Diagnosing, Differentiating, and Managing Status Epilepticus
December 1, 2023 29 minutes read
Author
Randall Lee Ung, MD, PhD, Emergency Medicine Resident, Penn State Health Milton S. Hershey Medical Center
Stephen M. Sandelich, MD, Pediatric Emergency Medicine, Penn State Health Children’s Hospital, Hershey, PA
Peer Reviewer
Catherine A. Marco, MD, FACEP, Professor, Department of Emergency Medicine, Penn State Health — Milton S. Hershey Medical Center, Penn State College of Medicine
Executive Summary
- Status epilepticus is defined as seizures lasting longer than five minutes or multiple seizures without returning to baseline in the interictal phase. It is the most common neurological emergency among children. Of all new-onset seizures in children, 10% will present as status epilepticus, with the highest incidence in the first four years of life.
- Febrile seizures are those that occur in individuals aged 6 months to 5 years in the setting of a fever without identifiable central nervous infection or underlying seizure disorder, including the occurrence of previous non-febrile seizures.
- A high incidence of some form of seizure is associated with children with traumatic brain injuries: 42.5% had some form of seizure, 16.1% had non-convulsive seizures, and 13.8% had non-convulsive status epilepticus. This population’s risk factors for status epilepticus include younger age, nonaccidental trauma, and intracerebral hemorrhage. These data suggest that clinicians should have a low threshold for electroencephalogram and a high suspicion for seizures.
- In children with an intracranial injury, most commonly younger than 1 year of age, seizure alone is associated with a 58% probability of abusive head trauma. The probability increased to 90% in the presence of seizure and rib fractures, which increased to 100% if associated with any two of the following: rib fractures, skull or long bone fractures, apnea, retinal hemorrhage, or head/neck bruising.
- Just as rapid recognition of status epilepticus is paramount, definitive management of status epilepticus is necessary to prevent adverse outcomes. As in any clinical emergency, initial management of airway, breathing, and circulation is critical.
- The first-line medication for status epilepticus is a benzodiazepine.
- A second-line agent is necessary if adequate dosing of benzodiazepines fails to manage seizures. Frequently used second-line agents include levetiracetam, valproate, and phenytoin/fosphenytoin.
- Neonates and very young children have unique considerations, including etiology and management. In this population, inborn errors of metabolism should be higher on the differential diagnosis. Particularly, pyridoxine-dependent epilepsy should be suspected in neonates with status epilepticus refractory to typical therapeutics but responsive to pyridoxine.
Pediatric seizures are a common acute care visit. Recognizing seizures, including the more subtle presentations, is critical for instituting appropriate, timely treatment to improve patient care. An awareness of a stepwise approach to seizure management will assist providers and optimize outcomes.
— Ann M. Dietrich, MD, FAAP, FACEP, Editor
Introduction
Seizures are common phenomena that bring children into the emergency department. They frequently self-resolve within minutes before arrival and require minimal workup and management in the emergency department. However, status epilepticus requires prompt attention, intervention, and may lead to significant morbidity if mismanaged. Status epilepticus also carries a sizeable financial burden — the cost per episode can be around $10,000 and up to $100,000 if it is refractory.1,2
The International League Against Epilepsy (ILAE) defines status epilepticus as a condition resulting in seizure activity for a prolonged duration (defined as timepoint 1) that can result in long-term consequences (after timepoint 2). The exact time points for this definition vary by seizure type and are outlined in Table 1.3
Table 1. Definition of Timepoints for Status Epilepticus |
||
| Timepoint 1 | Timepoint 2 | |
Generalized with impaired consciousness (tonic-clonic) |
5 minutes |
30 minutes |
Focal with impaired consciousness |
10 minutes |
60 minutes |
Absence |
10-15 minutes |
Undefined |
Historically, status epilepticus was defined as seizures lasting 30 minutes. However, this timeline was shortened to emphasize the importance of early treatment to prevent long-term complications with prolonged seizures. Theoretically, improved seizure outcomes would follow this change.
However, one study failed to demonstrate decreased mortality following this change in definition.4 The authors noted the study was significantly limited as a meta-analysis, particularly given the heterogeneity of datasets. Still, given the current framework and knowledge regarding status epilepticus, swift identification and management are prudent within the emergency department.
This review will highlight clinical characteristics relevant to pediatric patients in the emergency department. The focus will be on generalized convulsive status epilepticus in children outside the neonatal period. The studies reviewed here will have differing definitions for status epilepticus, with older studies using the 30-minute definition.
Epidemiology and Risk Factors
Status epilepticus is the most common neurological emergency among children.5 Of all new-onset seizures in children, 10% will present as status epilepticus.6 The overall incidence is about 3.6 cases per 100,000 per year, with the highest incidence in the first four years of life.1,7 Comparatively, strokes (the most common neurologic emergency among adults) have an incidence of about 2.4 cases per 100,000 per year.7 Considering this, status epilepticus is a common presentation that emergency physicians must be comfortable identifying and treating.
Status epilepticus carries significant morbidity and mortality. Mortality during hospitalization for status epilepticus is 2.7% to 5.2% in high-income countries.8 This rate is lower than in adults. Mortality measured at 30 days from presentation is 1.8% in children vs. 10.2% in adults; however, children have a higher rate of acquired neurologic complications (21.3% at 5 to 9 years of age vs. 10.7 % in the whole population).9 These complications include cerebral lesions, cognitive impairment, and intractable epilepsy.
One significant concern with seizures and status epilepticus is the risk of recurrence or underlying epilepsy. An estimated 12% of patients with epilepsy will have status epilepticus as the first seizure.10 However, in the general population, whether the first-time seizure is status epilepticus does not appear to affect the risk of later unprovoked seizure.2 Patients with cryptogenic (or unknown cause) status epilepticus do not have an increased risk of recurrent seizure in general.11
However, the risk of recurrent status epilepticus is 11% for acute symptomatic, 44% for remote symptomatic, and 67% for progressive symptomatic.2 Considering these patients, identifying and managing status epilepticus is important to prevent serious neurologic deficits and mortality.
Important factors to consider regarding the prognosis of status epilepticus are age, etiology, and refractory disease.9,12,13 Notably, these factors likely have some correlation. Status epilepticus in younger patients is more associated with acute symptomatic disease, which also may explain the higher prevalence of neurologic complications.9 The duration of seizure and adequate treatment also are important factors in managing outcomes and will be discussed later.14
Etiology
The causes of status epilepticus are similar to those of seizures in general. Some common etiologies are listed in Table 2. These broadly can be categorized into symptomatic (known) or cryptogenic (unknown) etiology.3 Symptomatic status epilepticus is defined as having a known, identifiable cause, such as infection or toxic ingestion. This category can be further divided into acute, remote, and progressive based on the temporal relationship of insult to status epilepticus. Acute symptomatic status epilepticus is caused by an identifiable and recent insult. No exact time frame is defined; the time will vary depending on the cause. If the insult is treated or removed, the patient is not expected to have a significant likelihood of recurrent seizures.
Table 2. Causes of Status Epilepticus |
|
Causes of acute symptomatic seizures include fever, central nervous system infection, stroke, intracranial hemorrhage, drug intoxication or withdrawal, and electrolyte derangement. These insults can cause lasting changes in some instances and increase the chances of long-term recurrent seizures, with stroke and trauma as notable examples. Status epilepticus that arises later because of these events is classified as remote symptomatic. On the other hand, progressive symptomatic status epilepticus is caused by progressive diseases, such as brain tumors, or progressive myoclonic epilepsy. Seizures become more frequent as these diseases progress.
Lastly, seizures with unknown causes are called cryptogenic, the second most common cause of status epilepticus at 29%.6
Fever
Fevers are the most common cause of status epilepticus in children, causing 32% of all status epilepticus.6 This reflects the high prevalence of febrile seizures. Febrile seizures are those that occur in individuals aged 6 months to 5 years in the setting of a fever without identifiable central nervous infection or underlying seizure disorder, including the occurrence of previous non-febrile seizures. Febrile status epilepticus, therefore, involves febrile seizures that are prolonged or recurrent without returning to the patient’s neurologic baseline. Most cases are focal (67%), and 24% of patients who present with febrile status epilepticus will have had a prior febrile seizure.15
Epilepsy
Epilepsy is a disease where a person has an increased propensity for recurrent seizures after an initial unprovoked seizure.16 The exact wording by ILAE is included in Table 3. By this definition, epilepsy cannot fall under acute symptomatic but may be classified as remote or progressive. In these patients, risk factors for status epilepticus include prior history of status epilepticus, young age, and symptomatic etiology.17 Additionally, 25% of new-onset status epilepticus patients have a family history of seizures, and about 6% of patients ultimately have a new diagnosis of epilepsy.6
Table 3. Definition of Epilepsy |
One of the following:
|
Trauma
Trauma is a less common cause of status epilepticus at about 1.4% (two out of 144 patients), and data in pediatric populations are sparse.6 Unfortunately, nonaccidental trauma always should be considered in pediatric trauma, including in the setting of status epilepticus. Research among the adult population shows that seizures in the setting of trauma often are associated with more severe head injuries, such as skull fractures or subarachnoid and subdural hemorrhages.18 One study in the pediatric intensive care unit showed that, of children with traumatic brain injuries, 42.5% had some form of seizure, 16.1% had non-convulsive seizures, and 13.8% had non-convulsive status epilepticus.19 This population’s risk factors for status epilepticus include younger age, nonaccidental trauma, and intracerebral hemorrhage. These data suggest that clinicians should have a low threshold for electroencephalogram (EEG) and a high suspicion for seizures. Seizures in the setting of head trauma require an increased suspicion of abuse. An estimated 43% to 50% of cases result from abuse, which is the most common cause of death in nonaccidental trauma.20 In children with intracranial injury, seizure alone is associated with a 58% probability of abusive head trauma. The probability increased to 90% in the presence of seizure and rib fractures, which increased to 100% if associated with any two of the following: rib fractures, skull or long bone fractures, apnea, retinal hemorrhage, or head/neck bruising.20
Nonaccidental trauma is essential to recognize given its associations, social implications, and significant morbidity and mortality.
Hypoglycemia
Low blood glucose levels are an uncommon cause of status epilepticus but may have various causes, including inborn errors of metabolism.21,22 The peak age for hypoglycemia is 0 to 28 days of age with a decreasing incidence afterward. Providers quickly should obtain fingerstick glucose serum levels in a seizing patient. Levels below 60 mg/dL should prompt immediate treatment., particularly in younger children.
Electrolyte Derangements
Numerous electrolyte changes may induce seizures and status epilepticus. In general, the rate of change is more important than the actual electrolyte levels. These derangements account for a small percentage of status epilepticus at about 1.4% in one study (two out of 144 patients).6
Hyponatremia is the most common electrolyte abnormality in the emergency department, especially in children younger than 4 years of age, and is an important cause of status epilepticus to consider.23 Younger infants are more susceptible to hyponatremia from dietary changes, such as diluting feeds. One study in adults shows increasing incidence with increasing severity of hyponatremia.24 Hyponatremia is further discussed in the “Neonates” section of this review.
Hypocalcemia also is associated with developing seizures and status epilepticus, and its etiology in children is broad. An initial approach should include assessing parathyroid hormone and magnesium levels. Parathyroid hormone is a principal modulator of calcium levels, and magnesium levels are important in regulating parathyroid hormone. Phosphate levels also can affect calcium levels by causing precipitates that take calcium out of the serum.
Drug Toxicity and Withdrawal
Many drugs potentially can induce seizures and status epilepticus. These seizures can result from intentional or unintentional overdose and drug withdrawal, specifically alcohol and benzodiazepines. Among the pediatric population, toxins account for about 1.4% (two out of 144 patients in one study) of cases of status epilepticus.6 Of all cases of drug toxicity in children, about 4.7% will result in seizure, and antidepressants are the main culprits of this.25 Other drug classes that commonly cause seizures include anticholinergics, antihistamines, sympathomimetics, antiepileptic drugs, and antipsychotics. Notable drugs include bupropion, diphenhydramine, tramadol, dextromethorphan, and isoniazid.
Bupropion came to the U.S. market in 1985 and quickly came off because of the risk of seizures. Indications for this drug include depression and smoking cessation. Bupropion is now available for prescription because of its benefits, and its increased use in clinical medicine has led to increased cases of toxicity and subsequent seizures among children. Urine drug screens often will reveal positive amphetamines, and this should raise suspicion for bupropion toxicity in the setting of seizures.26,27 Neurologic deficits with bupropion toxicity can be profound and mimic brain death.28 Bupropion also causes significant cardiotoxicity and may require extracorporeal membrane oxygenation in severe cases of cardiogenic shock.29 Although no specific antidote exists, lipid emulsion has been proposed as an option in severe cases.30 However, management mainly is supportive.
Isoniazid is another noteworthy cause of status epilepticus because of its specific treatment with pyridoxine (vitamin B6).31 Isoniazid often is associated with treating both latent and active Mycobacterium tuberculosis infection. Toxicity causes pyridoxine deficiency and subsequent gamma-aminobutyric acid (GABA) deficiency, leading to disinhibition and, thus, seizures.
Pathophysiology
Seizures are the result of abnormal synchronized or excessive neuronal activity. This abnormal activity classically manifests as generalized convulsions with specific changes on an EEG. When prolonged, seizures are classified as status epilepticus.
Multiple cellular mechanisms can contribute to developing seizures and status epilepticus.21 These include altered intrinsic properties of neurons, such as sodium, potassium, and calcium dynamics, and altered synaptic transmission through glutamatergic and GABAergic pathways. Ultimately, these mechanisms lead to increased excitability and disinhibition, creating a state promoting excessive and synchronized neuronal activity. The basis of multiple genetic diseases associated with seizures also suggests the complex pathophysiology underlying seizures. One review highlighted 41 different ion channel genes related to epilepsy.32 Many antiepileptic drugs have proposed mechanisms that target various ion channels and neurotransmitter pathways, and benzodiazepines, the first-line treatment for seizures, work by enhancing GABAergic transmission.33 Additionally, carbamazepine blocks voltage-gated sodium channels, and ethosuximide blocks T-type calcium channels.
Clinical Features
The diagnosis of status epilepticus is made clinically, and aspects of patients’ histories and presentations will guide management. Status epilepticus is defined as seizures lasting longer than five minutes or multiple seizures without returning to baseline in the interictal phase.
The overall presentation of status epilepticus is no different from that of a seizure but has the stipulation of a five-minute duration. Patients (or often patients’ family or friends) will report a loss of consciousness and concurrent convulsions. This episode may be preceded by an aura or prodrome and typically following the seizure there will be a period of altered consciousness, known as the postictal period. Important history includes prior seizures and any preceding or provoking events. Other features often obtained in the history and exam are tongue biting and incontinence. Tongue biting, particularly if involving the lateral aspect, may help differentiate seizure from other causes, such as syncope or psychogenic seizures.34,35 Urinary incontinence likely is less helpful but may have some diagnostic value.36,37 Notably, neither of these findings is necessary for diagnosis but may guide in developing the differential diagnosis, as discussed later.
Using clinical features, seizures and status epilepticus can be categorized based on four axes: semiology, etiology, EEG findings, and age of the patient.3 These characteristics are not always obtainable in the emergency department and are not necessary to ascertain in the acute setting.
Semiology describes the features of the seizure and is based on initial motor involvement and state of consciousness. Therefore, status epilepticus can be categorized as focal vs. generalized and impaired vs. intact consciousness. If conscious, this information may be obtained from the patient, but it often will come from family members or friends who witnessed the events.
Etiology is the second axis and has significant prognostic value. Patients may be able to describe certain circumstances, such as fever or trauma, but this may be information gleaned from witnesses. Essential considerations include new medications or medication changes, recent infections or fever, and trauma.
EEG is the definitive diagnosis method but rarely is valuable for acute management. However, in certain circumstances, this information already may be available, such as for patients who have ongoing EEG monitoring and are being evaluated for possible seizures. Regardless, EEGs are not routinely obtained in the emergency department and often are performed in the inpatient or even outpatient setting in patients that are stable enough for discharge.
An epileptologist can interpret findings to characterize seizures better and can help identify subtle forms of seizures and status epilepticus. Importantly, no specific signature exists to differentiate status epilepticus seizures from non-status epilepticus seizures on EEG; the differentiation is based on clinical features.
Age is the final axis to classify status epilepticus and helps categorize patients to the most likely underlying pathophysiology. Febrile status epilepticus, for instance, is associated with younger children. Additionally, younger age is associated with more frequent neurologic complications.9
Diagnostic Studies
Diagnostic studies can help guide diagnosis in uncertain cases or help with management but should not delay treatment. These studies often will start alongside treatment and run in parallel. One important assay that should be obtained at the onset of (if not before) status epilepticus is point-of-care blood glucose. Early identification of hypoglycemia will spare unnecessary interventions, such as benzodiazepines that can cause respiratory distress. Sodium levels also should be obtained quickly if a point-of-care assay is available to address hyponatremia if symptoms present swiftly. Another point-of-care test to remember is a urine pregnancy in females of childbearing age, which may significantly alter the management course.
Other helpful laboratory studies include a basic metabolic panel for electrolytes plus magnesium, antiepileptic drug levels (if applicable), and a toxic drug screen. One study showed that 6% of patients with status epilepticus had electrolyte or glucose abnormalities, 3.6% had a toxic ingestion, and 33% had subtherapeutic levels of antiepileptic drugs.38 Laboratory studies to consider are outlined in Table 4.
Table 4. Laboratory Studies for Status Epilepticus |
|
The American Academy of Pediatrics recommends a metabolic screen with the first afebrile seizure including glucose, electrolytes with calcium and magnesium, and renal function studies, although there is little evidence supporting this practice. In children with other concerning symptoms, including unexplained global delay or regression, organomegaly, unusual odor, or acute presentation with altered level of consciousness, multiorgan dysfunction, and vomiting, or if there are similarly affected siblings, a more extensive metabolic evaluation to identify inborn errors of metabolism may be indicated.
Lactic acid, prolactin, and neuron-specific enolase also may have utility in specific clinical scenarios. These markers may be elevated in the setting of status epilepticus but are not sensitive.39 One possible use for these is differentiating psychogenic causes, since levels would not be expected to be elevated. However, these assays' accuracy and utility must be strongly validated.
The patient’s clinical presentation should guide further laboratory studies. For instance, complete blood count, blood cultures, cerebrospinal fluid studies, and lactic acid may be helpful in the setting of fever or other infectious concerns.
Imaging
After initial management of status epilepticus, imaging studies can provide insight into the underlying cause. Head imaging can help identify pathology, such as intracranial hemorrhage or masses. One retrospective study showed that the yield from neuroimaging following status epilepticus was 36%, and 8.5% of status epilepticus cases revealed an urgent or emergent pathology.40
Neuroimaging in the emergency department typically is limited to computed tomography (CT) imaging, considering magnetic resonance imaging’s (MRI’s) availability and time constraints. For patients with urgent or emergent pathology on imaging, CT imaging did not reveal these findings in 27% of cases, such as acute demyelinating encephalomyelitis, meningoencephalitis, and acute ischemic stroke.40
Regardless, CT imaging may be helpful to identify other causes, such as intracranial hemorrhage or brain tumors. Although less commonly used in the emergency department, MRI may be useful to identify direct changes from seizure activity, such as edema, to help with further diagnosis and management, particularly in nonconvulsive status epilepticus.41 MRI also can better characterize underlying tumors if present and identify less subtle findings, such as those missed by CT in the study described earlier.40
Lumbar Puncture
Lumbar puncture is not routinely performed for status epilepticus, particularly within the emergency department. However, a lumbar puncture should be considered if meningitis is a concern. Results from this study may confirm an infectious process and guide antimicrobial therapy.
Electroencephalogram
EEG can make the definitive diagnosis of a seizure but has little utility in the emergency department. EEG should be considered following initial management to characterize the underlying pathology, including focality and other factors. EEG also is helpful if persistent seizures are a concern, particularly with refractory status epilepticus. This is especially true for sedated patients because physical manifestations are absent. EEG also may be useful if the diagnosis is unclear, such as nonconvulsive seizures or differentiating psychogenic or other non-epileptic causes.
Differential Diagnosis
The differential for status epilepticus is limited, considering that few pathologies mimic its presentation. Syncope may present with abnormal movements but is unlikely to persist for five minutes. One valuable differentiating factor is tongue biting.34 Particularly if the laceration of the tongue is along the lateral aspect, tongue biting likely is caused by an underlying seizure.
Psychogenic seizures can be more challenging to differentiate from epileptic seizures. Without EEG recording, making a definitive diagnosis can be difficult. These patients often are treated as having epileptic seizures when presenting to the emergency department, which unnecessarily adds to the healthcare system’s significant burden.42 Tongue biting and urinary incontinence may help make this differentiation.35,37 Although these findings may be specific, sensitivity is relatively low, and the absence of these findings cannot rule out underlying seizures. Additional findings that may be useful to distinguish psychogenic causes also have been identified through video EEG monitoring, including preserved awareness, eye flutter vs. opening, intensity modulation by bystanders, abrupt onset, and lack of a postictal phase.43
These attributes are not reliable differentiators if reported by eyewitnesses. Serum prolactin levels also may help differentiate psychogenic seizures, but negative levels cannot rule out epileptic seizures. Neuron-specific enolase and creatine kinase also have been proposed to have utility in determining psychogenic causes, yet evidence to support this also is weak.39
Management
Initial Management
Just as rapid recognition of status epilepticus is paramount, definitive management of status epilepticus is necessary to prevent adverse outcomes. As in any clinical emergency, initial management of airway, breathing, and circulation is critical. In the setting of status epilepticus, proper management of airway and breathing is even more important because they can be particularly tenuous. First-line treatment with benzodiazepines may worsen this. On the other hand, circulation often remains stable during a seizure, and sympathetic surge often results in increased heart rate and blood pressure.44 During this initial assessment, intravenous access is essential to administer antiepileptics, sedatives, and paralytics as needed.
Part of the initial assessment for status epilepticus is a point-of-care glucose level, since hypoglycemia is vital to identify if it is present. A low blood glucose level is an easily correctable cause of seizures; however, it is an uncommon cause of status epilepticus.22 Dextrose is the definitive treatment for hypoglycemia, with 0.5 mg/kg as a general goal for administration. Clinicians should carefully consider possible adverse effects of high concentrations of dextrose, such as thrombophlebitis, especially in neonates and younger children who would benefit from the use of 10% dextrose.
Selection of dextrose concentration may be guided by age. A reasonable guideline is 10% for children younger than 1 year of age, reserving 50% for children older than 8 years of age. Other considerations include the type of intravenous access and immediately available solutions. However, dextrose 50% (D50) can be diluted to 10% and administered at a dose easily remembered by the “rule of 50.”45 (See Table 5.)
Table 5. “Rule of 50” — Dextrose Dosing for Hypoglycemia |
|
| % Dextrose | Dosage |
D10 |
5 mL/kg |
D25 |
2 mL/kg |
D50 |
1 mL/kg |
Antiepileptic Medications
Seizures often will resolve independently without medical intervention. However, when seizures meet the criteria for status epilepticus, emergency physicians must use antiepileptics to abort the seizure. First-line medications are benzodiazepines, with intravenous lorazepam being the typical choice; however, intravenous diazepam is equally effective.46 Alternative medications with doses are included in Table 6. If one dose of benzodiazepines fails, another dose should be administered. However, more than two doses are associated with increased respiratory depression.47
Table 6. Medications for Status Epilepticus |
|
First-line treatment |
If no IV access:
|
Second-line treatment |
|
Refractory treatment** |
|
*Not as well studied IV: intravenous(ly); PR: rectally; IN: intranasally; IM: intramuscularly; PE: phenytoin-equivalent dose |
|
Adequate dosing is imperative in management. Benzodiazepines frequently are underdosed at first-dose administration.48 This underdosing likely is because of concerns for respiratory depression; however, one randomized controlled study in the prehospital setting showed that placebo was associated with twice as likely respiratory depression as compared to 2 mg of lorazepam or 5 mg of diazepam in an adult population.49 Additionally, delayed administration is associated with worse outcomes, including death.50
A second-line agent is necessary if adequate dosing of benzodiazepines fails to manage seizures. Frequently used second-line agents include levetiracetam, valproate, and phenytoin/fosphenytoin. Multiple studies show no significant difference in effectiveness among these agents.51-53 Levetiracetam’s low side effect profile makes it a popular choice for status epilepticus that has not adequately responded to benzodiazepines.
One randomized controlled study showed that levetiracetam may be superior to phenytoin for seizure control, but multiple other randomized studies have failed to validate this finding.54-56 Notably, valproate generally is avoided in children younger than 3 years of age because of hepatotoxicity and the potential for undiagnosed metabolic disorders.5
Ketamine also is a reasonable option as a second-line agent, especially considering its synergistic role with benzodiazepines as an antagonist to glutamatergic (excitatory) activity.57 However, this agent is not as well studied or commonly used.
Status epilepticus that fails to respond to two agents is considered refractory, and infusion of antiepileptics is indicated. Common choices for this include midazolam and pentobarbital. Propofol is frequently used in adults but is not commonly used in children because of the risk of propofol infusion syndrome. This risk has been reported to be fatal when administered with a ketogenic diet.58 Ketamine also is a potentially efficacious medication for managing refractory status epilepticus.59 Ketamine is a desirable alternative, considering it does not share the same side effects of hypotension and decreased respiratory drive as midazolam and pentobarbital.
With any of the antiepileptic infusions, patients also likely will require intubation, given the significant sedation from these drugs, and will require management in an intensive care unit.
Additional Therapeutics
A subset of patients with recurrent seizures will have neuromodulatory devices implanted to suppress seizure activity implanted.60,61 These typically produce neurostimulatory pulses regularly to provide around-the-clock control of seizures. Vagus nerve stimulation (VNS) was first used in 1988 for intractable partial seizures, and the Food and Drug Administration approved its use in 1997.62
Despite its usefulness, patients with this device still may experience breakthrough seizures. Fortunately, these devices also can deliver on-demand stimulation during auras to prevent seizure onset or during active seizures to attenuate or abort them.63-65 On-demand stimulation can be accomplished by placing a magnet over the device, often implanted in the left chest. This is similar to disabling features of pacemakers or implantable cardioverter defibrillators.
In patients without this device and with refractory status epilepticus, placing the device for seizure control may be beneficial during admission.60 Other neuromodulation devices include responsive neurostimulation (RNS) and deep brain stimulation; however, these devices do not have on-demand stimulation like VNS.61
Other therapeutics to consider include sodium repletion for hyponatremia and pyridoxine for pyridoxine deficiency. These generally are considered in the neonate population and are discussed later in the “Additional Aspects” section of this review. Rarely, patients with pyridoxine-dependent seizures are diagnosed outside the neonatal period.66 Pyridoxine also is helpful for isoniazid toxicity, another common drug that causes status epilepticus.25
Seizure precautions also should be employed. The specifics likely will vary between institutions but generally include ensuring a safe space for seizure occurrence, including soft padding and rails up in the bed. Additionally, having suction and oxygen readily available would be prudent.
A final step that is not strictly medical management is restricting driving and other dangerous activities following a seizure. The policy will vary by state, but patients who experience a seizure should not be allowed to drive for a defined time (often six months) until seizure-free or cleared by a neurologist. This restriction is both a public health issue and for patient care. Providers should be knowledgeable about and follow their local state regulations.
Additional Aspects
Neonates
Neonates and very young children have unique considerations, including etiology and management. In this population, inborn errors of metabolism should be higher on the differential diagnosis. Particularly, pyridoxine-dependent epilepsy should be suspected in neonates with status epilepticus refractory to typical therapeutics but responsive to pyridoxine. Other metabolic diseases to consider are biotinidase deficiency and molybdenum cofactor deficiency. Neonates also are susceptible to withdrawal seizures from maternal substance use, so maternal history is essential. Gestational and peripartum infections also are important causes to assess. Neonates are more vulnerable to changes in diet, so hyponatremia is a vital etiology. Dilution feeds often are the culprit of hyponatremia and may be seen in the setting of parents with poor financial resources attempting to help ration limited supply.
The management of status epilepticus also requires special attention in this younger population. The first-line agent frequently is phenobarbital (vs. lorazepam or other benzodiazepine), dosed at 10 mg/kg to 20 mg/kg.67-69 An acceptable and equally effective option is phenytoin.70 Levetiracetam is inferior to phenobarbital as a first-line agent in neonates.55 If first-line treatment fails, second-line agents often are poorly effective.71 Agents typically considered for this are levetiracetam, lidocaine, and midazolam. Pyridoxine and other agents to address the possibility of underlying inborn errors of metabolism also should be considered in refractory seizures.
However, newer agents are being explored, including ketamine, as discussed earlier in the “Management” section, and this may prove beneficial for refractory seizures in neonates.
Pregnancy and Eclampsia
Eclampsia needs to be considered in pregnant patients, especially if they are at more than 20 weeks’ gestation and have a history of preeclampsia. A point-of-care pregnancy test will help identify these patients if not obvious on history or physical exam. A high suspicion among pregnant pediatric patients is important, considering that eclampsia disproportionately affects these patients.72-74
Eclampsia is a generalized pregnancy or early postpartum seizure in patients with a pregnancy-related hypertensive disorder.73 An alternative etiology, such as epilepsy, should be ruled out. Eclampsia is important to differentiate given its unique treatment of magnesium. Magnesium is the first-line abortive medication with dosing at 4 g to 6 g intravenously or 10 g intramuscularly split into two administrations of 5 mg in each buttock.73,75 A 2 g/hour infusion should follow this bolus to prevent a recurrence. Magnesium is associated with reduced recurrence when compared to diazepam and phenytoin.76
If seizures are refractory to magnesium, patients should receive the same medications for status epilepticus not caused by eclampsia, including benzodiazepines.75 Valproate should be avoided, given its teratogenicity. Hypertension must be controlled with medications safe for pregnancy, such as hydralazine or labetalol. A reasonable goal is a systolic blood pressure of 160 mmHg and a diastolic blood pressure of 110 mmHg.73
Definitive management is with delivery once stable. Other considerations include relieving pressure from the inferior vena cava by placing the patient in full or near-full left lateral decubitus position.
Summary
Status epilepticus represents a neurological emergency that demands rapid identification and intervention. While it manifests most commonly in children, it can present across all age groups. Characterized by prolonged seizures or recurrent episodes without a return to baseline, this condition can result in significant morbidity and mortality, especially if left untreated. Etiologically, the causes range from metabolic derangements, trauma, and infections to drug toxicity.
Clinically, while convulsions and altered consciousness are hallmark features, the diagnosis hinges on a combination of history, physical findings, and ancillary diagnostic modalities like EEG. Point-of-care tests, especially for glucose and electrolytes, will prove crucial in guiding immediate management. First-line treatment primarily revolves around benzodiazepines, with alternative and adjunctive therapies considered based on the clinical scenario.
Special populations, particularly neonates, require nuanced approaches given their unique etiological considerations and treatment responses. As emergency medicine providers, a comprehensive grasp of status epilepticus, from its pathophysiology to therapeutic strategies, is indispensable to optimize patient outcomes and mitigate long-term neurological complications.
References
- Lu M, Faure M, Bergamasco A, et al. Epidemiology of status epilepticus in the United States: A systematic review. Epilepsy Behav 2020;112:107459.
- Gurcharran K, Grinspan ZM. The burden of pediatric status epilepticus: Epidemiology, morbidity, mortality, and costs. Seizure 2019;68:3-8.
- Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus — Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015;56:1515-1523.
- Neligan A, Noyce AJ, Gosavi TD, et al. Change in mortality of generalized convulsive status epilepticus in high-income countries over time: A systematic review and meta-analysis. JAMA Neurol 2019;76:897-905.
- Messahel S, Bracken L, Appleton R. Optimal management of status epilepticus in children in the emergency setting: A review of recent advances. Open Access Emerg Med 2022;14:491-506.
- Singh RK, Stephens S, Berl MM, et al. Prospective study of new-onset seizures presenting as status epilepticus in childhood. Neurology 2010;74:636-642.
- Williams CN, Piantino J, McEvoy C, et al. The burden of pediatric neurocritical care in the United States. Pediatr Neurol 2018;89:31-38.
- Chin RFM. The outcomes of childhood convulsive status epilepticus. Epilepsy Behav 2019;101(Pt B):106286.
- Choi SA, Lee H, Kim K, et al. Mortality, disability, and prognostic factors of status epilepticus. Neurology 2022;99:e1393-e1401.
- Shinnar S, Berg AT, Moshe SL, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216-215.
- Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: A systematic review. Lancet Neurol 2006;5:769-779.
- Crawshaw AA, Cock HR. Medical management of status epilepticus: Emergency room to intensive care unit. Seizure 2020;75:145-152.
- Valton L, Benaiteau M, Denuelle M, et al. Etiological assessment of status epilepticus. Rev Neurol (Paris) 2020;176:408-426.
- Neligan A, Shorvon SD. Prognostic factors, morbidity and mortality in tonic-clonic status epilepticus: A review. Epilepsy Res 2011;93:1-10.
- Shinnar S, Hesdorffer DC, Nordli DR, et al. Phenomenology of prolonged febrile seizures: Results of the FEBSTAT study. Neurology 2008;71:170-176.
- Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia 2014;55:475-482.
- Berg AT, Shinnar S, Testa FM, et al. Status epilepticus after the initial diagnosis of epilepsy in children. Neurology 2004;63:1027-1034.
- Fordington S, Manford M. A review of seizures and epilepsy following traumatic brain injury. J Neurol 2020;267:3105-3111.
- Arndt DH, Lerner JT, Matsumoto JH, et al. Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort. Epilepsia 2013;54:1780-1788.
- Paul AR, Adamo MA. Non-accidental trauma in pediatric patients: A review of epidemiology, pathophysiology, diagnosis, and treatment. Transl Pediatr 2014;3:195-207.
- Gataullina S, Delonlay P, Lemaire E, et al. Seizures and epilepsy in hypoglycaemia caused by inborn errors of metabolism. Dev Med Child Neurol 2015;57:194-199.
- Wu L, Wu J, Zhang H. Hypoglycemia-induced convulsive status epilepticus as the initial presentation of primary hepatic carcinoma. Neurol Sci 2012;33:1469-1471.
- Yen C-W, Yu M-C, Lee J. Serum electrolyte abnormalities in pediatric patients presenting to an emergency department with various diseases: Age-related differences. Pediatr Neonatol 2022;63:575-581.
- Halawa I, Andersson T, Tomson T. Hyponatremia and risk of seizures: A retrospective cross-sectional study. Epilepsia 2011;52:410-413.
- Finkelstein Y, Hutson JR, Freedman SB, et al. Drug-induced seizures in children and adolescents presenting for emergency care: Current and emerging trends. Clin Toxicol 2013;51:761-766.
- Casey ER, Scott MG, Tang S, Mullins ME. Frequency of false positive amphetamine screens due to bupropion using the Syva Emit II immunoassay. J Med Toxicol 2011;7:105-108.
- Brown KM, Crouch BI. Bupropion overdose: Significant toxicity in pediatrics. Clin Pediatr Emerg Med 2017;18:212-217.
- Reyes R, Figueroa S. Bupropion overdose as a clinically significant confounder of the neurological examination. J Neurocrit Care 2020;13:109-114.
- Heise CW, Skolnik AB, Raschke RA, et al. Two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno-arterial extracorporeal membrane oxygenation. J Med Toxicol 2016;12:301-304.
- Chhabra N, DesLauriers C, Wahl M, Bryant SM. Management of severe bupropion poisoning with intravenous lipid emulsion. Clin Toxicol (Phila) 2017;56:51-54.
- Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: A review. Eur J Emerg Med 2005;12:78-85.
- Wei F, Yan LM, Su T, et al. Ion channel genes and epilepsy: Functional alteration, pathogenic potential, and mechanism of epilepsy. Neurosci Bull 2017;33:455-477.
- Armijo JA, Shushtarian M, Valdizan EM, et al. Ion channels and epilepsy. Curr Pharm Des 2005;11-1975-2003.
- Brigo F, Nardone R, Bongiovanni LG. Value of tongue biting in the differential diagnosis between epileptic seizures and syncope. Seizure 2012;21:568-572.
- Brigo F, Storti M, Lochner P, et al. Tongue biting in epileptic seizures and psychogenic events: An evidence-based perspective. Epilepsy Behav 2012;25:251-255.
- Brigo F, Nardone R, Ausserer H, et al. The diagnostic value of urinary incontinence in the differential diagnosis of seizures. Seizure 2013;22:85-90.
- Oliva M, Pattison C, Carino J, et al. The diagnostic value of oral lacerations and incontinence during convulsive “seizures.” Epilepsia 2008;49:962-967.
- Riviello JJ, Ashwal S, Hirtz D, et al. Practice parameter: Diagnostic assessment of the child with status epilepticus (an evidence-based review). Neurology 2006;67:1542-1550.
- Willert C, Spitzer C, Kusserow S, Runge U. Serum neuron-specific enolase, prolactin, and creatine kinase after epileptic and psychogenic non-epileptic seizures. Acta Neurol Scand 2004;109:318-323.
- Lyons TW, Johnson KB, Michelson KA, et al. Yield of emergent neuroimaging in children with new-onset seizure and status epilepticus. Seizure 2016;35:4-10.
- Meletti S, Monti G, Mirandola L, et al. Neuroimaging of status epilepticus. Epilepsia 2018;59:113-119.
- Lehn A, Watson E, Ryan EG, et al. Psychogenic nonepileptic seizures treated as epileptic seizures in the emergency department. Epilepsia 2021;62:2416-2425.
- Syed TU, Lafrance WC, Kahriman ES, et al. Can semiology predict psychogenic nonepileptic seizures? A prospective study. Ann Neurol 2011;69:997-1004.
- Sánchez Fernández I, Goodkin HP, Scott RC. Pathophysiology of convulsive status epilepticus. Seizure 2019;68:16-21.
- Young TP, Borkowski CS, Main RN, Kuntz HM. Dextrose dilution for pediatric hypoglycemia. Am J Emerg Med 2019;37:1971-1973.
- Chamberlain JM, Okada P, Holsti M, et al. Lorazepam vs. diazepam for pediatric status epilepticus. JAMA 2014;311:1652-1660.
- Chin RFM, Neville BG, Peckham C, et al. Treatment of community-onset, childhood convulsive status epilepticus: A prospective, population-based study. Lancet Neurol 2008;7:696-703.
- Sathe AG, Underwood E, Coles LD, et al. Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial. Epilepsia 2021;62:795-806.
- Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-637.
- Gaínza-Lein M, Fernández IS, Jackson M, et al. Association of time to treatment with short-term outcomes for pediatric patients with refractory convulsive status epilepticus. JAMA Neurol 2018;75:410-418.
- Klowak JA, Hewitt M, Catenacci V, et al. Levetiracetam vs. phenytoin or fosphenytoin for second-line treatment of pediatric status epilepticus. Pediatr Crit Care Med 2021;22:e480-e491.
- Chamberlain JM, Kapur J, Shinnar S, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): A double-blind, responsive-adaptive, randomised controlled trial. Lancet 2020;395:1217-1224.
- Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019;381:2103-2113.
- Noureen N, Khan S, Khursheed A, et al. Clinical efficacy and safety of injectable levetiracetam vs. phenytoin as second-line therapy in the management of generalized convulsive status epilepticus in children: An open-label randomized controlled trial. J Clin Neurol 2019;15:468-472.
- Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam vs. phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): An open-label, multicentre, randomised controlled trial. Lancet 2019;393:2135-2145.
- Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam vs. phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): A multicentre, open-label, randomised trial. Lancet 2019;393:2125-2134.
- Buratti S, Giacheri E, Palmieri A, et al. Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children. Epilepsia 2023;64:797-810.
- Baumeister FAM, Oberhoffer R, Liebhaber GM, et al. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropediatrics 2004;35:250-252.
- Jacobwitz M, Mulvihill C, Kaufman MC, et al. Ketamine for management of neonatal and pediatric refractory status epilepticus. Neurology 2022;99:e1227-e1238.
- San-Juan D, Dávila-Rodríguez DO, Jiménez CR, et al. Neuromodulation techniques for status epilepticus: A review. Brain Stimul 2019;12:835-844.
- Ryvlin P, Rheims S, Hirsch LJ, et al. Neuromodulation in epilepsy: State-of-the-art approved therapies. Lancet Neurol 2021;20:1038-1047.
- Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: Preliminary results. Epilepsia 1990;31:S40-S43.
- Patwardhan RV, Stong B, Bebin EM, et al. Efficacy of vagal nerve stimulation in children with medically refractory epilepsy. Neurosurgery 2000;47:1353-1358.
- Hornig GW, Murphy JV, Schallert G, Tilton C. Left vagus nerve stimulation in children with refractory epilepsy: An update. South Med J 1997;90:484-488.
- Morris 3rd GL, Gloss D, Buchhalter J, et al. Evidence-based guideline update: Vagus nerve stimulation for the treatment of epilepsy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:1453-1459.
- Osman C, Foulds N, Hunt D, et al. Diagnosis of pyridoxine-dependent epilepsy in an adult presenting with recurrent status epilepticus. Epilepsia 2020;61:e1-e6.
- Xu Z-E, Li W-B, Qiao M-Y, et al. Comparative efficacy of anti-epileptic drugs for neonatal seizures: A network meta-analysis. Pediatr Neonatol 2021;62:598-605.
- Le VT, Abdi HH, Sánchez PJ, et al. Neonatal antiepileptic medication treatment patterns: A decade of change. Am J Perinatol 2021;38:469-476.
- Keene JC, Morgan LA, Abend NS, et al. Treatment of neonatal seizures: Comparison of treatment pathways from 11 neonatal intensive care units. Pediatr Neurol 2022;128:67-74.
- Painter MJ, Scher MS, Stein SD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-489.
- Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: A video-EEG monitoring study. Neurology 2004;62:486-488.
- Liu S, Joseph KS, Liston RM, et al. Incidence, risk factors, and associated complications of eclampsia. Obstet Gynecol 2011;118:987-994.
- Fishel Bartal M, Sibai BM. Eclampsia in the 21st century. Am J Obstet Gynecol 2022;226:S1237-S1253.
- Vousden N, Lawley E, Seed PT, et al. Incidence of eclampsia and related complications across 10 low- and middle-resource geographical regions: Secondary analysis of a cluster randomised controlled trial. PLoS Med 2019;16:e1002775.
- Rosenow F, Mann C. Status epilepticus in pregnancy. Epilepsy Behav 2023;138:109034.
- The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995;345:1455-1463.
Pediatric seizures are a common acute care visit. Recognizing seizures, including the more subtle presentations, is critical for instituting appropriate, timely treatment to improve patient care. An awareness of a stepwise approach to seizure management will assist providers and optimize outcomes.
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