Seizures and Status Epilepticus in Pediatric Critical Care



Fig. 22.1
Example of management pathway for pediatric status epilepticus





Status Epilepticus Management: Diagnostic Considerations


Medical stabilization is critical as part of the management of SE. The Neurocritical Care Society’s Guideline for the Evaluation and Management of Status Epilepticus provides a timed treatment pathway [31]. Steps to be completed in the initial 2 min include (1) noninvasive airway protection with head positioning and (2) vital sign assessment. Steps to be included in the initial 5 min include (1) neurologic examination and (2) placement of peripheral intravenous access for administration of emergent antiseizure medications and fluid resuscitation. Steps to be completed in the initial 10 min include intubation if airway or gas exchange is compromised or intracranial pressure is elevated. Intubation may be necessary due to seizure-associated hypoventilation, medication-associated hypoventilation, inability to protect the airway, or other causes of oxygenation or ventilation failure. Steps to be completed in the initial 15 min include vasopressor support if needed [31].

Multiple studies have characterized the various potential etiologies for SE [42, 6163]. Acute symptomatic conditions are identified in 15–20% of children with SE [42, 62, 64]. Rapidly reversible causes of seizures should be diagnosed and treated within minutes of hospital arrival, specifically evaluating for electrolyte disturbances such as hyponatremia, hypoglycemia, hypomagnesemia, and hypocalcemia. The American Academy of Neurology’s practice parameter on the diagnostic assessment of the child with SE reported that abnormal results among children who underwent testing included low anticonvulsant levels (32%), neuroimaging abnormalities (8%), electrolytes (6%), inborn errors of metabolism (4%), ingestion (4%), central nervous system infections (3%), and positive blood cultures (3%) [65]. The Neurocritical Care Society’s Guideline for the Evaluation and Management of SE provides suggestions regarding etiologic testing including bedside finger-stick blood glucose (0–2 min) and serum glucose, complete blood count, basic metabolic panel, calcium, magnesium, and antiseizure medication levels (5 min). In some patients, other diagnostic testing may include neuroimaging or lumbar puncture (0–60 min), additional laboratory testing (including liver function tests, coagulation studies, arterial blood gas, toxicology screen, and inborn errors of metabolism screening), and continuous EEG monitoring if the patient is not waking up after clinical seizures cease (15–60 min) [31]. These recommendations are similar to those of the prior American Academy of Neurology’s practice parameter [65]. Rarer infectious, metabolic, autoimmune, and paraneoplastic etiologies may be considered in specific situations [66].

Among children with SE, neuroimaging abnormalities have been reported in 30% of children and are described to alter acute management in 24% of children [62]. If no etiology is identified by computerized tomography, magnetic resonance imaging may still identify lesions. For example, one study described that among 44 children who underwent head computerized tomography and magnetic resonance imaging, 14 had a normal head computerized tomography but an abnormal magnetic resonance imaging [62].

There are two main urgent EEG indications. First, if the diagnosis of psychogenic SE is suspected, then rapid diagnosis using EEG monitoring may avoid continued escalation of antiseizure medications with potential adverse effects. Second, if there is concern that EEG-only seizures (also referred to as subclinical seizures or nonconvulsive seizures) are ongoing despite cessation of clinically evident seizures, then EEG monitoring may be required for identification and to assess the impact of continued management [19, 24]. A multicenter study of children who underwent EEG monitoring while in the PICU reported that 33% of 98 children who presented with convulsive SE had electrographic seizures identified. The seizure burden was often high with electrographic SE in 47% of patients with seizures. Further, 34% of children with seizures had exclusively EEG-only seizures which would not have been identified without EEG monitoring [67].

If no etiology is identified by the initial testing , then additional testing may be indicated. A targeted approach may be useful for some patients, but in some patients sending a full panel of tests initially may be optimal. Recent reviews have summarized issues related to detailed etiologic testing [56, 66]. Central nervous system infections are a common cause of acute symptomatic SE [62], accounting for 0.6–40% of all SE [68, 69]. The clinical presentation of encephalitis and other central nervous system infections is highly variable depending on the pathogen involved and specific host factors. Additionally, fever may be absent and clinical signs of infection may be subtle or absent, particularly in young children, individuals who are immunocompromised, or individuals who have received recent antibiotics. Therefore, lumbar puncture should be performed in all children with SE without an obvious noninfectious etiology. A lumbar puncture should also be obtained if an autoimmune etiology is suspected as neuro-inflammatory processes will often yield cerebrospinal fluid pleocytosis, elevated cerebrospinal fluid protein, and intrathecal immunoglobulin synthesis (oligoclonal band profile, IgG index, and IgG synthesis rate). Many causes of autoimmune encephalitis may be associated with neoplasms, although the frequency of tumor detection varies. Depending on the paraneoplastic autoantibody, distinct brain regions may be targeted, with seizures or SE resulting from autoimmunity to either the limbic system or cerebral cortex. Specific autoantibody testing for some of these disorders is available, and, in general, testing of the cerebrospinal fluid has superior sensitivity and specificity as compared to serum. Any patient with known or suspected paraneoplastic disease should have appropriate tumor screening imaging performed. In addition to paraneoplastic processes, Rasmussen’s encephalitis (imaging showing progressive unihemispheric cortical atrophy) and Hashimoto’s encephalopathy (serum antithyroid peroxidase antibodies or anti-thyroglobulin antibodies) may also cause autoimmune forms of SE. Some genetic epilepsies may present with new-onset SE that do not produce obvious metabolic or imaging changes. Thus, performing gene panel analysis or exome sequencing may be useful in some patients with unexplained SE.


Status Epilepticus Management: Emergent Benzodiazepine Management


The Neurocritical Care Society’s Guideline for the Evaluation and Management of SE states that “definitive control of SE should be established within 60 minutes of onset” [31] with termination of both clinical and electrographic seizures. Benzodiazepines are the “emergent” medications of choice with lorazepam for intravenous administration, diazepam for rectal administration, and midazolam for intramuscular, buccal, or intranasal administration [31]. Repeat dosing may be provided in 5–10 min if seizures persist. A double-blind randomized trial of 273 children with convulsive SE in the emergency department compared intravenous lorazepam (0.1 mg/kg) and diazepam (0.2 mg/kg). A half dose of either medication could be administered if seizures persisted after 5 min. The primary outcome, SE cessation by 10 min without recurrence in 30 min, was not significantly different in the two groups (72.1% with diazepam and 72.9% with lorazepam). Subjects receiving lorazepam were more likely to be sedated (67% with lorazepam, 50% with diazepam), but there was no difference in requirement for assisted ventilation (18% with lorazepam, 16% with diazepam) [70]. If intravenous access cannot be obtained, then rectal, intramuscular, buccal, or intraosseous benzodiazepines can be administered. For buccal or nasal dosing of midazolam, the intravenous version of the drug is generally used off-label in the United States.


Status Epilepticus Management: Urgent Antiseizure Medication Management


About one-third to one-half of children will have persisting SE after receiving benzodiazepines [45, 47, 70], yet there are few comparative data evaluating the antiseizure medication options available for this management stage. Options include phenytoin, fosphenytoin, phenobarbital, valproate, and levetiracetam. Optimal decisions may depend on patient characteristics, seizure characteristics, and also practical institutional factors such as which drugs are most rapidly available since some need to be ordered and dispensed from pharmacy as opposed to being immediately available in medication carts.

Phenytoin is reported as the second-line agent by most respondents in surveys of pediatric emergency medicine physicians [71] and neurologists [72]. Phenytoin has demonstrated efficacy in pediatric SE management [73, 74]. Phenytoin is prepared with propylene glycol and alcohol at a pH of 12 which may lead to cardiac arrhythmias, hypotension, and severe tissue injury if extravasation occurs (purple glove syndrome). Fosphenytoin is a prodrug of phenytoin, and it is dosed in phenytoin equivalents (PE). Cardiac arrhythmias and hypotension are less common than with phenytoin since it is not prepared with propylene glycol, but they may still occur. Fosphenytoin is associated with less tissue injury (purple glove syndrome) if infiltration occurs. Both phenytoin and fosphenytoin are considered focal anticonvulsants, and they may be ineffective in treating SE related to epilepsy with a generalized mechanism of seizure onset. There are numerous drug interactions due to strong hepatic induction and high protein binding, so free phenytoin levels may need to be assessed [75]. There is little respiratory depression, particularly when compared to some of the other antiseizure medication options, such as phenobarbital, midazolam, or pentobarbital.

Phenobarbital is often considered a third-line or fourth-line drug in pediatric SE pathways. One study of 36 children with SE indicated that phenobarbital stopped seizures faster than a combination of diazepam and phenytoin and safety was similar, [76] and several reports have described the use of high-dose phenobarbital to control refractory SE and allow withdrawal of pharmacologic coma [7779]. Phenobarbital may cause sedation, respiratory depression, and hypotension, so cardiovascular and respiratory monitoring is generally required. It is a hepatic enzyme inducer leading to drug interactions.

Valproate sodium is a broad-spectrum antiseizure medication reported to be safe and highly effective in terminating SE and refractory SE. Because it has mechanisms independent of GABA receptors, valproate may be effective later in refractory SE once GABA receptors have been targeted by other agents. Several studies and reports have reported that valproate sodium is effective in terminating SE [80] and refractory SE in children without adverse effects [8084]. It may cause less sedation, respiratory depression, and hypotension than some other antiseizure medications, such as benzodiazepines, phenobarbital, or phenytoin. Black box warnings from the Federal Drug Administration include hepatotoxicity (highest risk in children younger than 2 years, receiving anticonvulsant poly-therapy, and with suspected or known metabolic/mitochondrial disorders), pancreatitis, and teratogenicity. Other adverse effects include pancytopenia, thrombocytopenia, platelet dysfunction, hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), and encephalopathy (with or without elevated ammonia). There are numerous drug interactions due to strong hepatic inhibition.

Levetiracetam is a broad-spectrum antiseizure medication. Several observational studies in children have reported that levetiracetam may be safe and effective for managing SE and acute symptomatic seizures [8590]. Levetiracetam has no hepatic metabolism, which may be beneficial in complex patients with liver dysfunction, metabolic disorders, or in those at risk for major drug interactions. Additionally, in comparison to other intravenously available antiseizure medications, levetiracetam has a low risk of sedation, cardiorespiratory depression, or coagulopathy. Since levetiracetam clearance is dependent on renal function, maintenance dosage reduction is required in patients with renal impairment.


Refractory Status Epilepticus Management


Refractory SE is characterized by seizures that persist despite treatment with adequate doses of initial antiseizure medications. Definitions for refractory SE have varied in seizure durations (no time criteria, 30 min, 1 or 2 h) and/or lack of response to different numbers (two or three) of antiseizure medications. The Neurocritical Care Society’s SE Evaluation and Management Guideline states that “patients who continue to experience either clinical or electrographic seizures after receiving adequate doses of an initial benzodiazepine followed by a second acceptable anticonvulsant will be considered refractory” [31]. In contrast to prior definitions of refractory SE, there is no specific time that must elapse to define refractory SE, thereby emphasizing the importance of rapid sequential treatment. Depending on refractory SE definitions and the cohorts described, refractory SE occurs in about 10–40% of children [48, 49, 73] with SE. Studies in children have indicated that SE lasted more than 1 h in 26–45% of patients [91, 92], longer than 2 h in 17–25% of patients [92, 93], and longer than 4 h in 10% of patients [92].

In a subgroup of patients, refractory SE may last for weeks to months, despite treatment with multiple antiseizure medications. This lengthy course has been referred to as malignant refractory SE [94] or super-refractory SE [95, 96]. Malignant refractory SE is associated with an infectious or inflammatory etiology, younger age, previous good health, and high morbidity and mortality [94, 97, 98]. It has also been referred to as de novo cryptogenic refractory multifocal SE [98], new-onset refractory SE (NORSE) [97, 99, 100], and febrile infection-related epilepsy syndrome (FIRES) [101103]. Some of these entities in which refractory SE occurs in a previously healthy person with no identified cause except a recent infection may represent overlapping terms describing similar or identical entities [104].

The Neurocritical Care Society’s SE Evaluation and Management Guideline states that “the main decision point at this step is to consider repeat bolus of the urgent control anticonvulsant or to immediately initiate additional agents” [31]. Additional urgent control antiseizure medications may be reasonable if they have not yet been tried or if the patient needs to be transferred or stabilized prior to administration of continuous infusions. However, if an initial urgent control medication fails to terminate seizures, then preparations should be initiated to achieve definitive seizure control with continuous infusions.

The management of refractory SE has been reviewed previously in children [56, 57, 105107]. While there is variability in suggested pathways and reported management decisions [108], all pathways either administer additional antiseizure medications such as phenytoin/fosphenytoin, phenobarbital, valproate sodium, or levetiracetam or proceed to pharmacologic coma induction with intravenous or inhaled medications. The Neurocritical Care Society’s SE Evaluation and Management Guideline recommends rapid advancement to pharmacologic coma induction rather than sequential trials of many urgent control antiseizure medications [31]. Few data are available regarding management of refractory SE with midazolam, pentobarbital, and other anesthetic therapies [59]. Midazolam dosing usually involves an initial loading dose of 0.2 mg/kg followed by an infusion at 0.05–2 mg/kg/h titrated as needed to achieve clinical or electrographic seizure suppression or EEG burst suppression. If seizures persist, escalating dosing through additional boluses is needed to rapidly increase levels and terminate seizures. Increasing the infusion rate without bolus dosing will lead to very slow increase in serum levels which is inconsistent with the goal of rapid seizure termination. Pentobarbital dosing usually involves an initial loading dose of 5–15 mg/kg (followed by another 5–10 mg/kg if needed) followed by an infusion at 0.5–5 mg/kg/h titrated as needed to achieve seizure suppression or EEG burst suppression. If seizures persist, escalating dosing through additional boluses is needed to rapidly increase levels and terminate seizures. Anesthetics such as isoflurane are effective in inducing a burst suppression pattern and terminating seizures. Propofol may also be used to terminate seizures, but is rarely used in children due to its Federal Drug Administration black box warning because of the risk of propofol infusion syndrome.

Patients treated with continuous infusions or inhaled anesthetics require intensive monitoring due to issues with:


  1. 1.


    Continuous mechanical ventilation both for airway protection and to maintain appropriate oxygenation and ventilation

     

  2. 2.


    Central venous access and arterial access due to frequent laboratory sampling and high likelihood of developing hypotension requiring vasopressor or inotropic support

     

  3. 3.


    Temperature management and regulation since high-dose sedatives and anesthetics can blunt the shivering response and endogenous thermoregulation

     

  4. 4.


    Assessment for development of lactic acidosis, anemia, thrombocytopenia, and end-organ dysfunction such as acute liver or renal injury

     

  5. 5.


    Risk of secondary infections due to indwelling catheters (central catheters, endotracheal tubes, Foley catheters), as well as some medications (pentobarbital)

    The goals of pharmacologic coma induction are unclear. It remains unclear whether the EEG treatment goal should be termination of seizures, burst suppression, or complete suppression of EEG activity. The Neurocritical Care Society’s SE Evaluation and Management Guideline states that “dosing of continuous infusions anticonvulsants for refractory SE should be titrated to cessation of electrographic seizures or burst suppression” [31]. Further, it remains unclear how long the patient should be maintained in pharmacologic coma. The guideline states that “a period of 24–48 h of electrographic control is recommended prior to slow withdrawal of continuous infusion anticonvulsants for refractory SE” [31], and a survey of experts in SE management across all age groups reported they would continue pharmacologic coma for 24 h [108].

    Electrographic or electro-clinical seizures frequently recur during weaning of pharmacologic coma medications [109112] indicating that pharmacologic coma should be considered as a temporizing measure, and during this period other antiseizure medications should be initiated which may provide seizure control as coma-inducing medications are weaned. Case reports and series have described several add-on medications, and other techniques have been reported useful in reducing seizure recurrence as pharmacologic coma is weaned, but there are no large studies. These options include topiramate, ketamine, pyridoxine, the ketogenic diet, epilepsy surgery, immunomodulation (steroids, intravenous immune globulin, plasmapheresis), hypothermia, and electroconvulsive therapy. These have been reviewed recently [56, 57].

     



Conclusions


Seizures and SE are common in critically ill children. Rapid management is needed to manage systemic complications , identify and manage precipitating conditions, and terminate seizures. While data are limited, a predetermined management plan that emphasizes rapid progression through appropriately dosed antiseizure medications may help streamline management. Children with or without prior convulsive seizures may experience electrographic seizures requiring EEG monitoring for identification.


References



1.

Bell MJ, Carpenter J, Au AK, Keating RF, Myseros JS, Yaun A, et al. Development of a pediatric neurocritical care service. Neurocrit Care. 2008;10(1):4–10.


2.

LaRovere KL, Graham RJ, Tasker RC. Pediatric neurocritical care: a neurology consultation model and implication for education and training. Pediatr Neurol. 2013;48(3):206–11.PubMed


3.

Sanchez Fernandez I, Abend NS, Agadi S, An S, Arya R, Brenton JN, et al. Time from convulsive status epilepticus onset to anticonvulsant administration in children. Neurology. 2015;84(23):2304–11.PubMedPubMedCentral


4.

Chin RF, Verhulst L, Neville BG, Peters MJ, Scott RC. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. J Neurol Neurosurg Psychiatry. 2004;75(11):1584–8.PubMedPubMedCentral


5.

Tirupathi S, McMenamin JB, Webb DW. Analysis of factors influencing admission to intensive care following convulsive status epilepticus in children. Seizure. 2009;18(9):630–3.PubMed


6.

Tobias JD, Berkenbosch JW. Management of status epilepticus in infants and children prior to pediatric ICU admission: deviations from the current guidelines. South Med J. 2008;101(3):268–72.PubMed

Aug 25, 2017 | Posted by in NEUROLOGY | Comments Off on Seizures and Status Epilepticus in Pediatric Critical Care

Full access? Get Clinical Tree

Get Clinical Tree app for offline access