythmic waves and secondary criteria 1,2 and 3 with or without #4. Secondary Criteria 1. Incrementing onset: increase in voltage and/or increase or slowing in frequency. 2. Decrementing offset: decrease in voltage or frequency. 3. Postdischarge slowing or voltage attenuation. 4. Significant improvement in clinical state or baseline EEG after intravenous drug. Using animal models and human cases, Trieman and colleagues (1990) have defined 5 sequential electrographic stages when status epilepticus persists: Table 2. Stages of Status Epilepticus Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Discrete seizures Merging seizures with waxing and waning amplitudes and frequencies Continuous ictal activity Continuous ictal activity interrupted by flat periods Generalized periodic complexes on a flat

6 6 background Note that with protracted seizures the variation in EEG over time becomes limited, thus one does not see the evolution of phenomena that are described in Table 1 for discrete seizures. Classification of Status Epilepticus: Virtually any seizure type from the ILAE Classification has a status epilepticus component. However, a more practical classification is offered: Table 3. A Classification of Status Epilepticus Generalized Status Epilepticus 1. Tonic clonic status 2. Tonic status (e.g., in Lennox Gastaut) 3. Clonic status (infants and children) 4. Myoclonic status (bilaterally symmetrical jerks, mainly with acute/subacute brain disorders) 5. Absence status: typical and atypical 6. Nonconvulsive generalized status (NCSE) in ICU Partial Status Epilepticus 1. Simple partial (including epilepsia partials continua and secondary generalized) 2. Complex partial (limbic) status epilepticus 3. NCSE with localization related seizures, including transitional forms. Epidemiology of Status Epilepticus:

7 7 The first estimate of status epilepticus was made by Hauser et al. (1990), in Rochester MN based on retrospective data and antedating studies with CEEG monitoring. Their figure of 15/100,000/year is almost certainly an underestimate. DeLorenzo et al. (1996) conducted a prospective study in Richmond, VA that included CEEG monitoring and found 41/100,000/year. There is a marked difference among age groups: elderly>> children> young adults (DeLorenzo et al, 1996). Pathophysiology of Status Epilepticus: The transition from single seizures to status epilepticus is related first to a progressive loss of inhibition. In turn, this relates to a reduction in gamma amino butyric acid-a (GABA-A) receptors on neuronal membrane (Sloviter, 2009). In addition there is an augmentation excitatory activity with an increase in N-methy-D-aspartate (NMDA) receptors (Wasterlain et al., 2009). Thus, there is relatively unchecked excitatory epileptic activity. With increased calcium influx there is the potential for brain damage. In addition, the hippocampal damage can lead to a more persistent epileptic condition, if one was not present beforehand (Sloviter 2009). These facts have implication for management. Management of Status Epilepticus: The desirable results of management are: 1. Stopping the seizure/status; 2. Preventing recurrent seizures in at least the short term; 3. Return to baseline neurologic function. The optimal measures are discussed in turn: 1. Stopping the seizure: At least two randomized controlled studies showed the effectiveness of lorazepam. The San Francisco ambulance study showed that lorazepam (2.0 mg) IV was superior to diazepam or placebo in stopping seizures (Alldredge et al.,

8 8 2001). An in-hospital study revealed that lorazepam was more effective than phenytoin in stopping acute seizures (Trieman et al., 1998). 2. Preventing recurrence of seizures in the short term. Lorazepam s duration of action is brief (probably 45 minutes maximum). To keep the seizure stopped drugs with longer duration of action are used after lorazepam initially arrests the seizure. Most centres use phenytoin (PHT) given in normal saline (PHT precipitates in glucose solutions) at a rate no greater than 50 mg/minute to avoid hypotension. A loading dose of mg/kg provides a serum concentration that is in the therapeutic range of micromols/l for 24 hours. (There is no good evidence that phosphentoin is more effective or safer than regular PHT). Valproate given IV is probably equally effective and less prone to cause cardiovascular side effects. Its loading dose is mg/kg. Other drugs are usually reserved for refractory status epilepticus (see below). 3. Stopping status epilepticus. There is, however, a difference in stopping acute seizures and in stopping status epilepticus, with duration (by definition) of >30 minutes. Prolonged seizures are often refractory to benzodiazepines due to the downregulation of GABA-A receptors (to which the benzodiazepine receptors are linked). Second-line drugs are used both to stop seizures. If phenytoin and/or valproate fail after lorazepam, the patient is considered to have refractory status epilepticus (Mayer et al., 2002). Patients should be intubated and placed on a ventilator in an ICU for management. Propofol and midazolam are the most commonly used agents (Marik and Varon, 2004). Propofol act directly on GABA-A receptors, with some modulation of calcium channels and inhibition of NMDA receptors, while midazolam acts on benzodiazepine receptors. Midazolam has a higher failure rate than propofol (Classen et al., 2001) and propofol is generally preferred,

9 9 although care must be taken to avoid high dose, prolonged infusions. The dreaded syndromic complication (consisting of lactic acidosis, rhabdomyolisis and cardiovascular collapse with hypertriglyceridemia and high serum creatine kinase) occurs more commonly in children and it is best to avoid prolonged propofol infusions in this population. High dose anesthetic barbiturates (thiopental or pentobarbital) are effective and are still used; however, with prolonged use their half-life is very long and they can interfere with ciliary action and predispose to pneumonia. Ketamine has the theoretical advantage of being an NMDA antagonist. Human use has been limited, but the drug is worth exploring, perhaps before going to inhalational anesthesia. Regarding the latter, isoflurane and desflurane work within minutes, are easily titrable and are remarkably effective in stopping status epilepticus (Kofke et al., 1989; Mirsattari et al., 2004). However, they require an anesthetist and vapor extraction system in the ICU. Like other agents at higher concentrations and with prolonged use the drugs can cause hypotension, paralytic ileus and long duration as they redistribute from fat stores. 4. Additional pharmacological considerations: Recently topiramate (Bensalem et al., 2003; Towne et al., 2003) and levetiractam (Rossetti et al.,2006; Patel et al., 2006) have been used in the treatment of refractory status epilepticus. Although these are effective agents, they are not available parenterally in Canada. They have to be given via gastric tubes; their absorption is compromised if earlier anesthetic agents have produced an ileus. Lidocaine and magnesium have had their proponents, but are not generally used. Maintenance drugs, e.g., phenytoin, Phenobarbital, carbamazepine, and others are usually maintained during the treatment of status epilepticus, so that when the anesthetic agent is stopped there will be protection from a long term anti-epileptic medication.

10 10 In general, it is not necessary to treat the patient with bicarbonate, even though a profound, combined metabolic and respiratory acidosis is present. The blood gas abnormalities quickly resolve with correction of the seizures. As a caveat, if the patient shows a continuing anion-gap acidosis, suspect poisoning with a toxic agent such as ethylene glycol or methanol. Some of the anesthetic agents cause hypotension; inotropic agents, e.g, dopamine infusion, are often needed to maintain a satisfactory blood pressure. 5. Epilepsy surgery has sometimes been used in desperate situations to stop refractory seizures of focal origin (Lega et al, 2009). This can be life-saving and should be considered as an option. 6. The Role of Continuous EEG (CEEG) Monitoring: Continuous EEG monitoring is invaluable in the management of status epilepticus. Even when outward seizure activity has stopped, NCSE may still be ongoing and can contribute to brain damage. NCSE is essentially undetectable without CEEG monitoring. The EEG can also be used to titrate the anesthetic agent to achieve a burst-suppression pattern that is thought to be neuroprotective, but also to avoid overshooting with the drug. We recommend that the anesthetic agent be stopped daily with CEEG monitoring to help determine if seizures are breaking through. If they are, the anesthetic can be resumed and maintenance drugs optimized; this is repeated until the seizures are stopped.

11 11 Prognosis: It is generally acknowledged that convulsive status epilepticus leads to brain damage and that absence status epilepticus does not contribute to morphological changes (Young and Jordan 1998). Although there is abundant support that neuronal death, especially in the hippocampus, happens in animal models of NCS/NCSE (Brandt et al., 2003;Bengzon et al., 2002; Mikulecka et al, 2000; Nevander et al., 1985; Sloviter 1983), it has been problematic to establish this in human cases. Evaluating the relative contributions of the etiology and NCS/NCSE in causing brain damage has always been the issue. The conditions causing NCS and NCSE in the ICU setting include trauma, anoxic-ischemic encephalopathy, encephalitis, vascular lesions, neoplasms, metabolic disorders, sepsis and pre-existing epileptic conditions. Many of these in themselves are associated with significant tissue destruction in the cerebrum. How can we dissociate injury due these etiologies from damage from seizures themselves? This question has enormous potential clinical importance as: 1. NCSE is common in ICU (especially neuro-icu) patients, much more common than convulsive seizures. 11 In general ICUs at least 8% of comatose patients have NCSE. The prevalence of NCS/NCSE is about 48% of patients who remain comatose after convulsive seizures (De Lorenzo et al. 1996) and occurs in at least 20% in patients with acute structural brain lesions, including trauma. 2. NCS/NCSE cannot be readily detected without continuous EEG monitoring. Comatose patients require at 48 hours of continuous EEG (CEEG) recording for optimal seizure detection; standard (20-30 minute) recordings are inadequate, detecting fewer than 10% of seizures found with prolonged recordings (Claassen et al, 2004)

12 12 3. Seizure duration is strongly associated with outcome, including mortality, and refractoriness of the seizures (Lowenstein and Alldredge, 1992; Towne et al., 1994; Delorenzo et al., 1992; Young et al. 1996). Note that the above 3 points do not prove that NCSE damages the brain and that detection and treatment lessen mortality and morbidity, as NCSE severity may just reflect the severity of the inciting cause. However, they raise at least the possibility of a contributory role for NCSE in contributing to further brain damage and ICU mortality. Conclusions: Status epilepticus is a medical emergency and should be promptly stopped to ameliorate brain damage and to reduce the chances of mortality. Continuous EEG monitoring is strongly advised. Lorazepam followed by phenytoin or valproate is an appropriate initial treatment. For refractory status epilepticus, ICU management is needed. Propofol is commonly used; ketamine and inhalational anesthesia are suitable alternatives.

13 13 References: Alldredge BK, Gelb AM, Isaacs SM, et al (2001). A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 345: Bengzon J, Mohapel P, Ekdahl CT, et al. (2002). Neuronal apoptosis after brief and prolonged seizures. Prog Brain Res 135: Bensalem MK, FakhouryTA (2003). Topiramate and status epilepticus : report of three cases. Epilepsy Behav 4: Brandt C, Glien M, Potschaka H, et al. Epileptogenesis and neuropathology after different types of status epilepticus produced by prolonged electrical stimulation of the basolateral amygdala in rats. Epilepsy Res 2003;55: Claassen J, Hirsch LJ, Emerson RG, et al. (2001). Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 57: Claassen J, Mayer SA, Kowalski RG, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004;62: DeLorenzo RJ, Towne AR, Ko D, et al. (1996). Prospective, population-based epidemiological study of status epilepticus in Richmond VA. Neurology 46: DeLorenzo RJ, Towne AR, Pellieck JM, et al. (1992). Status epilepticus in adults, children and the elderly. Epilepsia 33(Suppl 4): Shorvon SD, Pellock JM, DeLornzo RJ. (2008). Acute physiological changes, morbidity, mortality in status epilepticus. In Engel JE, Pedley TA, Aicardi J, Dichter MA (Eds). Epilepsy: A Comprehensive Textbook Vol1, Chapter 64, pp

14 14 Gastaut H, Roger J, Lob H. (1962) Les états de mal épileptique: compte rendu de la reunion européene d information électroencéphalographique. Xth Colloque de Marseille. Masson. Paris. Hauser WA. (1990). Status epilepticus: epidemiology considerations. Neurology 40 (suppl 2):9-12. Kofke WA, Young RS, Davis P, et al. (1989) Isoflurane for refractory status epilepticus: a clinical series. Anesthesiology 71: Lega BC, Wilfong AA, Goldsmith IL, et al. (2009) Cortical resection tailored to awake, intraoperative ictal recordings and motor mapping in the treatment of intractable epllepsia partialis continua: technical case report. J Neurosurgery111: Lothman E. (1990). The biochemical basis and pathophysiology of status epilepticus. Neurology 40: Lowenstein DH, Alldredge BK. (1992). Status epilepticus at an urban public hospital in the 1980s. Neurology 43: Marik PE, Varon J. (2004) The Management of Status Epilepticus. Chest 126: Mayer SA, Claassen J, Lokin J, et al. (2002). Refractory status epilepticus. Frequency, risk factors, and impact on outcome. Arch Neurol 59: Mikulecka A, Krsek P, Hlinak Z, et al. (2000) Nonconvulsive status epilepticus in rats: impaired responsiveness to exteroceptive stimuli. Behav Brain Res 117: Mirsattari SM, Sharpe MD, Young GB (2004). Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 61:

15 15 Nevander G, Ingvar M, Auer R, et al. (1985)Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann Neurol 18: Patel NC, Landan IR, Levin J, et al. (2006) The use of levetiracetam in refractory status epilepticus. Seizure 15: Rossetti AO, Bromfield EB. Rossetti AO, et al. (2006). Determinants of success in the use of oral levetiracetam in status epilepticus. Epilepsy Behav 8: Sloviter RS. (1983). Epileptic brain damage in rats induced by electrical stimulation of the perforant path: acute electrophysiological and light microscopic studies. Brain Res 1983;10: Sloviter RS (2009). Experimental status epilepticus in animals: What are we modeling? Epilepsia 50(Suppl12): Towne AR, Garnett LK, Waterhouse EJ, et al. (2003) The use of topiramate in refractory status epilepticus. Neurology 60: Towne AR, Pellock JM, Ko D, et al. (1994). Determinants of mortality in status epilepticus. Epilepsia 5: Treiman DM, Walton NY, Kendrick C (1990). A progressive sequence of electrographic changes during generalized convulsive status epilepticus. Epilepsy Res 5: Treiman DM, Meyers PD, Walton NY, et al. (1998). A comparison of four treatments for generalized convulsive status. epilepticus. N Eng J Med 339:

16 16 Wasterlain CG, iu H, Naylor DE, et al. (2009) Molecular basis of self-sustaining seizures and pharmacoresistance during status epilepticus: the receptor trafficking hypothesis revisited. Epilepsia 50(Suppl 12): Woking Group on Status Epilepticus (1993). Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America s Working Group on Status Epilepticus. JAMA 270: Young GB, Jordan KG, Doig GS.(1996) An assessment of nonconvuslve seizures in the intensive care unit using continuous EEG monitoring: an invovestigation of variables associated with mortality. Neurology 47: Young GB. (1998) Do nonconvulsive seizures damage the brain? Yes. Arch Neurol 1998;55:

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