Presentación

Status epilepticus (SE) is classically defined as the occurrence of two or more seizures without recovery of consciousness or 30 minutes of continuous seizure activity. However, due to the seriousness of SE more recent literature has reduced this time to merely 5 minutes of seizure activity (Huff and Fountain, 2011). Unlike more classic seizure disorders, SE represents the inability of inherent cellular mechanism to terminate the seizure (Coulter and DeLorenzo, 1999), and thus the seizure persists. This sustained seizure activity suggests that

Figure 1.1. Seizure classification. Two broad categories of seizures exist, those that are self-terminating and those that are sustained, referred to as status epilepticus (SE). Self-terminating seizures can be further classified into partial and generalized seizures. Partial seizures are localized to a particular brain region whereas generalized seizures can affect the entire cortex. These categories are further identified based upon behavioral consequences including loss of consciousness. Partial seizures can spread to more severe generalized seizures. Sustained seizures, SE, can be subdivided into non-convulsive SE (NCSE) and generalized convulsive SE (GCSE). Additional types of SE exist but are not easily classified into NCSE or GCSE categories.

SE is composed of both an activation and a maintenance phase (Mazarati et al., 1998). The proposed phases of SE are likely regulated by the several different receptor populations which can mediate excitatory and inhibitory neurotransmission.

In the United States there are approximately 150,000 cases of SE each year (Chapman et al., 2001), of which at least 50% are diagnosed as the more severe GCSE. SE is associated with nearly a 20% mortality rate, a figure even higher in cases of RSE (Aminoff and Simon, 1980; Towne et al., 1994). In 20 – 40% of patients a single SE event eventually leads to the development and diagnosis of epilepsy (Hesdorffer et al., 1998; Sankar et al., 2000). While 50% of SE cases occur in patients with no known seizure disorder, a previous diagnosis of epilepsy does significantly increase the risk of SE (Hesdorffer et al., 1998), with approximately 15% of epilepsy patients experiencing an episode of SE during their lifetime (Trinka et al., 2012). While risk factors for the development of SE are limited it is acknowledged that one factor is age, as approximately 40% of SE patients are under 2 years of age and the greatest incidence of SE occurs in adults over 60 years of age (Shinnar et al., 1997). Additional risk factors include possible genetic factors and lower socioeconomic standing.

There are two general categories of underlying causes of SE, acute and chronic. Acute etiology includes an imbalance in electrolytes, drug toxicity, infection of the central nervous system (CNS), cerebral trauma, etc., while more chronic etiologies include a pre-existing seizure disorder, alcoholism, cerebral tumors or lack of AED compliance (Trinka et al., 2012). Understanding the

possible origin for the development of SE greatly influences potential treatment protocols for the patient.

1.3.1SEIZURE MECHANISMS

At a basic level seizures initiate due to abnormal neuronal firing or imbalance within the inhibitory and excitatory systems of the brain. Due to the highly interconnected network of the brain, epileptiform activity in one area or within one population of neurons can easily spread to neighboring areas and may eventually alter transmission throughout the entire cerebrum. The majority of seizures are considered self-limiting, in that within seconds to minutes the seizure will terminate without the need for intervention. However when a seizure does not self-terminate it may continue indefinitely, a neurologic emergency referred to as SE. The exact mechanism by which seizures terminate is not clear. It is postulated that mechanisms involved in seizure termination occur at the level of a single neuron or within a network of neurons, and that in some individuals these mechanisms may simply fail (Lado and Moshe, 2008).

One of the most critical mechanisms involved in regulation of neuronal firing is proper regulation of the afterhyperpolarization (AHP) which occurs at the level of the single neuron. Action potential invasion into a neuron produces an increase in intracellular Ca2+ which activates voltage-gated K+ channels that allow for K+ to flow out of the cell. This efflux of K+ leaves the intracellular space more negatively charged and the cell hyperpolarizes, which prevents further excitability (Alger and Nicoll, 1980; Timofeev et al., 2004). Network regulation of

seizures includes depletion of synaptic glutamate which serves to limit burst activity (Staley et al., 1998), and acidification of both the intracellular and extracellular spaces due to the increase in CO2 levels during prolonged seizure activity (Chesler and Kaila, 1992). Network synchronization, a hallmark of seizures, is partly regulated by interneuronal gap junctions (Mancilla et al., 2007). The acidification during a seizure also results in the decoupling of these gap junctions, which serves to limit neuronal discharge and network synchronization (de Curtis et al., 1998). There are many different mechanisms that serve to limit seizure activity, any number of which could be altered resulting in prolonged status epilepticus.

1.3.2TREATMENT OF REFRACTORY STATUS EPILEPTICUS

A major component to successful termination of SE is the ability of the patient to receive rapid treatment. It has been demonstrated that treatment even prior to arrival at a hospital is critical (Pellock et al., 2004). In a study investigating seizure treatment it was determined that over half of patients who were not successfully treated prior to a hospital were twice as likely to require intensive care (Alldredge et al., 2001). Fast and effective treatment of SE is so essential that standard treatment algorithms have been developed that indicate the hierarchy of available drugs (Pellock et al., 2004). In agreement with clinical studies indicating the need for pre-hospital treatment of SE, treatment algorithms begin with conventional antiepileptic drugs (AEDs) including benzodiazepines

(BZDs) and advance to the use of barbiturates and even anesthesia in extreme cases.

BZDs, including diazepam, are considered the first line of treatment of SE. To achieve the highest rate of seizure termination BZDs should be administered within minutes of seizure onset. One rationale for immediate treatment is that while BZDs are considered the safest of the available AEDs they have been shown to lose effectiveness during the progression of SE (Walton and Treiman, 1988; Kapur and Macdonald, 1997; Jones et al., 2002; Grosenbaugh and Mott, 2013). Patients who develop pharmacoresistance to BZDs and other medications may develop RSE. Despite adequate treatment with available AEDs nearly 45% of patients with SE will develop RSE, which brings with it an increased risk for a variety of neuropathological consequences including death in nearly 25% of cases (Mayer et al., 2002; Holtkamp et al., 2005; Rossetti et al., 2005). In cases of RSE when available AEDs are ineffective patients are often put into medically induced comas through exposure to a variety of anesthetics (Knake et al., 2009).

Chapter 3 will explore the use of stiripentol, a novel AED, for the treatment of BZD-refractory status epilepticus.