1. Which benzodiazepine do you prefer for the treatment of status epilepticus (SE)? Which do you prefer for pediatric patients?

An epileptic seizure (ES) is defined as an abrupt disruption in brain function secondary to abnormal neuronal firing, and is characterized by changes in sensory perception and or motor activity. The clinical manifestation of a seizure is vast, encompassing focal or generalized motor activity, sensory or autonomic dysfunction, and mental status changes. Numerous types of seizures exist, broadly classified as simple versus complex, partial versus generalized, and convulsive versus non-convulsive. All can progress to status epilepticus (SE); this discussion pertains to convulsive SE.

SE was historically defined as any seizure activity lasting longer than thirty minutes, but is now more conservatively defined as a seizure lasting longer than five minutes, or consecutive seizures without a return to baseline in between seizures. It is important for emergency physicians to rapidly recognize and treat SE as studies estimate an associated mortality of 10-40%, depending on the etiology. (Shearer 2006) Initial interventions include evaluation of the airway, IV access, cardiac monitoring, and the administration of supplemental oxygen and antiepileptic agents. The goal is to terminate all seizure activity within sixty seconds.

Benzodiazepines potentiate GABA activity, thus decreasing neuronal firing, and are widely accepted as the preferred first-line treatment for SE. (Alldredge 2001, Leppik 1998, Treiman 1998, Brophy 2012, Shearer 2006) In addition to a favorable safety profile, benzodiazepines have the advantage of multiple routes of administration, including intravenous (IV), intramuscular (IM), and various mucosal routes. The IV route is generally preferred for speed of onset of action, however environmental circumstances and patient variables can complicate IV access, particularly in children. (Shearer 2006, Berg 2009)

In children (neonatal seizure not discussed), seizures are commonly treated via mucosal administration of benzodiazepines, particularly by parents and EMS in the pre-hospital setting. Mucosal routes include rectal diazepam and buccal or intranasal midazolam. Rectal diazepam has long been the favored drug in this setting and is FDA approved for such use. (Berg 2009) Rectal diazepam, however, has several limitations including social stigma, short duration of action, and risk of expulsion due to seizure induced fecal incontinence. As a consequence, administration of a second agent or repetitive diazepam dosing is often required, leading to increased risk of side effects and potential harm. Rectal diazepam has been proven to be more efficacious than placebo, but has only recently been compared to other mucosal routes of administration. (Dreifuss 1998) In 2005, a randomized controlled trial (RCT) demonstrated the superiority of buccal midazolam to rectal diazepam for seizure termination without increasing the risk of respiratory depression.(McIntyre 2005) Several RCTs comparing intranasal midazolam to rectal diazepam show superiority for intranasal midazolam when looking at time-to-seizure cessation. (Fisgin 2002, Bhattacharyya 2006, Holsti 2007, Holsti 2010) Given the disadvantages of rectal diazepam combined with the above evidence, buccal and intranasal midazolam should be considered viable alternatives for treatment of pediatric seizure. Regarding administration of IV benzodiazepines to children, IV lorazepam appears to be as effective and safer than IV diazepam. (Appleton 1995, Appleton 2008) Further studies are needed to compare non-IV and IV routes of administration in the pediatric population, particularly with comparisons to IV lorazepam. If difficult IV access is anticipated, buccal and intranasal routes should be considered. (Ulgey 2012)

Similar to the pediatric population, in adults, diazepam was historically the benzodiazepine of choice for treatment of SE. After years of research however, lorazepam has emerged as the preferred agent due to its extended duration of anticonvulsant activity and its ability to be administered via the IM route. (Treiman 1998, Leppik 1998, Walker 1979) Large RCTs comparing benzodiazepines head-to-head, however, are limited. A 2005 Cochrane review of RCTs established IV lorazepam as superior to IV diazepam for cessation of SE, evaluating three studies including 289 patients. The relative risk (RR) of non-cessation of seizures for lorazepam compared to diazepam was 0.64. The comparison to midazolam, however, was less clear. A single study found IV midazolam, when compared to IV lorazepam, to have a RR 0.2 for non-cessation of seizures. The authors concluded a non-significant trend favoring IV midazolam compared to IV lorazepam. Unfortunately much of the pediatric data is based on single studies and is not conclusive. (Prasad 2005)

In addition to a trend towards improved efficacy in SE, midazolam does not require refrigeration, lending it another advantage over lorazepam in the pre-hospital setting. To further compare these two antiepileptic agents in the pre-hospital environment, the RAMPART (Rapid Anticonvulsant Medication Prior to Arrival) study was completed in 2012. It compared 10 mg IM midazolam to 4 mg IV lorazepam in a double-blinded RCT. Children over 13 kg were included in this analysis. Upon arrival to the ED, seizures were absent in 73.4% of patients in the midazolam treatment group and in 63.4% of patients in the lorazepam group (p<0.001, primary outcome). Admission rates were also significantly lower in the midazolam treatment group (p<0.001). Although the time-to-administration of the drug was shorter in the midazolam group, the onset of action was shorter in the lorazepam group. This study showed IM midazolam to be non-inferior to IV lorazepam when given by EMS providers prior to ED arrival. (Silbergleit 2012) Important limitations of this study include use of an autoinjector for midazolam as opposed to standard IM injections, and occurrence of study in the pre-hospital environment where IV access is often more difficult to obtain. While extrapolation of this study to ED patients should be limited, IM midazolam for SE appears to be a viable option.

What do the experts say? In 2012, the Neurocritical Care Society published guidelines for the treatment of SE based on limited available evidence and consensus opinion. They recommend lorazepam as the preferred agent for IV administration, midazolam for the IM route and diazepam for the rectal route. Lorazepam, midazolam and diazepam all carry Level A recommendations for emergent treatment of SE. (Brophy 2012)

2. Which second-line agents do you use for treatment of SE?

Unless the underlying cause of SE is known and reversible by another means (i.e. metabolic, toxic ingestion), the initial benzodiazepine is immediately followed by a second anti-epileptic agent. If the seizure has already been successfully terminated, the goal of this second agent is to prevent recurrence through rapid achievement of therapeutic levels of an antiepileptic drug (AED). However, if the benzodiazepine has failed, the goal is to rapidly stop all seizure activity. While the use of benzodiazepines as the first-line treatment for SE is widely accepted, there remains a significant debate over what this second-line agent should be.

Phenobarbital, a long-acting barbiturate that potentiates GABA activity, is the oldest AED still in use today. Historically a first-line agent, it has fallen out of favor due to its significant adverse event profile, namely hypotension and respiratory depression. Currently, it is typically reserved for refractory SE. (Shearer 2006)

Phenytoin has emerged as the preferred second-line agent after benzodiazepines for the treatment of SE. Phenytoin prolongs inactivation of voltage-activated sodium channels, thus inhibiting repetitive neuronal firing. Although it is possible to rapidly achieve therapeutic levels of phenytoin, the drug is limited by side effects including ataxia, hypotension, cardiac dysrhythmias and tissue necrosis secondary to extravasation. (Shearer 2006) Fosphenytoin, a precursor of phenytoin, allows for IM administration with preserved bioavailability, but can have similar hemodynamic side effects. The combination of benzodiazepines and phenytoin is only effective in approximately 60% of patients, leaving a substantial group in SE. (Treiman 1998, Knake 2009) This, combined with its side effect profile, has led to a search for alternative second agents for the treatment of SE.

Valproic acid is an established AED used to treat many forms of seizures, and has been available for IV administration since 1996. Like phenytoin, it acts through prolonging the recovery of voltage-activated sodium channels. The efficacy of valproic acid in treating SE has been quoted ranging from 40-80%. Its primary side effect is hepatotoxicity, either from chronic use over the first six months or as an idiosyncratic reaction. Compared to phenytoin’s risk with local extravasation and significant hypotension, valproic acid is a potentially safer option for some patients. (Shearer 2006). A 2012 meta-analysis sought to compare valproic acid to other available AEDs for SE. Unfortunately, heterogeneity in defining SE and variability within the data limited the conclusions of the meta-analysis. Despite this, authors deemed valproic acid to be as effective as phenytoin in treating SE based on three randomized studies including 256 patients. (Misra 2006, Agarwal 2007, Gilad 2008, Liu 2012) An Italian meta-analysis that same year found no difference in time to seizure cessation when comparing the use of valproic acid and phenytoin, with a trend towards fewer side effects with valproic acid. The authors warn however, against over-interpretation of this data given its inherent limitations and suggest waiting for larger RCTs before changing one’s clinical practice. (Brigo 2012)

Levetiracetam is a comparatively newer medication, with an IV formulation only available since 2006. Its exact mechanism of action is unknown, but it has fewer side effects and limited drug-drug interactions when compared to the older AEDs. (Shearer 2006) Given this favorable safety profile, many have heralded levetiracetam as an ideal second agent for SE. In 2012, a review paper by Zelano et al. compared ten studies looking at levetiracetam for treatment of SE, including one prospective randomized study and a total of 334 patients. The authors found that levetiracetam had an efficacy ranging from 44% to 94%, and was not associated with any significant adverse events. Overall, however, the efficacy was significantly higher in the retrospective studies, raising concern over potential bias influencing the positive results. The single randomized study reported an efficacy of 76%, however this group received levetiracetam as primary therapy and it is unclear if this group was “less sick” and would have responded to initial benzodiazepines. (Misra 2012) Furthermore, in many of the studies, levetiracetam was used because phenytoin was contraindicated, creating another source of bias. Zelano’s review concluded that despite its favorable safety profile, there is scarce evidence to support levetiracetam as a second-line agent in the treatment of SE. (Zelano 2012) More studies are needed.

Currently, using the limited data available, the Neurocritical Care society recommends fosphenytoin as the preferred second-line agent for treatment of SE. They do allow for consideration of other agents on a case-by-case basis, including SE in patients with known epilepsy, in which valproic acid may be preferred. Additionally, an IV bolus dose of the patient’s maintenance AED is also recommended in such cases. (Brophy 2012)

If SE has not resolved after administration of the second agent, the patient is considered to have refractory SE (RSE), and should receive additional treatment immediately. Continuous infusion of an AED, typically propofol, midazolam, phenobarbital, valproic acid or high dose phenytoin, is recommended. (ACEP 2014) Bolus doses of the infusion AED can also be given for breakthrough seizures. Available data do not support the use of one agent over another. (Brophy 2012)

Other agents may soon be available for the treatment of SE and RSE. Animal data reporting decreased GABA receptors in the setting of SE has sparked interest in targeting the NMDA receptor. The theory being, if you cannot potentiate the inhibitory GABA system, perhaps antagonizing the excitatory NMDA system could have efficacy. Ketamine, an NMDA antagonist, has been discussed as a potential future direction in the treatment of RSE. (Kramer 2012)

3. In which adult patients with first-time seizure do you obtain emergent imaging?

Seizure is a common presentation to the ED and represents between 1-2% of ED visits. Although manifested by a common presentation, the etiology of seizure is incredibly broad, including trauma, hemorrhage, metabolic derangements, toxic exposures, infection, and congenital abnormalities. For adult patients with new-onset seizures, the evaluation can be tailored to the history provided by the patient. Laboratory investigation in particular should be fitted to the specific patient as multiple studies have shown the history and physical exam to predict laboratory abnormalities (Shearer 2006). Serum glucose and sodium tests, however, are recommended (Level B) in all patients who have returned to baseline. A pregnancy test is recommended in all women of childbearing age. (ACEP 2014)

When it comes to neuroimaging first-time seizure, the best course of action is less clear. Although it is established that all patients presenting with first-time seizure should receive neuroimaging, the timing and modality of that imaging is highly controversial. Neurologists prefer brain magnetic resonance imaging (MRI) for seizure work up, but it is rarely available in the ED setting. Computed tomography (CT) is the predominant test available to ED providers, however it is inferior to MRI for evaluation of seizure, with the exception of detection of acute hemorrhage. (Jagoda 2011)

Who then, needs a screening CT in the ED prior to discharge and who can wait for the definitive MRI? Experts suggest dividing patients into two groups. First are those with persistent neurologic deficits, an abnormal mental status, or evidence of medical illness, and second are those who have returned to baseline with a non-focal exam. The first group is clearly high-risk and warrants an extensive work up including an emergent head CT. In fact, abnormal head CTs have been documented in 81% of patients with neurologic deficits on exam. (Tardy 1995) The second group is more nuanced and the utility of emergent head CT is less defined. Even in patients with non-focal neurologic exams, however, the rate of CT abnormalities ranges from 17-22%. (Tardy 1995, Sempere 1992, Jagoda 2011) The clinical significance of a nonspecific abnormal head CT, the definition of which often includes simple atrophy, is uncertain in a neurologically intact patient. Furthermore, there may be elements of the presentation or history that place the patient at higher risk. Several studies have noted advanced age (Tardy 1995), HIV (Jagoda 2011, Harden 2007) and chronic alcohol abuse to be associated with increased risk of abnormal head CTs in the setting of seizure, despite normal exams. (Tardy 1995, Harden 2007, Jagoda 2011, Earnest 1988)

In 2007 a multidisciplinary committee including ED physicians, in association with the American Academy of Neurologists (AAN), updated guidelines on neuroimaging for the emergency patient with seizure. The authors specifically sought evidence for emergent neuroimaging that would change ED management to offer a clinically relevant guideline. Based on a nearly forty-year literature review, they offer a weak recommendation (Level C) for emergent CT in adults with first time seizure, noting CT to make acute management changes in 9-17% of cases. They offered a higher recommendation (Level B) for a subset of patients more likely to have significant findings on CT. In addition to patients with an abnormal neurologic exam, this subset included those with focal seizures, predisposing history such as trauma, neurocutaneous disorders, malignancy and shunt. (Harden 2007)

Due to limited data, the above recommendations and summary of evidence ultimately fail to provide a clear, universal algorithm for all cases. An abnormal mental status, focal neurologic exam, predisposing history, trauma, immunocompromised state, or focal seizures should prompt emergent imaging in the ED. Increased age and inability to obtain reliable follow up should also tip the scales in favor of obtaining a CT prior to discharge. A patient without a concerning history, at his/her baseline with a normal neurologic exam will need an outpatient MRI and EEG for definitive diagnosis. Whether that work up includes a CT in the ED will be up to the discretion of the provider. The ACEP clinical policy guideline, last updated in 2004, offer Level B recommendations as follows: 1. When feasible, perform neuroimaging of the brain in the ED on patients with a first time seizure. 2. Deferred outpatient neuroimaging may be used when reliable follow up is available. (ACEP 2014) Neither ACEP nor the AAN are able to make a comment on the use of MRI in the ED based on insufficient evidence.

4. How do you diagnose pseudoseizure?

Pseudoseizures, formally known as psychogenic nonepileptic seizures (PNES), are characterized by motor, sensory, automatic or cognitive behavior similar to epileptic seizures (ES) but without abnormal neuronal firing. PNES is often misunderstood and patients are perceived as malingering or “faking it”. PNES, however, is a defined psychoneurologic condition falling under the same umbrella as conversion and somatoform disorders. Interestingly, epilepsy and PNES frequently coexist in the same patient. It has been estimated that up 60% of patients with PNES have another seizure disorder, however more conservative studies place the estimate closer to 10%. (Benbadis 2000, Benbadis 2001, Shearer 2006) PNES is found across cultures and occurs more frequently in women in the third and fourth decades of life. (Reuber 2003, Lesser 1996)

It can be extremely difficult to distinguish PNES from ES in the ED. Video EEG is the gold standard for diagnosis of ES, however this is not typically possible in the ED setting. There is utility, however, in differentiating PNES from ES as antiepileptic treatment is not benign and creates potential for iatrogenic harm. (Reuber 2003) Many have attempted to clarify PNES semiology in studies of variable quality, including many case reports and uncontrolled studies. In 2010, Avbersek reviewed rigorous studies that included EEG to establish clinical signs distinguishing PNES from ES. A sign was considered well supported for PNES if it had positive findings in two controlled studies and the remaining studies were also supportive. Based on their findings, clinical signs suggestive of PNES, applicable to the ED setting included:

1. Duration of event >2 minutes
2. Fluctuating course
3. Asynchronous movement of limbs
4. Pelvic thrusting
5. Side to side head or body movement
6. Closed eyes
7. Ictal crying
8. Recall of event
9. Absence of postictal confusion
10. Absence of postictal stertorous breathing

Flailing or thrashing movements and absence of tongue biting or urinary incontinence are frequently cited as suggestive of PNES, however this study did not find sufficient evidence to support this distinction. (Avbersek 2010) It is important to remember that many of these findings apply to generalized seizures only and cannot be used to separate PNES from partial seizures. Frontal seizures, for example, often demonstrate bizarre movements and emotional displays easily mistaken for PNES. (Reuber 2003) When applying this information to ED patients, one must take the entire history and exam into account, never relying upon a single sign to rule out ES. Ultimately, PNES is not a diagnosis to make in the ED, as it requires video EEG monitoring along with the assessment of experienced epileptologists.

In addition to clinical signs, physiologic parameters including cortisol, prolactin, white blood cell count, creatine kinase and neuron-specific enolase have been investigated in PNES. Though most have met significant limitations, prolactin, a hormone secreted by the anterior pituitary, has emerged as the most promising serum marker. (Willert 2004, LaFrance 2010) In 1978, Trimbel first demonstrated prolactin elevation in ES. Many subsequent studies have replicated similar findings while showing no prolactin elevation in PNES. (Trimble, 1978, Mehta 1994, Fisher 1991, Mishra 1990)

Serum prolactin is known to peak fifteen to twenty minutes after seizure, returning to baseline at one hour. (Trimble 1978) Interestingly, however, prolactin levels do not consistently rise in all types of seizures. On average, prolactin is elevated in 88% of generalized tonic-clonic seizures, 64% of complex partial seizures and 12% of simple partial seizures. (LaFrance 2013) In one study, patients with PNES also demonstrated a statistically significant increase in prolactin from baseline. Notably, the prolactin elevation in PNES was much smaller than that in ES. Nevertheless, this study raises questions over the specificity of prolactin elevation for diagnosis of ES. (Alving 1998) To further complicate interpretation of prolactin, levels are subject to significant variations. Up to 100% fluctuations are seen prior to awakening from sleep, levels in women and men differ, and baseline prolactin levels are elevated in those with epilepsy. (Chen 2005) These factors, combined with variability in seizure classification and definition of prolactin elevation has made interpretation of the limited data difficult. Despite these limitations, The American Academy of Neurology Therapeutics and Technology Assessment Subcommittee reviewed available high quality data. They determined elevated prolactin to have a specificity of 96% for detection of ES. They conclude that a twice-normal rise in serum prolactin, drawn ten to twenty minutes after an ictal event, compared to a baseline prolactin, is useful in differentiating GTC and CPS from ES. The pooled sensitivity for this data was very poor, however, averaging 53% for all types of ES. (Chen 2005) Another review, including less rigorous data, reported an average sensitivity of 89%. (Cragar 2002) Both studies agree that absence of an elevated prolactin level should not be used to rule out ES. Additionally, baseline prolactin levels are often not available, further limiting the utility of this test.