AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Status epilepticus (SE) is defined as seizure activity that lasts more than 30 minutes, constituting a neurological emergency. Seizure activity may be continuous or intermittent without the patient recovering consciousness. Most of the literature deals with the generalized tonic-clonic status epilepticus (GTCSE), but almost as many types of status epilepticus are recognized as types of seizures. This review primarily addresses generalized tonic-clonic seizures but, when appropriate, comments on nonconvulsive status epilepticus (NCSE) are included.

In the past, the common definition of status epilepticus was seizure activity exceeding 60 minutes (as opposed to 30 min). This longer time limit may be one of the reasons for the higher incidence of sequelae in older studies. Other factors accounting for outcome differences include improvement in intensive medical care and the retrospective nature of these older studies, which tended to create a bias toward more severe cases. The rationale for equating intermittent seizures without recovery of consciousness with continuous seizures is 2-fold. First, in animal models, intermittent seizures were quite powerful agents in causing neuropathological changes. Second, in cases of prolonged status epilepticus, outward motor manifestations may become less prominent or intermittent over time without necessarily indicating decreasing intensity of EEG seizure activity.

Types of status epilepticus other than generalized tonic-clonic status epilepticus

Although the terms status epilepticus and generalized tonic-clonic status epilepticus are often used synonymously, status epilepticus includes a few other status types, including the following:

• Complex partial and absence status epilepticus
• • Many studies combine cases of complex partial and absence status epilepticus under the name nonconvulsive status epilepticus. This is because of the similarity in the seizure semiology, despite of the divergent EEG patterns.
  • In children, about two thirds of nonconvulsive status epilepticus cases have generalized EEG changes suggestive of either typical or atypical absences with or without a myoclonic component.
• Simple partial status epilepticus
• • Seizures may be quite sustained, especially when associated with focal brain lesions.
  • Simple partial seizures may be tonic (sustained muscle contraction of part of the body) or clonic (alternating muscle contraction and relaxation) without major impairment of consciousness.
  • Simple partial seizures may be accompanied by recurrent subjective feelings, bodily sensations, or visual hallucinations.
  • Prolonged simple partial seizures (often motor and clonic) are frequently termed epilepsia partialis continua.
  • Simple partial seizures are not necessarily associated with diffuse brain damage, unless they become complex partial status epilepticus or are associated with secondary generalization.
• Complex partial status epilepticus
• • Episodes of complex partial status epilepticus are characterized by major alteration in consciousness, lack of recollection for the event associated with stereotypic automatisms, staring, and, in some cases, vocalization or screaming. Most patients are described as confused (one third of the cases) or unresponsive (one third of the cases).
  • Complex partial status epilepticus episodes have been followed by cognitive deficits in some cases; recognizing the impairment is important.
• Absence seizures
• • Typical absence seizures are prolonged (hours or even days) episodes of alteration in responsiveness with poor or no recollection for events.
  • Typical absence seizures that exceed 30-minutes duration should be treated because of the risk of secondary generalization. However, prolonged absence status has been described that was not associated with subsequent neurologic deterioration.
  • Alteration of consciousness may not be severe; automatic behavior sometimes occurs, with patients able to perform customary daily activities such as combing their hair, playing video games, and even driving. Preceding behavioral changes have been documented in some cases, which cleared with the use of antiabsence medications. In some cases, the clue for absence status may come from observing myoclonic jerking of the eyelids.
  • Absence seizure status may occur in teenagers and adults who were thought to have outgrown the condition.
• Myoclonic seizures
• • Myoclonic seizures are characterized by quick, often repetitive, jerks that randomly involve the limbs.
  • Seizures are often repetitive and, in some cases, may be unabated for lengthy periods.
  • Some patients with myoclonic epilepsies may sustain repetitive myoclonus that persists for days with or without altered consciousness.
  • Myoclonic status epilepticus is a term sometimes used to describe these patients' condition.

Classifications of status epilepticus

Most studies of SE epidemiology and outcome have classified episodes, as follows:

• Acute symptomatic (26%) - Episodes caused by an acute infection, head trauma, hypoxemia, electrolyte disturbance, hypoglycemia, intoxication or drug withdrawal
• Progressive encephalopathy (3%) – Status epilepticus occurring with an underlying progressive CNS disorder, such as mitochondrial disorder, CNS lipid storage diseases, aminoacidopathies, or organic acidopathies
• Remote symptomatic status epilepticus (33%) - A status epilepticus secondary to static conditions (eg, remote cerebral insult in the perinatal period)
• Remote symptomatic with an acute precipitant (1%) – Status epilepticus that occurs with a chronic encephalopathy but with an acute precipitant such as the same reported in acute symptomatic
• Febrile (22%) – Status epilepticus that occurs when the only provocation is a febrile illness, after excluding a direct CNS infection
• Cryptogenic (15%) – Status epilepticus that occurs without identifiable cause

Pathophysiology

Status epilepticus is the result of a failure of the normal factors that serve to terminate a typical seizure, such as changes in GABA receptor composition, loss of benzodiazepines efficacy, excessive glutamate excitation, and activation of drug resistance genes. GABA receptor–mediated inhibition may be responsible for the normal termination of a seizure. In addition, the activation of the N-methyl-D aspartate (NMDA) receptor by the excitatory neurotransmitter glutamate may be required for the propagation of seizure activity. In experimental models, resistance to benzodiazepines and barbiturates may develop during prolonged seizures that may alter the structure and function of GABAa receptors.¹

In adolescent baboons, brain damage can be observed after 90 minutes of sustained seizures, with the neocortex, thalamus, and hippocampus most affected.^{2, 3} In the neocortex, small pyramidal cells in layers 3, 5, and 6 were most affected, and resultant lesions tended to be more prominent in the occipital lobe. In this animal model in which seizures were induced by bicuculline or pentylenetetrazol (PTZ), intubation/ventilation and paralyzation did not improve these types of CNS lesions, suggesting that excessive neuronal discharge caused the damage. These studies also established that hyperpyrexia may also contribute to CNS damage observed in prolonged seizures. This observation has been confirmed in studies of adult humans. Cerebellar damage can also be observed; however, because it is more prominent in the border zones of arterial blood supply, this type of damage probably relates to ischemia and/or hyperthermia.

Most definitions of status epilepticus do not distinguish between uninterrupted seizures and intermittent seizures without recovery of consciousness. This concept is supported by the finding that the pattern of brain damage in animals with repetitive seizures induced by allyl glycine (glutamic acid decarboxylase inhibitor) included hippocampal sclerosis (at times asymmetrical or unilateral), cortical gliosis, and ischemic cell-type damage. Lesions in the cortex sometimes were restricted to the occipital cortex or watershed zones, a pattern very similar to that observed in continuous prolonged seizures.

Frequency

United States

The percentage of patients with epilepsy who develop status epilepticus varies from 1.3-16%. The first seizure lasts longer than 30 minutes in 12.6% of cases. Among patients with febrile seizures, duration exceeds 30 minutes in 5% of cases. Almost half (48%) of adults who present with status epilepticus have no prior history of seizures. Among children diagnosed with status epilepticus, a history of prior unprovoked seizures was even less common (32%); pediatric patients who present with febrile status epilepticus rarely have a history of epilepsy.

Although the data are contradictory, status epilepticus incidence may have increased since the advent of modern antiepileptic drugs (AEDs). Data has showed that 43% of patients taking anticonvulsant medications concurrent with a status epilepticus episode had low levels of AEDs. In 19% of cases, some levels were low and other levels were within the therapeutic range. In 38% of cases, all AED levels were in the therapeutic range.

Generalized tonic-clonic status epilepticus may be recurrent in 17-25% of children with status epilepticus. Recurrent status epilepticus primarily occurs in neurologically abnormal children. Risk of generalized tonic-clonic status epilepticus recurrence also varies among etiologic groups. The idiopathic and remote symptomatic groups have the highest recurrence risk (ie, 28% in prospective studies). The febrile seizure group has a prospective recurrence risk of 3%.

Mortality/Morbidity

Studies of outcomes conducted over the past 15 years report low morbidity and mortality among pediatric patients with status epilepticus. Among children with generalized tonic-clonic status epilepticus, sequelae occurred in 9% of cases. Of these, approximately 58% were only motor sequelae, 29% were motor and cognitive, and 13% were only cognitive.

A striking difference was noted in the respective incidences of sequelae among the etiologic categories.⁴ Patients classified as having idiopathic febrile seizures and remote symptomatic seizures had a low (1.4%) incidence of sequelae. Patients classified with progressive encephalopathy (chronic progressive) had the highest rate of morbidity at follow-up, reaching 80% on the prospective analysis. Patients classified as having acute symptomatic seizures had an intermediate sequelae rate of 12%. Sequelae rates for patients with generalized tonic-clonic status epilepticus were highest among patients younger than 1 year (29%). Rates declined to 11% for children aged 1-3 years and to 6% for children older than 3 years. Although children younger than 1 year have greater incidence of acute symptomatic generalized tonic-clonic status epilepticus, no difference in the etiologic categories among the other age groups is observed.

Studies show that pediatric patients who die after status epilepticus are almost exclusively included in the acute symptomatic or progressive encephalopathy groups. The mortality rate for both classifications combined was 12%. No patients in the remote symptomatic, idiopathic, and febrile status groups died. Most modern pediatric series report mortality rates of 2% that are directly related to status epilepticus, whereas overall mortality rates, including deaths not directly related to status epilepticus, range from 4-6%. Adults with status epilepticus have a much higher mortality rate. The overall mortality rate for adult patients who die from status epilepticus ranges from 16-35%, with 1-5% of deaths directly related to status epilepticus.  

Refractory generalized tonic-clonic status epilepticus that requires high-dose barbiturate or continuous benzodiazepine infusion is positively associated with long-term cognitive deficits and recurrent seizures even in children who were previously normal. 

Early treatment of seizures with rectal medication (diazepam) is thought to be associated with a better outcome but further testing is required to confirm this statement. 

At least 60% of the patients show some degree of cognitive deterioration after an episode of nonconvulsive status epilepticus.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Although the sequence of clinical and EEG manifestations during the course of generalized convulsive status epilepticus (SE) in humans and in experimental models has been described in adults, similar patterns are observed in children with partial and generalized seizures, as follows:

• Phase 1: Initially, discrete partial seizures or, less frequently, generalized seizures can be observed both clinically and on EEG. Blood pressure usually remains within the reference range, but metabolic acidosis may be observed in association with elevated serum lactate and glucose levels.
• Phase 2: Discrete status epilepticus events fuse, and partial seizures become secondarily generalized. The main outward manifestation of continuous clinical and EEG seizure activity consists of a tonic phase (sustained muscle contraction) followed by clonic jerks (alternating contraction and relaxation of the 4 limbs). Phase II may include altered blood pressure.
• Phase 3
• • Over time, the patient's EEG findings start to show slow-frequency discharges similar to periodic lateralizing epileptiform discharges (PLEDs). At this stage, clinical seizures may become quite subtle, with brief rhythmic clonic or myoclonic movements often restricted to a single part of the body.
  • Rhythmic activity may be observed as myoclonus that affects only the feet, hands, facial muscles, or eyes as nystagmus.
  • As the episode progresses, a motionless patient's EEG may reveal generalized or PLED-like discharges. This type of activity is thought to represent a burned-out form of status epilepticus. This conclusion is supported by cases in which patients with abnormal mental status and PLED-like discharges as observed on EEG after an episode of status epilepticus revealed hypermetabolism of the mesiotemporal region on positron emission tomography (PET) scanning.
  • Hyperthermia, respiratory compromise, hypotension, and hypoglycemia may be observed. If not promptly treated, these metabolic, cardiovascular, and respiratory complications can exacerbate the patient's clinical condition and neurologic deficit.
• Nonconvulsive status epilepticus (NCSE): Patients with nonconvulsive status epilepticus are described as appearing forgetful and sleepy, behaving as if deaf and blind (like a zombie), or having the appearance of being drugged. More severe cases are described as unresponsive. Sometimes parents describe the motor component of frequent falls, poor motor control, or abnormal balance.

Physical

During the initial physical examination, seek signs of trauma (eg, bruises, hemotympanum, periorbital hematoma). When the patient's situation stabilizes, look for lymphadenopathy, which suggests catscratch fever.

• Carefully observe patients who present to the emergency department (ED) after an episode of prolonged seizure for signs of subtle seizures or status epilepticus, such as clonic or myoclonic rhythmic movements involving the limbs or face and eyes. These movements often are easy to recognize in overt generalized tonic-clonic seizures and in status epilepticus. Clonic activity may start focally then spread to the hemibody and finally become generalized. Focal clonic activity may assume the form of rhythmic facial muscle contractions, or it may involve the limbs.
• Patients with generalized tonic-clonic status epilepticus (GTCSE) usually have bilateral and synchronous movements of the extremities.
• Although asynchronous alternating movements of the extremities are often thought to be caused by pseudoseizures, a similar pattern can be observed in cases of frontal lobe epilepsy. Epilepsia partialis continua manifests by unilateral and, at times, focal (eg, one hand or even one finger) clonic activity (ie, twitching). Nonetheless, the relationship of seizure-mediated brain damage and duration of simple partial motor seizures is not as clear as in the generalized tonic-clonic status epilepticus studies.
• Patients with absence seizure status epilepticus present with altered consciousness, with or without clonic movements of the eyelids or upper extremities, and automatisms involving the hands and face. A child may sometimes continue to perform a motor act that he or she was engaged in before onset of the absence (eg, bouncing a basketball). In some cases, the patient may answer simple questions, but detailed examination reveals slowed mentation and poor processing of complex information. Episodes of absence seizure status epilepticus may last 12 hours or longer.

Causes

Most studies that deal with the epidemiology and outcome of status epilepticus have classified the etiology of episodes as (1) acute symptomatic, (2) chronic-progressive neurologic disorders, and (3) remote symptomatic status epilepticus.

• Acute symptomatic status epilepticus may be caused by an acute infection, head trauma, hypoxemia, hypoglycemia, or drug withdrawal. Acute symptomatic status is the most common etiologic category in children, causing as many as 35% of cases. Idiopathic status is the second most common cause, with a frequency of 30%; febrile status constitutes 25% of the causes. Meningitis is a common cause of convulsive status epilepticus; fever is present in 17% of the cases in children. In patients with febrile convulsive status epilepticus, the classic signs of meningitis may not be present.
• • Always consider the possibility of infections in pediatric patients presenting with generalized tonic-clonic status epilepticus. Sources of infection often, but not always, are obvious (eg, otitis media, pneumonia). Treat these infections appropriately because they contribute to lowering the seizure threshold in predisposed patients.
  • Infections can be the precipitating factor for both generalized tonic-clonic status epilepticus and nonconvulsive status epilepticus. Patients with CNS infections and mental status changes should not be assumed to have infection-related neurologic dysfunction before EEG findings rule out nonconvulsive status epilepticus.
  • Consider catscratch fever (catscratch disease), particularly in a school-aged child with a cat or kitten at home who presents with a history of unexplained mental status changes, status epilepticus of unknown etiology, prolonged seizures, or persistent fatigue. Catscratch fever is an infection acquired from cats (often from kittens) infected with Bartonella henselae via the cat flea.
  • • Elevated titers of B henselae are observed in more than 85% of patients, although similar clinical pictures are observed in patients infected by Bartonella quintana and Afipia felis. Confirmation of a catscratch fever diagnosis is based on elevated indirect fluorescent antibody titers to B henselae.
    • The peak incidence of catscratch fever is in children aged 3-12 years. The disease affects teenagers and adults less frequently.
    • In 90-95% of cases, the patient has had contact with a cat, usually a kitten younger than 1 year. Although the disease may be transmitted by any close contact with a cat, scratches or bites cause 75% of cases.
    • Lymphadenopathy in the region draining the primary inoculation site is almost universal, ranging from 95-100% in most series. An inoculation lesion often occurs as well.
    • The possible manifestations of catscratch fever include CNS complications, fever, malaise, anorexia, Parinaud syndrome, sore throat, rash, arthralgia, and conjunctivitis. Neurologic effects of catscratch disease include seizures and status epilepticus, meningoencephalitis, behavioral changes (eg, combativeness), coma, neuroretinitis, myelopathy, radiculitis, cerebral arteritis, and facial nerve palsy.
• Chronic-progressive neurological disorders represent just 5% of cases.
• Remote symptomatic status epilepticus, referring to status epilepticus secondary to static conditions (eg, such as a remote cerebral insult on the perinatal period), constitutes 10-15% of cases.
• More recently, the use of cephalosporin antibiotics (cefepime and ceftazidime) has been associated with the precipitation of status epilepticus. This association is especially important in the setting of impaired renal function.
• Some anticonvulsants may produce de novo nonconvulsive status epilepticus (both absence and complex partial types). Carbamazepine and tiagabine are commonly mentioned. Patients with Lennox-Gastaut syndrome may develop status epilepticus due to excessive sedation (usually chronic benzodiazepine use). 
• No precipitant is found in 8-10% of cases of generalized tonic-clonic status epilepticus. Of the many precipitants described in children, infection and fever collectively make up the most common (35.7%). Other common precipitants and their reported frequencies are as follows:
• • Medication changes - 20%
  • Metabolic precipitants - 8%
  • Congenital precipitants - 7%
  • Anoxia - 5%
  • CNS infection - 5%
  • Trauma - 3.5%
• Generalized tonic-clonic status epilepticus recurrence is as follows:
• • Generalized tonic-clonic status epilepticus may recur in 17-25% of children. Recurrent status epilepticus primarily occurs in children with neurologic abnormalities.
  • The risk of recurrence also varies among the etiologic groups. Idiopathic and remote symptomatic groups have the highest recurrence risk (28% in prospective studies). The febrile seizure group has a prospective recurrence risk of 3%. 
• Nonconvulsive status epilepticus is commonly associated with a prior diagnosis of the following epileptic syndromes: Lennox-Gastaut syndrome, myoclonic-astatic epilepsy, childhood absence epilepsy, and localization-related epilepsy (partial seizures).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Psychogenic seizures

Occasionally, psychogenic seizures can be confused with generalized tonic-clonic status epilepticus (GTCSE). Patients with nonepileptic seizures can reproduce an outward clinical seizure pattern as a manifestation of an unresolved psychological conflict (psychogenic seizure), or the seizure may be a malingering manifestation, providing the patient with a clear secondary gain.

However, pediatric patients rarely fake a seizure. Symptoms of true psychogenic seizures resemble conversion symptoms. Symptoms are often similar to those of generalized tonic-clonic status epilepticus; however, many times, a few details make the physician aware of the nonepileptic nature of the event (eg, no loss of consciousness in the presence of bilateral movements, asynchronous movements, pelvic thrusting, inconsistency of movement patterns). Nonetheless, no loss of consciousness in the presence of bilateral movements, pelvic thrusting, and asynchronous and thrashing movements can be part of frontal lobe seizures, which may lead to status epilepticus in some cases. Only careful observation of the patient (eg, video) with simultaneous EEG allows the physician to differentiate between sustained nonepileptic seizures and generalized tonic-clonic status epilepticus.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

The following studies are indicated in patients with status epilepticus (SE):

• Stabilization phase: While attending to the ABCs and inserting an intravenous (IV) line, obtain CBC count and laboratory studies for anticonvulsant medication, electrolyte, BUN/creatinine, calcium, and magnesium levels.
• • Serum glucose measurement should be performed by a fast assay (eg, Dextrostix); this measurement is particularly important because hypoglycemia may be a contributing factor or cause of seizures in adults or children.
  • Although routine laboratory studies are not always useful in assessing patients with brief seizures who present to the emergency department (ED), children with generalized tonic-clonic status epilepticus (GTCSE) require a more aggressive workup. Other necessary tests may include urine/serum toxicology, especially in teenagers with unexplained seizures. If school-aged children who have cats (particularly kittens) at home present with unexplained mental status changes and prolonged seizures, evaluate for catscratch fever based on elevated indirect fluorescent antibody titers to B henselae. A lumbar puncture is commonly indicated in children with generalized tonic-clonic status epilepticus, especially those with unexplained fever or mental status changes preceding or following the seizure episode.
• Continued evaluation: Continue evaluation after seizures are controlled.
• • Basic tests recommended by the Epilepsy Foundation Working Group on Status Epilepticus include liver function tests (LFTs), toxicology screen, and brain imaging.⁵
  • After a status epilepticus episode, perform a lumbar puncture for individuals with fever or other evidence of CNS infection. Remember that febrile convulsive status may be associated with CNS infection without typical meningeal signs. Brain imaging should be part of the workup for status epilepticus prior to lumbar puncture for patients with acute neurologic changes as evidenced by increased intracranial pressure.

Imaging Studies

• Imaging studies are indicated in patients with generalized tonic-clonic status epilepticus once they are stabilized. In many centers, head CT scanning is available on an emergency basis. If CT scanning is unavailable and the patient is stable and has no signs of increased intracranial pressure, CT scanning can be temporarily deferred.
• Perform an imaging study for all patients who have histories of neurologic (including mental status) changes and for patients who have actual deficits on the neurologic examination that persist after cessation of seizures.
• Brain imaging should be part of the workup for status epilepticus prior to lumbar puncture for patients with acute neurologic changes as evidenced by increased intracranial pressure.
• Children with complex partial seizures preceding or leading to the episode of generalized tonic-clonic status epilepticus should undergo brain MRI. In many centers, CT scanning is performed in the ED because MRI services are often unavailable after hours. If not immediately available, MRI should be performed in the following days.
• Brain imaging may be unnecessary for patients who have already had MRI performed as part of workup for epilepsy or when the cause or precipitant for their episode of status epilepticus is obvious (eg, low anticonvulsant levels, acute infection).
• On follow up many patients with documented a priori normal MRI findings may develop increased T2, diffusion and fluid attenuated inverted recovery (FLAIR) signal. This is especially true in cases of prolonged partial seizures leading to secondary generalized tonic-clonic status epilepticus. Most of these changes are either due to transient vasogenic or cytotoxic edema.

Other Tests

• Every patient who presents with status epilepticus requires EEG; however, treatment should not be delayed to wait for EEG results. When a seizure persists longer than 30-60 minutes, making immediate arrangements for an EEG is advisable.
• The EEG helps in differentiating the convulsive status from pseudoseizure (nonepileptic or psychogenic seizure). Nonconvulsive status epilepticus (NCSE) may need to be differentiated from postictal state–related depression and unresponsiveness from metabolic (renal and hepatic) as well as anoxic encephalopathies. Especially when treatment with anticonvulsant medication does not improve the patient’s alertness.
• Patients who ultimately require continuous infusion with a barbiturate or benzodiazepine (see Medical Care) should undergo continuous EEG monitoring.
• During a prolonged seizure, EEG manifestations follow a sequence of partial (focal) EEG seizures, leading to discrete generalized tonic-clonic seizures that eventually become fused (ie, continuous EEG seizure). Rhythmic lateralized or generalized discharges later appear to slow in frequency and may appear similar to periodic lateralizing epileptiform discharges (PLEDs). A patient who arrives at the ED may be at any of these EEG stages; historical information concerning seizure progression usually correlates somewhat with stage. Patients at the later stages of EEG with generalized tonic-clonic status epilepticus may be more difficult to treat.
• Patients who cannot be aroused following a seizure should have an EEG performed to rule out subclinical status epilepticus. An EEG can confirm the seizure pattern and help indicate the most appropriate long-term treatment, if necessary. For example, a toddler with a history of one unprovoked seizure presents with a generalized tonic-clinic convulsion that lasts 45 minutes; after the event, her EEG findings reveal frequent unilateral spikes. In this situation, the physician would probably recommend treatment with a medication effective against partial seizures (eg, carbamazepine, phenytoin) when the child leaves the hospital.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Status epilepticus (SE) treatment should follow a logical sequence of interventions. Every institution dealing with this problem should design a thoughtful and periodically revised plan, such as the plan outlined below. The lack of a structured protocol has been blamed for increased morbidity in the treatment of status epilepticus. Physicians should become familiar with the pharmacology of the drugs used to treat status epilepticus. Prudence calls for doses of these drugs to be placed in visible locations within emergency departments (EDs), pediatric units, and nursing stations.

Treatment for generalized status epilepticus should be part of a continuum of the management for seizures of shorter duration. Any algorithm for treating seizures should consider the time of onset of the ictal activity (continuous or intermittent without recovery of consciousness) and the number and type of drugs that did not control the seizures, despite appropriate dosages and routes of administration. Remember that seizures of longer duration tend to be more difficult to treat. Before starting any pharmacologic intervention, be mindful of the patient's basic care. Thus, attend to the ABCs first as in any emergency situation. The table below is based on the Emergency Management Guidelines of Children's Hospital and Regional Medical Center.

• Early management to stabilize patient
• • As in any medical emergency, first attend to the ABCs. Place patients in the lateral decubitus position to avoid aspiration of emesis and to prevent epiglottis closure over the glottis. Further adjustments of the head and neck may be necessary to improve patency of the airways (use care in the setting of potential neck trauma without full radiographic evaluation).
  • Respiratory depression is a common complication of the management of prolonged seizures. Ensure that equipment is available to deliver supplemental oxygen and positive pressure ventilation when initiating anticonvulsant therapy.
  • Carefully monitor the patient's vital signs, including blood pressure.
  • Carefully monitor the patient's temperature because hyperthermia may worsen brain damage caused by seizures.
  • In the first 5 minutes of seizure activity, before starting any medications, try to establish intravenous (IV) access and to obtain samples for laboratory tests and for seizure medication levels.
  • Perform blood glucose measurement by a fast assay (eg, Dextrostix); this is particularly important because hypoglycemia may be a contributing factor or cause of seizures in adults or children.
  • Administer IV glucose if serum glucose is low or cannot be measured. In these instances, children should receive 2 mL/kg of 25% glucose, and adults should receive 50 mL of 50% glucose, as well as 100 mg of thiamine. The latter drug is used to avoid Wernicke-Korsakoff syndrome.
  • Electrolytes and BUN/creatinine levels are also commonly measured in these patients.
  • Calcium and magnesium measurement may also be important, especially for infants fed with cows' milk and, in some special situations, in adults (eg, renal failure, hypoparathyroidism).
  • If the onset of the seizure is witnessed, initiate anticonvulsant treatment only after 5 minutes of seizure duration. Most seizures stop without intervention.
  • Obtain a history of the prehospital treatment of the seizures. Cumulative doses of benzodiazepine medication (prehospital included) increase the risk of respiratory failure.
  • In cases of repetitive convulsions without recovery of consciousness, the duration of the seizure is defined as the time elapsed from the onset of the first seizure to the termination of the last.
  • Call for the pediatric ICU (PICU) service and respiratory therapists (or anesthesiologists) if seizures persist for more than 20 minutes.

Medical Treatment of Seizures and Status Epilepticus Based on Time Elapsed Since Seizure Onset

*Not approved by the FDA for the indicated use

†Doses for fosphenytoin administered in phenytoin equivalents (PE)

‡An alternative third step preferred by some authors is midazolam* administered by continuous IV infusion with a loading dose 0.1-0.3 mg/kg followed by infusion at a rate of 0.1-0.3 mg/kg/h.

• Sequence of pharmacologic treatment for generalized tonic-clonic status epilepticus (GTCSE)
• • Following the early stabilization phase (the first 5-10 min after seizure onset) the treatment sequence for generalized tonic-clonic status epilepticus includes IV administration of a benzodiazepine (lorazepam or diazepam) under cardiorespiratory monitoring.
  • If an IV line cannot be established in a child after 5-10 minutes, use PR diazepam. IM midazolam has recently been used as an alternative to PR medication, but IM midazolam is not approved by the FDA for that indication. Intranasal midazolam may also be an option in children with prolonged seizure without an IV access.
  • When benzodiazepines do not stop the seizures, start phenytoin (or fosphenytoin) as the second medication. If phenytoin/fosphenytoin is ineffective in arresting the ictal activity, then use phenobarbital. Many pediatric institutions use benzodiazepine as the first treatment for infants with seizures, followed by phenobarbital and phenytoin/fosphenytoin as the third option if ictal activity persists.
  • Although respiratory depression that requires endotracheal intubation may occur at any time during treatment of generalized tonic-clonic status epilepticus, it is especially common during administration of phenytoin/fosphenytoin.
  • If seizure activity persists despite appropriate treatment with a benzodiazepine, phenobarbital, or phenytoin/fosphenytoin, then start midazolam drip (not approved by the FDA), barbiturate, or propofol (not approved by the FDA) anesthesia. PR paraldehyde can be tried before midazolam drip or barbiturate anesthesia, although paraldehyde requires knowledge of techniques for handling a drug that may dissolve plastic syringes. In recent years, paraldehyde has become more difficult to obtain commercially.
  • Begin cardiorespiratory monitoring with initiation of pharmacological therapy.
  • Transfer any child who requires continuous infusion of medications (eg, midazolam, barbiturate) because of prolonged seizure to an ICU; EEG monitoring is strongly advised.
• Refractory generalized tonic-clonic status epilepticus
• • The term refractory generalized tonic-clonic status epilepticus has been used when seizures do not respond to benzodiazepines, phenytoin/fosphenytoin, and phenobarbital. Several options are presently available for these patients.
  • Barbiturate anesthesia is among the most popular treatments, although midazolam infusions (neither are approved by the FDA) have gained growing acceptance in the United States over the past 5 years. In the United States, barbiturate anesthesia is commonly performed with pentobarbital infusions; in the United Kingdom, thiopental (thiopentone) is often used. High-dose phenobarbital has been used in patients with generalized tonic-clonic status epilepticus.
  • All barbiturates used in anesthetic doses have been associated with such complications as hypotension, cardiac depression, and infections.
  • Increasing acceptance throughout the world of midazolam and propofol as alternative treatments for refractory generalized tonic-clonic status epilepticus relates to the comparative ease of handling these drugs in a continuous infusion. Due to reports of severe acidosis and movement disorder after prolonged propofol use, this agent is not currently recommended for long-term status epilepticus control. Also worrisome is the association of propofol related metabolic acidosis with the use of the ketogenic diet. Midazolam has been used, even in neonates, and has a reasonably predictable pharmacology, although movement disorders have been reported from prolonged use of midazolam for sedation. (See Medication for barbiturate, midazolam, and propofol dosages.)
  • In a few cases, adding a maintenance anticonvulsant medication to the patient's regimen may help wean the patient off a continuous barbiturate infusion. Although the experience is still very small, both IV valproic acid and topiramate via nasogastric tube have been used with that goal.
  • High-dose topiramate has been used in adults with status epilepticus, with doses as high as 1600 mg/d. One pediatric study used relatively lower initial doses 2-3 mg/kg/d before proceeding within 48-72 hours to a maintenance of 5-6 mg/kg/d (divided twice daily), which terminated the episode of status epilepticus.⁶ Another study reported loading dose of 10 mg/kg followed by 5 mg/kg/d maintenance (divided twice daily).⁷ Treatment of status epilepticus with topiramate is suggested by the neuroprotective action of this drug in animal models. Nonetheless, further data is necessary to show similar action in humans.
  • IV valproic acid is used for 3-Hz spike and wave stupor (absence status epilepticus) and myoclonic status in cases of juvenile myoclonic epilepsy and postanoxic myoclonus.^{8, 9} Treatment of convulsive status (ie, generalized tonic-clonic status epilepticus) with IV valproic acid after other drugs (eg, benzodiazepines, phenytoin, phenobarbital) have failed has been rarely reported. Both secondary and primary generalized tonic-clonic status epilepticus seem to equally respond to IV valproic acid. A loading dose of 15-20 mg/kg is used, followed by 10 mg/kg every 6 hours. Alternatively, Uberall et al recommend a loading dose of 20-40 mg/kg over 5 minutes, followed by an infusion at a rate of 5 mg/kg/h.¹⁰ After 12 hours of clinical and EEG cessation of seizures, the dose is reduced to 1 mg/kg every 2 hours.
  • In Europe, alternative agents such as paraldehyde, lidocaine (Sweden and United Kingdom), and chlormethiazole (mostly United Kingdom) have been used. Paraldehyde is no longer commercially available in the United States whereas chlormethiazole is not approved by the FDA. Lidocaine is unpopular in the United States because of its narrow therapeutic index and proconvulsant effect in toxic levels.
  • Paraldehyde is a very effective drug, despite problems such as sterile abscess and pulmonary edema. Respiratory failure and hypotension of sudden onset has been described. Shorvon recommends pediatric doses of 0.07-0.35 mL/kg.¹¹ The adult dose is 5 mL PR diluted on the same volume of water. Exposure to air and light causes conversion of paraldehyde to acetaldehyde and then to acetic acid, with subsequent metabolic acidosis when administrated. Paraldehyde dissolves some plastic syringes and tubing if not used immediately. Approximately 80% of the paraldehyde is absorbed after a single rectal dose. Because of the high solubility of paraldehyde in lipids, the passage through the blood brain barrier may depend more on the cerebral blood flow; this is an attractive quality because of the possibility of a differential absorption concentration of the drug by the regions of the cortex involved in the epileptiform activity because they have higher blood flow than the rest of the brain during seizures.
  • Reports have shown the efficacy of levetiracetam in the management of status epilepticus as an add-on therapy in adults with refractory cases, with reported loading doses of 500-2000 mg/d and maintenance dose of 2000-3000 mg/d.

Consultations

Consultation with a neurologist is recommended for patients whose seizures last longer than 15-30 minutes.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

For the sequence of pharmacologic interventions in seizures and status epilepticus (SE), see the Table. This section primarily addresses dosages and pharmacologic properties of anticonvulsant medications used to treat generalized tonic-clonic status epilepticus (GTCSE).

Drug Category: Anticonvulsant benzodiazepines

This class of medications has long been used to treat generalized tonic-clonic status epilepticus and is often mentioned as first-line treatment for seizures in general. Diazepam has been advocated as a first-line agent alone or in combination with phenytoin. Whether a benzodiazepine followed by phenytoin is really the ideal sequence for this combination or if phenytoin (or fosphenytoin) should be followed by a benzodiazepine is unclear. Although the latter sequence appears better in animal models of generalized tonic-clonic status epilepticus, human data are lacking. Experience with benzodiazepines in the treatment of status epilepticus is large. This class of drugs has been described as the most potent used in status epilepticus management.

Although benzodiazepines have presynaptic, postsynaptic, and nonsynaptic actions, probably only their action at the GABA receptor level and their reduction of repetitive firing occur at the unbound drug concentrations observed in vivo.

Benzodiazepines increase chloride conductance by interacting with the GABA receptor. In animals and humans, benzodiazepines effectively stop early status epilepticus; however, late status epilepticus is less responsive to treatment with these drugs. Availability and pharmacokinetic differences should determine the choice of benzodiazepine.

Benzodiazepines are reportedly more effective against primary generalized epilepsy (90-100% effective) and partial hemiclonic convulsions in children without brain lesions. This class of drugs is effective in approximately 60% of status epilepticus cases occurring in partial epilepsy, but they are effective in only 15-59% of cases of tonic status epilepticus or various types of absence seizure status epilepticus (eg, atypical absence) occurring in secondary generalized epilepsy, although no other drug is more effective.

Drug Category: Hydantoins

These agents may act in the motor cortex where they may inhibit the spread of seizure activity.

Drug Category: Barbiturates

These agents have sedative, hypnotic, and anticonvulsant properties and can produce all levels of CNS mood alteration.

Drug Category: General anesthetics

Propofol is a phenolic compound unrelated to other types of anticonvulsants that has general anesthetic properties when administered IV. The development of propofol infusion syndrome, an irreversible chain of events associated with significant morbidity and mortality, is a concern. Propofol infusion syndrome was first described in 1992 by Parke et al.¹² Since then, numerous case reports and reviews have been published.^{13, 14, 15, 16, 17} For more information, see Medscape Medical News. 

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Treat patients with status epilepticus (SE) who have suspected herpes encephalitis with acyclovir until the diagnosis can be confirmed. Suspect herpes virus encephalitis in all patients with fever, mental status changes, and de novo onset of partial seizures, with or without secondary generalization.
• Treatment of catscratch disease is not universally efficacious; rifampin, ciprofloxacin, and trimethoprim-sulfamethoxazole have been successfully used.
• Electrolyte disturbances may cause or perpetuate seizures; hypocalcemia and hyponatremia are the most common. Efforts to correct hyponatremia should be performed carefully because quick shifts in serum osmolality may cause irreversible brain damage from central pontine myelinolysis. Correcting hypocalcemia with intravenous (IV) calcium gluconate should be performed under ECG monitoring because of the possibility of cardiac arrhythmias.

Further Outpatient Care

• Long-term antiepileptic therapy after generalized tonic-clonic status epilepticus (GTCSE) includes the following:
• • Although a complete guide for outpatient management of epilepsy is beyond the scope of this article, the Epilepsy Foundation Working Group on status epilepticus recommends starting some patients, including those with a history of epilepsy or brain lesion, on long-term antiepileptic therapy after a status epilepticus episode.
  • No long-term therapy is indicated for status epilepticus caused by transient problems (eg, metabolic disturbances [hyponatremia], intoxications).
  • No consensus regarding the need for treatment after an instance of febrile status epilepticus or when a first unprovoked seizure is a status epilepticus episode has been reached.
  • Although many studies have shown that recurrent seizure risk is unrelated to seizure duration, a recurring generalized tonic-clonic status epilepticus episode is more likely to be a prolonged seizure.
  • Choose long-term treatment medications based on the patient's seizure type and EEG pattern. Knowledge of the seizure type and EEG pattern should help the physician confirm the diagnosis of an epileptic syndrome and improve selection of anticonvulsant medication.
• Patients with partial seizures respond better overall to carbamazepine, phenytoin, and phenobarbital (infants). Valproic acid and phenobarbital are better treatments for patients with generalized tonic-clonic seizures, although carbamazepine and phenytoin can also be administered for patients with secondary generalized seizures. Valproic acid carries a higher risk of liver failure in patients younger than 2 years and those on polypharmacy.

Comp