Febrile seizures and febrile status epilepticus

Febrile seizures (FSs) are the most common type of pediatric seizure, occurring in patients between 6 months and 5 years of age. They are associated with fever but without intracranial infection or defined cause. They occur at a peak incidence of about 18 months, are generalized tonic-clonic, and last less than 10 minutes followed by a brief postictal period. Factors associated with the risk of having an FS include a family history of FS, peak temperature, and the nature of the underlying illness. The mean temperature associated with FS is 39°C or higher. It appears that it is the peak temperature, not the rising phase of the fever, that is relevant. FSs are considered simple when they are generalized, do not recur within a defined illness, and last less than 10 to 15 minutes. Complex FSs are defined as those that are focal, last longer than 10 to 15 minutes, or occur multiple times within the same febrile illness.

Approximately 5% of children who present with an FS will have an episode of febrile status epilepticus (FSE), accounting for almost 25% of cases of pediatric SE. FSE rarely stops spontaneously, is fairly resistant to ASMs, and even with proper treatment may persist for a significant period of time. The consequences of prolonged FSs in childhood was reported in the FEBSTAT study, in which 199 subjects with FSE had a mean seizure duration of 81 minutes in subjects receiving medications before arriving at the emergency department (ED). The median time from the first dose of an ASM to the end of the seizure was 38 minutes; the initial dose of lorazepam or diazepam was suboptimal in 19% of patients (34 of 166). ^,

Chemically induced seizures

It is difficult at times to determine the immediate precipitant of a seizure/SE in critically ill patients. Multiple factors can lower the seizure threshold, including the underlying medical or surgical process, medications, renal or hepatic dysfunction or failure, fever, hypoxia, metabolic abnormalities, or alkalosis ( Box 64.1 ). Medications commonly associated with a decreased seizure threshold include antidepressants, antibiotics, analgesics, antiarrhythmics, baclofen, chemotherapeutic agents, drug withdrawal (barbiturates, alcohol, opiates), immunomodulators (cyclosporine, tacrolimus, interferons), lithium, neuroleptics, radiographic contrast agents, and theophylline. Drugs of abuse associated with seizures/SE include cocaine, amphetamines, phencyclidine, and γ-hydroxybutyric acid. Less common causes include carbon monoxide, lead, envenomations, camphor, iron, and organophosphates.

Dialysis disequilibrium syndrome

Dialysis disequilibrium syndrome is characterized by neurologic symptoms (headache, nausea, disorientation, restlessness, blurred vision, asterixis, confusion, seizures, coma, and even death) seen during or immediately after hemodialysis. The pathophysiology is thought to involve the movement of water into the brain, causing cerebral edema following the rapid removal of urea, which lowers the plasma osmolality, causing a transient osmotic gradient that favors movement of water into the brain.

Hepatic mechanisms

Postulated hepatic mechanisms of seizures in liver failure include hyperammonemia, abnormal glutamine metabolism, cerebral ischemia, accumulation of toxins, or associated electrolyte abnormalities, such as hyponatremia, hypomagnesemia, or elevated blood urea nitrogen or creatinine. The management of these seizures and possible SE is the same as in other conditions except that one must be cautious with the selection of an antiepileptic medication that is cleared by the liver. The degree of hepatic failure may influence the metabolism of an ASM—in the later stages of hepatic failure with necrosis and loss of hepatic cellular function, the ASM may not be cleared, leading to elevated and potentially toxic ASM levels. Hypoalbuminemia may also contribute to antiepileptic drug (AED) toxicity, particularly in highly protein-bound drugs such as phenytoin and valproic acid.

Hypertensive encephalopathy

Patients with hypertensive encephalopathy have exceeded the upper limit of cerebral autoregulation and may develop what has been termed posterior reversible encephalopathy syndrome (PRES). Presenting signs and symptoms include headache, visual complaints, vomiting, and seizures. Cerebral autoregulation is the process by which cerebral blood flow (CBF) remains constant across a wide range of cerebral perfusion pressures (CPPs). As the mean arterial pressure (MAP) exceeds 150 to 160 mm Hg, arteriolar vasoconstriction is exhausted, and hydrostatic pressure increases continuously, resulting in a breakdown of the blood-brain barrier and cerebral edema. The increased incidence of vasogenic edema in the parietal and occipital lobes is thought to be due to poor sympathetic innervation of the posterior circulation of the brain.

Renal failure

Acute renal failure is associated with uremic encephalopathy and seizures that may result from metabolic abnormalities, including hyponatremia, calcium disorders, uremia, and hypertensive encephalopathy or disequilibrium syndrome seen with hemodialysis. Treatment of seizures in these patients can be difficult as a result of ASM pharmacokinetics in uremia, decreased albumin, and dialysis effects. ASMs that are tightly protein bound (phenytoin, valproic acid) are not significantly dialyzed and usually do not need to be replaced. Clinicians should be cautious, however, as the unbound portion of drug may be higher and dosing adjustments may be necessary.

Transplantation

Solid-organ transplantation can be complicated by a spectrum of seizure types, including single partial-onset or generalized tonic-clonic seizures, acute repetitive seizures, or SE. These seizures can result from hyponatremia, hyper/hypoglycemia, immunosuppressive agents, high-dose antibiotics, infections, cerebral edema, infarction, or postanoxic encephalopathy following hypotension or sepsis. Most seizures occur in the postoperative period on days 4 to 6. The immunosuppressive agents most frequently implicated are the calcineurin inhibitors cyclosporine and tacrolimus. Medication interactions have been described, as phenytoin decreases absorption of cyclosporine, and enzyme inducers (phenytoin, phenobarbital) may increase the clearance of cyclosporine and methylprednisolone.

Pediatric hematopoietic stem cell transplantation (HSCT) is associated with a large spectrum of complications. The most frequent complications are CNS infections, cerebrovascular or metabolic events, and neurotoxicity of immunosuppressive agents manifesting as PRES. Seizures are reported in 7% to 12% of HSCT patients and in 53% to 75% of patients with neurologic complications. There is currently no specific evidence to guide the selection, administration, or duration of ASM treatment in HSCT patients.

Autoimmune status epilepticus

Autoimmune SE is an increasingly recognized condition by neurologists and PICU physicians. SE may be considered autoimmune if it is refractory to ASMs and there is no other known cause, and/or with detection of circulating anti-CNS antibodies; this may then lead to empiric immunomodulatory therapy. Major factors that raise the index of suspicion are recent cognitive or behavioral alterations, a history of malignancy or tumor, or the presence of other neurologic features. Treatment includes immunotherapy, such as corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis (plasma exchange [PLEX]), chimeric antibodies, and other immunosuppressive agents while attempting to optimize ASM therapy.

Cardiorespiratory failure in status epilepticus

Respiratory failure associated with SE is multifactorial in origin. There is an increase in carbon dioxide production from the hypermetabolic state, a decrease in respiratory drive, and an increased mechanical load on the respiratory muscles. The decrease in drive (hypoventilation) may be due to muscle fatigue or secondary to medications used to suppress the seizure. There may also be an increase in dead-space ventilation from aspiration or neurogenic pulmonary edema. ^,

The cardiovascular changes and initial hyperadrenergic state are due to the release of endogenous catecholamines. Patients will have an initial increase in heart rate and systemic vascular resistance that will decrease over time. Of note, there is an entity called ictal bradycardia , which is a rare and probably underestimated manifestation of epileptic seizures whose pathophysiology is still being debated. Autonomic modifications may result from either a sympathetic inhibition or a parasympathetic activation probably due to the ictal discharge arising from or spreading to the structures of the central autonomic network.

Other organ systems

As SE progresses, it is imperative to prevent hyperpyrexia, as it will contribute to neuronal cell death. Studies in adult patients have shown that there may be a CSF pleocytosis. However, any elevation in the CSF cell count in a pediatric patient should suggest a possible infectious etiology. Prolonged muscle activity may produce an elevation in creatine kinase as well as myoglobinuria and acute kidney injury (AKI). Thus, attention to hydration, electrolyte status, and renal function is essential. Acidemia may be worsened by impaired ventilation, hypoxemia, and anaerobic metabolism.

Evaluation and electroencephalography in status epilepticus

The clinical presentation of SE is variable depending on seizure type and baseline developmental and medical status of the child. Diagnosis depends on the identification of continuous or repetitive seizures, typically straightforward with convulsive seizures. However, after prolonged convulsive seizures, the motor manifestations often diminish, and the seizures may become subtle or even nonconvulsive. Differentiating between such NCSs and a postictal state can be challenging. Patients with NCSE, including absence SE, may be difficult to identify by history and physical examination alone. These patients can have intermittent altered awareness and continuous lethargy or unresponsiveness with or without subtle myoclonic jerks of the face or limbs. In such cases, cEEG monitoring is critical for diagnosis. EEG monitoring also can be used to identify nonepileptic (psychogenic) pseudoseizures. Although uncommon, delays in EEG-based diagnosis of pseudoseizures can lead to unnecessary medical intervention.

Common clinical indications for cEEG monitoring in the PICU include (1) titration of ASMs; (2) screening for subclinical seizures among patients at high risk with conditions such as encephalitis, hypoxic ischemic encephalopathy (postarrest, drowning), TBI, and stroke; (3) screening for seizures among patients receiving neuromuscular blockade and at risk for seizures (extracorporeal membrane oxygenation); and (4) characterization of paroxysmal events suspected to represent electrographic seizures. Only half of critically ill children undergoing cEEG monitoring experience their first electrographic seizure during the initial hour of monitoring. Therefore, a routine 20- to 30-minute EEG recording will fail to identify the majority of children who go on to develop seizures, justifying the need for cEEG monitoring to accurately diagnose seizures and quantify seizure burden. The majority of electrographic seizures in the PICU are either subclinical or are accompanied by only subtle clinical signs and would likely go undetected without cEEG monitoring.

EEG interpretation requires the assistance of a trained neurologist or neurophysiologist. Abnormal waveforms on EEG can be divided into two categories: epileptiform and nonepileptiform. Epileptiform abnormalities are discharges associated with an increased risk of seizures, including sharp waves, spikes, polyspikes, and spike and slow-wave discharges. When present between seizures, these waveforms are termed interictal abnormalities . Seizures are defined electrographically by the presence of ictal EEG abnormalities, whose hallmark is rhythmicity and evolution in frequency or distribution over the course of a seizure. Generalized seizures are characterized by widespread bilateral rhythmic epileptiform discharges ( Fig. 64.1 A). Focal seizures are characterized by rhythmic epileptiform discharges that are confined to one brain region ( Fig. 64.1 B). Focal seizures may spread to involve both cerebral hemispheres, a process termed secondary generalization .

Electroencephalography in status epilepticus. (A) Generalized seizure. (B) Left focal seizure. (C) Burst-suppression pattern in a patient treated with a midazolam infusion for refractory status epilepticus.

Nonepileptiform abnormalities are not necessarily associated with a risk of seizure but suggest CNS dysfunction. Slow waves are a nonspecific finding, suggesting a structural or functional abnormality, and often are seen after a seizure or SE. The location of slow waves after a seizure may aid in the differentiation between generalized and focal seizures. Generalized slow waves are associated with a diffuse encephalopathy such as a metabolic disturbance, hypoxia-ischemia, or a postictal state.

Two further EEG patterns are of particular relevance to the treatment of prolonged seizures. Burst suppression is characterized by brief bursts containing a mixture of spikes, sharp waves, and slow waves alternating with periods of very low voltage ( Fig. 64.1 C). An isoelectric EEG pattern refers to a continuous low-voltage record without any discernable cortical activity. Both burst-suppression and isoelectric EEG patterns can be seen in persons in a coma and may carry a poor prognosis in certain clinical situations. However, in the context of refractory SE, these patterns are often the desired end point for treatment with high-dose barbiturates or benzodiazepines.

Management of status epilepticus

The therapeutic goals for SE include (1) general supportive care, (2) termination of SE, (3) prevention of seizure recurrence, (4) correction of precipitating causes, and (5) prevention and treatment of potential complications. Immediate attention to the airway, breathing, and circulation (ABC) is essential. SE is a situation in which simultaneous evaluation and management should be undertaken.

Although most seizures (≈75%) are self-limited and stop within 5 minutes, it is reasonable to assume that most children who arrive at the ED or PICU have been seizing for over 5 minutes. This may include time seizing before discovery, time waiting for emergency personnel, time spent en route to the hospital, and time before administration of the first ASM. Many patients may have already received potentially sedating medications from family members or emergency medical personnel that may contribute to respiratory depression on arrival.

General supportive care

Immediate assessment of the airway, administration of supplemental oxygen, and airway management—including tracheal intubation, if necessary—apply to patients with SE and are discussed in Chapters 44 and 127 in more detail. It is essential to realize that some patients may require the administration of a neuromuscular blocking agent (NMBA) and, if so, it should be one with a short half-life. The NMBA will stop the motor component of the seizure but will not stop the underlying electrographic seizure activity in the brain. Patients with seizures who are going to receive continuous infusion of an NMBA require cEEG monitoring.

Tachycardia, cool extremities, delayed capillary refill, diminished pulses, and poor urine output suggest reduced cardiac output. Providers should follow established Pediatric Advanced Life Support guidelines to obtain vascular access (see Chapter 14 ). Once established, the patient may require isotonic fluid boluses (20 mL/kg). Consideration for the administration of antipyretics should occur early in the management of the patient in SE.

Diagnostic testing in children and adolescents with SE varies among centers and likely reflects the limited evidence supporting most diagnostic approaches in SE. Specific studies should be tailored to match the patient history; however, serum glucose should be checked immediately in all pediatric patients, particularly young infants. Other blood work may include serum electrolytes (sodium, calcium, and magnesium), liver function tests, arterial blood gas, urine toxicology, and AED levels if the patient is a known epileptic on medication.

In the event of respiratory, cardiovascular, or neurologic concerns or other contraindications to lumbar puncture (such as a coagulopathy or elevated ICP), antibiotics and antivirals (if indicated) should be administered. Although blood cultures and a lumbar puncture have a high yield in children with SE and a clinical suspicion of infection, there is insufficient evidence to either support or refute whether these studies should be routinely performed in children in whom there is no clinical suspicion of infection. Currently, evidence to support the performance of most diagnostic tests relies on limited data collected in heterogeneous settings with different study objectives.

Monitoring and termination of status epilepticus

Clinicians need to consider NCSE in patients who do not quickly return to their baseline. A study by Allen et al. demonstrated that most children regain consciousness within 30 to 40 minutes, although some took many hours to recover without a sinister cause. The two variables determining recovery were seizure etiology and the administration of medications to terminate the seizure. Children recover most quickly from FSs and most slowly from acute symptomatic seizures. The authors stated that, “it was surprising that seizure duration did not significantly affect recovery time; clinical dogma is that it does.”

Electrographic seizure activity has been reported to occur in up to 15% of patients whose overt clinical seizures are pharmacologically controlled. NCSE presents with altered mentation and absent or subtle motor findings (e.g., finger twitch) and is therefore defined by EEG criteria. The ictal episodes must be continuous or recurrent for at least 30 minutes without improvement in the patient’s clinical state. The incidence of NCSE in pediatrics is currently unknown; adult studies have shown a mortality rate between 30% and 50%. Adult studies have also shown that approximately 8% of patients in coma are in NCSE. Adult etiologies included hypoxia and cerebrovascular accident as the most common causes followed by infection, metabolic conditions, TBI, tumor, and a low ASM level.