EPILEPTICUS

Abstract

Status epilepticus (SE) is divided into convulsive and non-convulsive types; both are
associated with significant morbidity and mortality. Although convulsive SE is easily
recognized, non-convulsive SE remains an elusive diagnosis as physical signs are varied and
subtle. Successful management depends on a comprehensive approach that involves
diagnostic testing and pharmacological interventions while ensuring cerebral oxygenation
and perfusion at all times. There are a limited number of well-designed studies to support the
development of evidence-based recommendations for the management of SE, especially for
the management of non-convulsive status. Benzodiazepines, specifically lorazepam, continue
to be the most commonly recommended first-line therapy; best treatment for refractory status
cases depends on resources available and must be tailored to the individual institution. In
order to facilitate care, it is recommended that each institution develop a management
protocol for these patients.

Introduction and definitions

Status epilepticus (SE) is a potentially life-threatening condition. A seizure, as defined

by the International League Against Epilepsy and the International Bureau of Epilepsy is a
transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous
neuronal activity in the brain. Most seizures last less than 12 min : Seizures that last more
than 510 min are less likely to stop without intervention. The International League Against
Epilepsy originally defined SE in 1964 as a situation in which a seizure persists for a
sufficient length of time or is repeated frequently enough to produce a fixed and enduring
epileptic condition.This definition lacked a specific duration, and 30 min became a popular
time frame based on neuronal injury patterns seen in animal models. Recent research supports
a modified working definition of SE as an event lasting 5 min or more.

Epidemiology

- Generalized convulsive status epilepticus

GCSE has an annual incidence of 6.841 cases per 100 000 people, or about 50 000
150 000 cases in the USA. Incidence is bimodal, with the first peak at less than 4 years of age
and a second peak between 60 and 75 years. Acute mortality is between 110%, with total
deaths in the USA numbering 55 000 per year. For patients with pre-existing epilepsy, up to
16% will have one episode of SE during their lifetime.
 - Non-convulsive status epilepticus
Population-based incidence of NCSE is difficult to ascertain for several reasons. The
variety of definitions and classifications of NCSE make it difficult to compare incidence and
frequency across studies. Also, many studies investigating NCSE suffer from selection bias as
they are based at tertiary care centres. The reported incidence of NCSE ranges from 4% to
50% of all cases of SE.
In one prospective study of 164 patients with convulsive SE who were subjected to
continuous EEG monitoring for at least 24 h after seemingly successful treatment, 14% were
found to have NCSE and 48% had some persistent electrographic seizure activity. In another
study of 384 patients, Treiman et al. used EEG early during the course of treatment and found
that up to 25% of patients treated for GCSE had ongoing seizure activity in the form of subtle
convulsive SE or NCSE.

Refractory SE
Refractory SE occurs in up to 45% of all adults and children with SE. In a
retrospective study of 107 patients at two tertiary care hospitals, Rossetti et al. reported that
first-time seizures have a slightly higher rate of evolving into refractory SE (4050%)
compared with recurrent seizures. In up to 20% of patients with refractory SE, seizures might
last weeks or even months. In a retrospective cohort of 74 patients with SE,
Mayer et al. found that patients with NCSE have a higher rate of progression to refractory SE
than those with GCSE. A retrospective study of 134 children in SE reported an association
between delay in provision of first- and second-line anti-epileptic drugs (AED) and the
development of refractory SE. In addition to delay in treatment, other factors that have been
associated with the development of refractory SE include CNS infections, metabolic
abnormalities and hypoxic-ischaemic injury.

Pathophysiology

Ordinarily, seizures self-terminate via gamma-aminobutyric acid (GABA)-mediated

inhibitory pathways. In SE, GABA receptors appear to be internalized and destroyed by
lysosomes, thus inactivating the inhibitory mechanism, and persistent seizures appear to
change the GABA receptor's conformation, making them less responsive to
benzodiazepines. Both of these findings help explain why benzodiazepines appear to be less
effective as seizure duration increases. When seizures last more than 30 min, the body's
homeostatic regulating mechanisms begin to deteriorate, as autonomic control is lost.
Hypotension ensues along with a decrease in oxygen saturation and a decrease in pH,
especially if the patient's respiratory status is compromised. Hyperthermia, hypoglycaemia
and lactic acidosis occur as a result of excess neuromuscular activity. Animal models suggest
that even if systemic factors, such as acidosis and hypoxia, are controlled, prolonged SE
results in neuronal damage secondary to the release of neurotoxic excitatory amino acids and
influx of calcium into cells. Ultimately, all of the above can contribute to adverse outcomes
through the development of cardiac dysrhythmias, hypoxia , hypotension, Hyperthermia,
rhabdomyolysis, acidosis (respiratory and metabolic) and pulmonary oedema .

Aetiology

SE can present in individuals with known epilepsy or de novo. The key for ED
management is identifying reversible causes. SE can be the result of an acute or remote event:
the acute causes include metabolic abnormalities, infections, toxicities, structural lesions and
vascular events. Remote events are usually related to past CNS injuries (e.g. head trauma,
anoxia or stroke). In patients with existing epilepsy, the most common aetiology of SE is
AED non-compliance or sub-therapeutic AED levels.
NCSE has been associated with benzodiazepine or other medication withdrawal,
excessive use of psychotropic drugs, infections, trauma, metabolic derangements, stroke and
alcohol use. Several drugs, including ceftazidime, ifosfamide, chloroquine, digoxin and
penicillin, have been associated with NCSE. Carbamazepine, a commonly use anti-epileptic
medication, has also been found to have the potential to precipitate NCSE.

Toxicological causes
Toxicological causes account for a small number of cases of SE each year. In a
retrospective review, Thundiyil et al. found that 386 cases of seizures related to poisoning or
drug intoxication were reported to California Poison Control in 2003, of which 14 (3.6%)
featured SE. Drugs involved included benzonatate, cocaine, bupropion, ethylene glycol,
isoniazid, citalopram, amitriptyline, methamphetamine and tiagabine. In 1993,
Lowenstein et al. found that drug toxicity accounted for 9% of all cases of SE presenting to
an urban ED over 10 years. Although recreational drugs, such as cocaine, amphetamine,
heroin and phencyclidine, appear to induce seizures, the rate of SE among these patients
appears to be low (4%).

Outcomes and complications

As mentioned above, SE might have grave consequences as the body's homeostatic

mechanisms are disrupted. Subsequent complications might affect any organ system and will
eventually lead to death. Several articles have attempted to determine the mortality of SE.
The best available estimates suggest a range between 10% and 40%. Recently, one article
estimated the case-fatality rate using the National Inpatient Sample based on ICD-9 codes
and found an overall mortality of 3.43%. The study was large (n= 11 580), subtle SE (which
features high mortality rates) was excluded and this might explain why these findings were
very different from prior results. Estimates in children appear to be lower, with case-fatality
rates between 2.7% and 5.2% for younger populations, and up to 13% for adolescents. 103 The
most common cause of GCSE in children is febrile convulsive SE, which has a negligible
morbidity and mortality.
As expected, mortality appears to be related to the underlying cause and to the level of
secondary brain injury from that cause. CNS anoxia and infection carry higher mortality. Any
identifiable cause usually portends a higher mortality as well. Recently,
Rossetti et al.developed a Status Epilepticus Scoring System (STESS) to predict survival
from SE. Their system used four factors (age, history of seizure, type of seizure and
impairment of consciousness). A STESS score was calculated for 154 patients with SE in
three centres before assessment of outcomes. STESS predicted survival with a high negative
predictive value for mortality (0.97). This scoring system still requires prospective validation,
as their study was only an observational cohort.
In terms of morbidity, neurological impairment after SE is usually the greatest
concern. Although data on adults are sparse, studies in children have found that neurological
disability follows in up to 15% of patients. Reduction of IQ has been studied in children, and
some studies, but not all, document a measurable decline. Rates of epilepsy following index
event are also higher. Even with a prolonged febrile convulsion, the rate of subsequent
epilepsy is 10 times higher than for the general population. Animal studies have found that
SE causes hippocampal damage, including oedema and injury, predisposing to recurrent
seizures.

Innovative therapies for refractory SE

In addition, several agents and techniques have been tried in small case series as
innovative therapies for refractory SE. None of the following may be considered for routine
use, but are mentioned here as future directions for treatment. Ketamine has been explored as
a unique agent to control seizures because it targets N-methyl-D-aspartate receptors and
therefore represents a way to activate separate inhibitory mechanisms. One small case series
of five patients with NCSE found that all were controlled, but concerns about its effect on
intracranial pressure linger. Intravenous levetiracetam features a wide therapeutic index and
one small case series of 18 patients with refractory SE similarly showed some promise, with
control achieved in all patients. Of the inhalational anaesthetics, isoflurane in particular has
been studied in a small case series of nine patients and seizure activity ceased in all
patients. Unfortunately, seizures quickly returned in 73% once the gas is discontinued,
limiting its use. Surgery,electroconvulsive therapy and hypothermia have all been tried in
small case series with some success, but further trials are required before these may be
considered for general use.

Conclusions

- Generalized convulsive status epilepticus

SE is a condition that requires early and aggressive therapy for better outcomes.
GCSE in particular features a high mortality, especially in older adults. To prevent seizure
activity from becoming entrenched, the emergency physician must act quickly with the use of
a benzodiazepine, preferably lorazepam, followed by a second- or third-line agent, such as
phenytoin, barbiturate, valproate or benzodiazepine infusion. Although clinical trials are
lacking to recommend a specific protocol, smaller studies suggest that any of these agents
might be of benefit. Admission to an intensive care unit is recommended for patients
continuing to seize, and EEG must be considered in cases where definitive diagnosis cannot
be established.
- Non-convulsive status epilepticus
In NCSE, seizure activity is manifested primarily through behavioural alteration or
obtundation. Confusion and altered mental status, which are commonly encountered in ED,
have very large differential diagnoses. Clearly, the majority of patients presenting to the ED
with altered mental status will not have NCSE asthe cause. Making the diagnosis can be
challenging, although certain scenarios, such as patients who have had a change in their anti-
epileptic medication or those who are having a prolonged post-ictal state after a generalized
convulsion, might indicate the presence of NCSE. The key is for the emergency physician to
have a high index of suspicion and be alert to the possibility of this treatable cause of altered
mental status.