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Annals of Indian Academy of Neurology
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REVIEW ARTICLE
Year : 2007  |  Volume : 10  |  Issue : 5  |  Page : 7-18
 

Convulsive status epilepticus in children


Neurosciences Unit, UCL-Institute of Child Health, London; Epilepsy Unit, Great Ormond Street Hospital for Children NHS Trust, London; The National Center for Young People with Epilepsy, Lingfield, United Kingdom

Correspondence Address:
Rod C Scott
Neurosciences Unit, UCL - Institute of Child Health. The Wolfson Center, Mecklenburgh Square, London WC1N 2AP
United Kingdom
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Source of Support: None, Conflict of Interest: None


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   Abstract 

Convulsive status epilepticus (CSE) is the most common neurological emergency in childhood. It differs from adult CSE in aspects of epidemiology, pathophysiology and clinical presentations, which justifies a separate analysis. The incidence is 18-20/100,000 children/year and distribution of aetiologies is markedly age-dependent: Febrile and acute symptomatic CSE are most common in children aged <2 years, whereas cryptogenic-idiopathic and remote symptomatic aetiologies are more common in older children.
Mortality is 3-5% and morbidity directly attributable to CSE is less than 15%. When compared to brief seizures, the incidence of subsequent epilepsy is increased only in symptomatic goups. Aetiology is the main determinant of outcome, while the separate effect on outcome of duration, age and treatment remains controversial. The risk of sequelae in unprovoked and febrile CSE is low. There is some evidence that CSE, especially febrile CSE, might cause hippocampal injury, although its role in the development of mesial temporal sclerosis remains uncertain. Prolonged seizures lasting over 5-10 minutes are unlikely to stop spontaneously and should be treated as CSE. Prehospital administration of benzodiazepines is safe and simplifies subsequent management of CSE in the hospital setting. Treatment includes resuscitation measures, identification and treatment of causal factors and early antiepileptic treatment following local guidelines that may be based on national guidelines.


Keywords: Children, epilepsy, outcome, status epilepticus, treatment


How to cite this article:
Raspall-Chaure M, Scott RC. Convulsive status epilepticus in children. Ann Indian Acad Neurol 2007;10, Suppl S1:7-18

How to cite this URL:
Raspall-Chaure M, Scott RC. Convulsive status epilepticus in children. Ann Indian Acad Neurol [serial online] 2007 [cited 2020 Nov 24];10, Suppl S1:7-18. Available from: https://www.annalsofian.org/text.asp?2007/10/5/7/33492



   Introduction Top


Status epilepticus (SE) is a common condition in acute medical care. Approximately 4.5 million SE events occur worldwide every year and, in the United States, the cost of care of SE has been estimated at $3-4 billion/year.[1] The number of studies that are annually published on SE has steadily increased during the last few years and >50% out of the over 5000 currently Medline-indexed studies on SE have been published during the last decade. But despite the socioeconomic burden of SE and the interest among the medical community, many questions concerning its pathogenesis, management and outcome remain unanswered.

While some features of SE are common to all age groups, there are specific epidemiological, pathophysiological and clinical presentations in childhood that differ from that in adult populations and thus will be emphasized during the current review. We will focus on pediatric convulsive SE (CSE) as nonconvulsive SE and neonatal SE are separate disorders with differing epidemiology, clinical presentation and prognosis and deserve study in their own right.


   Definition Top


The ILAE defines SE as "a seizure that shows no clinical signs of arresting after a duration encompassing the great majority of seizures of that type in most patients or recurrent seizures without interictal resumption of baseline central nervous system function",[2],[3] but has not set a temporal criterion in its last revised proposal of terminology as has previously been the case. Most studies use the 30 min duration criteria, which may demarcate the transition point at which SE may become self-sustaining, pharmacoresistance may have developed and seizure-induced neuronal injury may take place.[4]

This 30 min definition is obviously inappropriate as a guide for treatment. Consequently, "operational" definitions with durations ranging from 5 to 20 minutes have been proposed, i.e., a time when the patient should be treated as having CSE, even if such patient is not in established CSE (see below).[5],[6] Operational definitions are necessary for research studies evaluating the efficacy of antiepileptic drugs (AEDs) and match the widely accepted practice of treating patients with prolonged seizures well before the seizure has lasted 30 min.

There are strong statistical arguments for using a shorter duration operational criterion i.e., five minutes. Mean duration of generalised tonic-clonic seizures in adults is 62 seconds[7] and mean duration of complex partial seizures in children is 97 seconds.[8] Seizure duration in children with new-onset seizures shows a biexponential distribution: 3.6 minutes in one group (76% of cases) versus 31 minutes in the other (24%).[9] Children who have seizures lasting more than five minutes are very likely to be in the latter group.

Classification

From a clinical point of view, SE can be classified into as many types as there are epileptic seizure categories.[10] In the most recent ILAE revision of the classification of seizures and epilepsy syndrome, a distinction between generalized and focal SE is made [Table - 1].[3]

From a practical viewpoint, it is classically separated into convulsive and nonconvulsive status epilepticus as a result of marked differences regarding aetiology, management and outcome.[11] However, the term "non-convulsive status epilepticus" is falling out of favour and is no longer included in the ILAE's revision of classification and terminology since it comprises dissimilar conditions (i.e ., focal limbic SE and generalised absence SE), which also differ in aetiology, management and outcome.[3]

According to aetiology, CSE can be grossly classified into provoked (including the febrile and the acute symptomatic aetiologies) and unprovoked CSE (including the idiopathic-cryptogenic, remote symptomatic and progressive aetiologies) [Table - 2].[12]


   Epidemiology Top


Most epidemiological studies of CSE have been primarily or exclusively based on adult populations and their results may not reflect a reliable characterisation of CSE in childhood.[13] To our knowledge, only one purely pediatric prospective population-based study addressing the epidemiology of CSE has been published.[14]

Overall estimated incidence is 18-20/100000 children/year. The incidence is highest during the first year of life (51/100000 children/year) and subsequently declines (2/100000 children/year in children 10-15 years-old).[14]

CSE in childhood is more commonly seen as the first manifestation of seizure disorders than later in life, especially in younger children[15] and when CSE does not occur in the first few years of the epilepsy, it is less likely to occur at a later date.[16] In a prospective study that followed children with a first unprovoked seizure, 12% of children were seen with CSE as their first unprovoked seizure. After a mean follow-up of 6.3 years, only 1% of the children with a recurrence following an initial brief seizure met criteria for CSE in the recurrent event.[17],[18]

The spectrum of aetiologies in childhood CSE differs markedly to that in adult populations. Febrile CSE occurs in about 5% of patients with febrile seizures[19],[20] and it is the most common form of CSE in childhood, accounting for 25-40% of all cases. Children with progressive disorders represent <10% of patients, with the remaining cases being approximately equally distributed among the idiopathic-cryptogenic, acute symptomatic and remote symptomatic categories. However, the distribution of aetiologies is markedly age-dependent: in children younger than two years, febrile CSE and acute symptomatic aetiologies are most common, whereas cryptogenic and remote symptomatic aetiologies are more common in the older children. The reported effect of age on outcome may, at least in part, be determined by this uneven distribution of aetiologies.[12],[14],[21],[22],[23],[24],[25]

Duration is commonly reported to be a function of aetiology, with >60% of acute symptomatic cases lasting >1 hour.[26],[27] However, a recent population-based study did not find significant differences in seizure duration between aetiological groups.[14]

Children with preexisting neurological abnormalities or prior episodes of CSE are at highest risk of experiencing an episode of CSE. Neurologically abnormal children are more susceptible to develop seizures in general and CSE in particular. In a general epilepsy population, 30% of children are expected to be neurologically abnormal although this proportion is lower in children with first unprovoked seizures. In contrast, >40% of children with CSE are neurologically abnormal prior to the episode.[15]

Finally, epidemiology of CSE may be influenced by genetic, ethnic and socioeconomic factors. The role of genetic factors is clear in some genetically determined epilepsy syndrome (i.e., Dravet syndrome and febrile CSE; ring chromosome 20 and non-convulsive status epilepticus)[28],[29],[30] and twin studies suggest that there might also be some still unrecognized genetic predisposition to CSE in many other individuals.[31] There is some evidence that incidence of CSE is higher in non-white ethnic groups.[32] Whether perceived ethnicitiy effects are influenced by socioeconomic factors is currently being investigated in a prospective pediatric population-based study in children with CSE (Chin et al. , personal communication).


   Pathophysiology Top


Most of our understanding of the pathophysiology of CSE is from animal models rather than from observations in humans. Seizures are usually pharmacologically or electrically induced in adult animals and therefore we must be cautious about extrapolating these experimental findings to spontaneous and prolonged seizures in childhood.

CSE initiation requires neurons with intrinsic burst generation, failure or loss of inhibition surrounding the abnormally firing neurons and then spread, synchronization and maintenance of a discharge. It is likely that seizure initiation is caused by an imbalance between excitatory and inhibitory neurotransmission. The extracellular concentration of the excitatory neurotransmitter glutamate increases at the site of the seizure focus at the beginning of seizure activity.[33] With increasing seizure length, inhibitory GABAA receptors are internalized from synaptic membranes to endosomes, where they are inactive, leading to the failure of the inhibitory systems.[34] At the same time, N-methyl-D-aspartate (NMDA) and a-amino-5-hydroxy-3-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors are recruited to synaptic membranes were they form functional receptors. These mechanisms may underlie the observed refractoriness to treatment with GABA-acting medications observed during refractory CSE and, in some animal models, improved responsiveness to NMDA antagonists with increasing duration of CSE.[35],[36] Both excessive excitatory neurotransmission and failure of inhibition are closely related, i.e., decreased GABAA receptor function has been observed to be dependent on NMDA receptor activation.

The initial systemic effects of a generalized tonic clonic seizure are dominated by the body's attempt to maintain homeostasis and include increase in cerebral blood flow, blood glucose and oxygen utilization. After 30-60 minutes homeostatic failure begins, as cerebral blood flow and thus brain glucose supply and parenchymal oxygenation, all decrease. Respiratory and metabolic acidosis, cardiac arryhthmias, electrolyte imbalance, hyperthermia and rhabdomyolysis may all occur.[37],[38] Furthermore, many of the AEDs used in CSE have depressant cardiorespiratory side effects and may worsen the systemic effects of CSE. However, neuronal damage associated with CSE has been reported in the absence of systemic complications such as hypotension, hypoxemia or hypoglycemia.[39]


   CSE and Brain Damage Top


CSE can result in permanent brain damage. There is pathological evidence of acute changes in the hippocampus, amygdala, thalamus, basal ganglia, cerebellum and neocortex, although pathological descriptions in humans are limited to case reports.[39],[40] Two recent series using diffusion weighted images have also shown prominent white matter abnormalities in children with febrile CSE who subsequently develop neurological sequelae.[41],[42] The knowledge of the basic mechanisms underlying brain damage and acquired epilepsy associated with CSE is essential for developing novel strategies to prevent neuronal injury (i.e., neuroprotective therapies) and the development of epilepsy following CSE (i.e., antiepileptogenic therapies).

The hypothesis that cell damage is mediated by glutamate excitotoxicity is the most widely accepted.[43] Excessive activation of NMDA glutamate receptors leads to an increase of intracellular calcium,[44] which underlies the basis for calcium second-messenger effects on both cell death and neuronal plasticity in survival neurons.[45] A high level of intracellular calcium generates reactive oxygen species, uncouples oxidative phosphorylation and activates a wide range of enzymes that collectively have adverse consequences for cell function.

Although seizures can induce changes in multiple brain regions, the hippocampus seems particularly vulnerable to seizure-induced damage. In animal models, CSE causes neuronal loss in hippocampal fields CA1 and CA3, the dentate granule cell layer and the dentate hilus, as well as sprouting of mossy fibers.[46] In humans, it has long been hypothesized that CSE (and in particular febrile CSE) can cause mesial temporal sclerosis (MTS) and associated temporal lobe epilepsy. Retrospective studies from tertiary epilepsy centres highlight this association, with a history of febrile CSE being present in 35-63% of patients with MTS.[47],[48],[49],[50] However, neither population-based nor prospective hospital-based studies report a significant association between CSE in childhood and subsequent MTS.[51],[52],[53] Although febrile CSE has been associated with increased incidence of subsequent partial seizures, the structural basis for these seizures has not been characterized.[20],[23]

Prospective MRI-based studies have tried to further characterize the relationship between febrile CSE and MTS. Hippocampal asymmetry consistent with hippocampal oedema, identified using hippocampal volumetry, was first reported in 4/15 children following a prolonged and lateralized febrile seizure.[54] Subsequently, another group found symmetrical large hippocampal volumes and prolongation of hippocampal T 2 relaxation times in patients investigated within 48h of febrile CSE, also consistent with hippocampal oedema.[55] Follow-up investigations on the latter patient population after four to eight months demonstrated a reduction both in hippocampal volumes and in T 2 relaxation times, with significant increase in hippocampal volume asymmetry when compared with the initial data supporting the view that febrile CSE can cause hippocampal damage. Length of follow-up was insufficient to detect if any of the patients developed temporal lobe epilepsy.[56]

Genetic factors may also play a role on the pathogenesis of CSE-related MTS. A higher frequency of interleukin-1β-511T allele occurrence in patients with temporal lobe epilepsy associated with MTS has been reported, with the maximum increase in the allele frequency being observed in patients with a previous episode of febrile CSE.[57],[58] Additionally, homozygosity for a low expression allele for dynorphin was shown to be strongly associated with CSE, while heterozygosity was associated with familial temporal lobe epilepsy, implying a common genetic link between the allele, CSE and temporal lobe epilepsy.[59]


   CSE and the Immature Brain Top


The seizure threshold appears to be lower in the immature brain although the mechanisms that underlie this increased susceptibility remain unclear. Several developmental factors might be responsible for the higher frequency of CSE in childhood: 1) Excitatory synapses mature earlier than inhibitory synapses and this, coupled with an increase in the susceptibility of excitatory neurotransmitter receptors, increases the likelihood that an excitation-inhibition imbalance may occur, 2) Stimulation of GABAA receptors in the immature brain results in depolarization rather than hyperpolarization, as occurs in the adult brain and 3) The immature cerebral cortex has a high synaptic density at around two months of age and this may contribute to the development of hypersynchrony of neural groups.[60]

Current evidence suggest that seizures can damage the developing brain.[61],[62],[63],[64] However, while experimental studies show that the immature brain is more prone to develop seizures and CSE, they also show that the developing brain may be more resistant to the toxic effects of glutamate and to CSE-induced damage, at least in terms of MTS-like pathology.[64] Despite the experimental evidence, clinical evidence is sparse.[46]


   Clinical Characteristics Top


Generalized CSE is the most frequent, dramatic and life-threatening form of SE. It may present either as a series of generalized tonic clonic seizures without intervening recovery (i.e., intermittent CSE) or as a continuous seizure, which is usually clonic in nature (i.e., continuous CSE). The latter type is especially common in children and it is noted in 40-80% of cases.[11] In children with intermittent CSE, generalized tonic clonic seizures usually last from one to three minutes. They tend to become briefer as time elapses and the clonic phase may disappear. Other forms of CSE (i.e. myoclonic, tonic, etc) are much less frequent.

Both clinical and EEG progression during CSE has been observed. Proposed clinical stages include:[65]

  1. Premonitory (prodromal). This usually manifests as confusion, myoclonus or increasing seizure frequency (i.e., serial seizures).
  2. Incipient (0 to 5 minutes)
  3. Early stage (5 to 30 minutes)
  4. Late or Established stage (30 to 60 minutes)
  5. Refractory stage (60 to 90 minutes). Definitions of refractory CSE vary in terms of the number of AEDs (2 or 3) that must be employed before CSE is considered refractory;[66],[67] others define refractory CSE on the basis of its duration (usually 60 minutes).[68],[69] Refractory CSE may only manifest as "subtle" generalized CSE. 14% of adults treated for generalized CSE will continue to have electroencephalographic seizure activity after cessation of clinical signs of convulsive activity.[70] The proportion of children with clinically controlled CSE but persisting electrical seizure activity is unknown.
  6. Postictal stage. Postictal (and interictal) neurological signs may include unilateral or bilateral Babinski responses, hyperreflexia and hemiplegia. Hemiconvulsion-Hemiplegia syndrome was reported in 11-19% of children with febrile CSE in older studies.[22],[71] It's incidence has considerably declined over the past 20 years in developed countries, probably due to improvement in treatment. A minimum duration of hemiplegia is arbitrarily set at seven days to separate it from the more common postictal or Todd paralysis.[72]


Treiman et al. has also distinguished five successive EEG stages in adults[73] and animal models, which are more or less correlated with the clinical stages: 1) discrete seizures with interictal slowing, 2) waxing and waning of ictal discharges, 3) continuous ictal discharges, 4) continuous ictal discharges punctuated by flat periods and 5) periodic epileptiform discharges on a flat background.


   Outcome Top


CSE is associated with significant mortality and morbidity. Aetiology is the main determinant of outcome and there is still much controversy as to which other factors such as age, duration, treatment or CSE itself, modify the outcome. Much of the controversy arises from the methodological differences of the studies that have addressed this topic.[74],[75],[76] The impact of these non-biological variables on reported outcomes of pediatric CSE was recently investigated in a systematic review. According to its results, prospective design and overall better methodological quality were associated with better outcome.[77]

Mortality

Short-term mortality following CSE, i.e., that occurring during hospital admission or during the first 30-60 days from seizure onset, is 2.7-5.2%. Most deaths occur in children with acute symptomatic or progressive aetiologies and may not be attributable to the CSE itself.[12],[25],[68],[78],[79],[80] Mortality directly attributable to CSE, as that observed with unprovoked CSE or febrile CSE, is 0-2%, compared to 12.5-16% in children with acute symptomatic CSE.[12],[81],[82],[83] Particularly high mortality is seen with some acute symptomatic aetiologies such as anoxia[84] or meningoencephalitis.[25]

A correlation between younger age at CSE and higher mortality has been reported,[22],[81],[85] with studies on CSE occurring in the first one to two years of life, reporting mortality rates of 3-22.5%.[81],[86],[87],[88] However, this relationship may only reflect the higher incidence of acute symptomatic CSE in this age group. Similarly, a direct relationship between longer duration of CSE and higher mortality is also frequently reported[32],[89],[89],[90],[91] although the effect of duration is difficult to separate form aetiology.[92] One meta-analysis concluded that the overall mortality in children treated for refractory generalized CSE was 16%,[93] but it was not possible to rule out the contribution of potential selection bias, i.e most studies were retrospective and hospital-based. Additionally, the studies included for review did not correct for the severity of the underlying aetiology (which is acute symptomatic CSE in >60% cases of refractory CSE).[94]

Long-term mortality data after a first-ever episode of CSE range from 5.4% to 17% and is significantly increased only among children with symptomatic aetiologies.[16],[23],[95],[96]

Subsequent epilepsy

The overall risk of subsequent unprovoked seizures two years following a first-ever unprovoked episode of CSE is 25-40%,[12],[24] which is similar to the 37% reported risk following a brief first unprovoked seizure.[18],[97] However, this effect is dominated by children with acute symptomatic aetiologies or previous neurological abnormalities in whom more than 50% will develop epilepsy.[12],[23],[85],[98]

Data on epilepsy following febrile CSE are controversial and much of the variability of estimates arises from differences in inclusion criteria. Those studies that include children with prior neurological abnormalites reveal that, when compared to brief febrile seizures, the risk following febrile CSE is not different in neurologically normal children but it is significantly increased (38%) in those with prior neurological abnormalities.[53],[83] Nelson et al. reported that 4.1% of children with first febrile seizure as febrile CSE developed epilepsy, which is significantly higher than in the normal population, but did not reach statistical significance when compared to children who had brief febrile seizures.[19] In contrast, Verity et al found a significantly greater risk of developing afebrile seizures in children with febrile CSE compared with children with brief febrile seizures (21% vs 3.4%; x 2 9.77; P <0.005).[23]

The risk of seizure recurrence is highest during the first year following CSE and tends to decrease with increasing interval from the index seizure.[18],[99] The impact of early treatment on the prevention or course of epilepsy remains largely unknown and the current recommendation of not starting long-term treatment after a first unprovoked CSE is based on the reported low impact of CSE on the risk of recurrence.[12]


   Recurrence Top


Overall recurrence of CSE is 20% at four years and 70% of recurrences occur within one to two years of the initial episode of CSE.[16],[100] Recurrence is low in febrile CSE and idiopathic CSE (<4%) and increases in the acute symptomatic, remote symptomatic and progressive groups (11%, 44% and 67% respectively). Children with pre-existing neurological abnormalities and prior history of CSE are at highest risk of recurrent CSE. Most neurologically abnormal children are receiving AEDs at the time of recurrence.[12],[79],[95],[100],[101]

Association with neurological, developmental, cognitive and behavioral impairments

In addition to epilepsy, focal neurological deficits, cognitive impairment and behavioural problems can be associated with CSE although consistent specific risk factors for each of these complications are not reported.

The poorest outcome is observed in acute symptomatic CSE, which is followed by new neurological dysfunction in >20% of cases.[12],[24],[98] In the absence of an acute or progressive neurological disorder, morbidity of CSE is low and <15% of children with febrile CSE and unprovoked CSE develop new neurological deficits attributable to CSE.[12],[24],[27],[98],[102] However, low power and lack of detailed neurocognitive assessment might have underestimated the incidence of minor sequelae in most of the studies.

Other factors that are reported to influence the outcome are longer duration and younger age at onset. As mentioned above, the poorer outcome observed in refractory CSE and in young children might be only explained by the greater incidence of acute symptomatic CSE in these groups.[103]


   Management Top


General principles

Most generalized tonic clonic seizures will stop spontaneously, often within five min, before the child arrives in the emergency department. Children that present to an emergency department with a generalized tonic clonic seizure are likely to be having a seizure that it is unlikely to stop spontaneously and which will ultimately meet the definition of CSE. Therefore, for practical (or operational) purposes, the approach in these circumstances should be the same as that with the child who is in established CSE.

CSE is an emergency and the fact that aetiology emerges as the most powerful predictor of outcome should not be read as meaning that interventions may not alter that outcome. The main objectives of treatment, which should be addressed simultaneously, are:

a) Support of vital functions.

b) Termination of seizure .

c) Identification and treatment of causal or precipitating factors.

a) Support of vital functions

Treatment should follow the ABC principles of resuscitation in order to maintain airway, ventilation-oxygenation and blood pressure. High flow oxygen should be given and continuous monitoring of vital signs, EKG and pulse oximetry are recommended.

The underlying aetiology, the seizure itself or the treatment can all contribute to complications from CSE. Careful diagnosis and management of such complications, i.e., hypotension, hypoxemia, hyperthermia or hypoglycemia, is essential throughout the course of CSE. Maintaining cerebral blood flow and thereby adequate supply of oxygen and glucose to the brain are as important as reducing cerebral metabolic needs by restricting seizures and hyperthermia.

b) Termination of seizure

The deleterious effects of seizure duration remain controversial and there is no documented clinical evidence that early seizure control prevents neurologic sequelae or improves outcome. However, experimental evidence suggests that this should be true. It is believed that early pharmacological intervention leads to termination of seizures with smaller doses than would be required if seizures were allowed to progress.[104] As previously discussed, experimental data show time-dependent loss of synaptic GABAA receptors and thus of GABA-mediated inhibition, which correlates with the progressive pharmacological resistance to GABAergic medication observed in refractory CSE.[34],[36]

The feasibility of early treatment with transmucosal benzodiazepines, i.e., rectal diazepam and buccal or nasal midazolam or lorazepam, has been addressed in several randomized controlled studies both in the pre-hospital and hospital settings.[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116],[117] Most have provided positive results regarding both efficacy (i.e., shortening the duration of CSE and simplified subsequent management in the emergency department) and safety (i.e., lack of respiratory depression) in both settings.[118] However, the risk of respiratory depression is higher when more than two doses of benzodiazepines are administered and prehospital benzodiazepine administration should be taken into account during further treatment.[119] Early administration of transmucosal benzodiazepines is especially advisable in that population of patients with a tendency to have prolonged seizures.

The risk-benefit ratio for antiepileptic treatments is one of the biggest challenges in seizure management. As a general rule, the intensity of the treatment should reflect the risk to the patient from CSE. The ideal AED should be available for intravenous administration, efficacious, with a rapid and long-lasting effect and lack of major side effects. Clearly none of the current AEDs meets all these characteristics [Table - 3].

The optimum pharmacological therapeutic scheme for CSE needs to be further defined by controlled trials. Published studies are typically observational, describing the efficacy of single agents. Only a few controlled, double-blind, clinical studies of treatment of CSE have been published and none has been conducted in children.[120],[121],[122] Because of the paucity of randomized controlled trials, treatment protocols vary enormously from hospital to hospital. Implementation of institutional treatment protocols based on national guidelines is recommended as this helps avoid unnecessary delays in starting treatment. Simply adopting a protocol (irrespective of the detail within the protocol) has itself been shown to reduce mortality and morbidity.[123] Although there is evidence about the individual efficacy of most of the drugs included, none of the recommended protocols has been shown to be better than any other. Thus, the treatment protocol suggested in the [Figure - 1] should be simply read as a proposal that may be modified locally.

Initial AED treatment should start within the first 5-10 minutes of seizure onset with a benzodiazepine, which can be repeated after five to ten min if seizure persists. In the hospital setting the intravenous route is the first choice and rectal or buccal medications should only be administered where there is failure to secure an intravenous access. Lorazepam is the preferred agent, as its duration is longer than for diazepam or midazolam, which minimizes the risk of relapse.[124] However, the superiority of lorazepam over other benzodiazepines in children has not yet been demonstrated.[125]

If a seizure fails to respond to two doses of benzodiazepines, most protocols will recommend administration of phenytoin, which is usually preferred to phenobarbitone at this stage as it causes less respiratory and central nervous system depression. Some authors advice the administration of a long-acting AED even when seizures cease following benzodiazepine administration so as to avoid seizure recurrence when the benzodiazepine is eliminated. Phenytoin infusion can only be made up in 0.9% saline and at a maximum concentration of 10 mg/mL. It should be infused at no more than 1 mg/kg/min because of the risk of hypotension and cardiac arrythmias associated with faster administration.[126] Such complications are in part attributable to its 40% propylene glycol diluent. Fosphenytoin is a prodrug of phenytoin, which is rapidly converted to phenytoin after either intravenous or intramuscular injection. Fosphenytoin is freely soluble in aqueous solutions, does not require organic solvents and does not precipitate in commonly used intravenous diluents. It can be infused up to three times more rapidly than phenytoin (i.e., 3 mg/kg/min), although the time to peak brain concentration is almost identical.[127] Potential benefits of fosphenytoin include reduced local and systemic adverse effects.[128],[129]

Sodium valproate is a nonsedating AED that does not cause respiratory depression or hypotension even if administered to critically ill patients.[130],[131] Although it is being increasingly included into therapeutic protocols, its efficacy in CSE is yet to be formally characterized. Lidocaine is another nonsedating agent which has been shown effective in CSE and in particular in infantile convulsions with mild diarrhea.[132] The antiepileptic action of the drug is transient and a continuous infusion is usually necessary to avoid seizure recurrence.[133] Paraldehyde is included in some protocols although there are limited published data on its efficacy. Intramuscular paraldehyde stopped 61% of seizures in a recent open randomized trial in children and was not associated with clinically important cardiorespiratory events.[113] Although the efficacy of rectal paraldehyde is not supported by any randomized trial, it is still included in some pediatric guidelines, mainly in the United Kingdom.[126]

Intravenous pyridoxine 100 mg should be administered to all children below two years with cryptogenic CSE as soon as possible during the course of CSE if the rare diagnosis of pyridoxine-dependent seizures is not to be missed.[11],[134]

If seizure persists following phenytoin (or any of the proposed alternatives), rapid sequence induction of anesthesia with either thiopentone or pentobarbital is commonly recommended. Propofol and midazolam infusions have been proposed as alternative AED in this situation based on a more favorable side effects profile.[69],[135],[136],[137] However, some studies reporting fatal cases of propofol infusion syndrome (i.e., metabolic acidosis, rhabdomyolysis and bradycardia) have limited the use of propofol in children.[138] Additionally, a systematic review of studies involving only adult populations found pentobarbital superior to propofol or midazolam in seizure control.[139] Other agents that have been used include clonazepam, lorazepam, ketamine or inhalation anesthetics. Exceptionally, children with focal abnormalities might be amenable to surgical treatment if CSE persists or recurs when treatment is withdrawn. At experienced centers, these children might be at lower risk of morbidity than by having prolonged high-dose suppressive therapy.[140] Furthemore, seizure outcome after surgery in children presenting with CSE may not be altered when compared with other epilepsy surgery patients.[141]

It is suggested that aiming for background suppression, as opposed to simply seizure termination, is associated with less breakthrough seizures (4% vs 53%) and better control of refractory CSE.[139] Reported optimal interburst intervals ranging from 5 to 30 seconds are proposed as an endpoint of titration.[36],[65] If neuromuscular paralysis is used this should be short acting so as not to mask the clinical signs of the convulsion. Treatment is usually withdrawn after 24h of seizure control and resumed if CSE recurs.

At this stage, the endpoint of treatment should be individualized. In previously normal children with refractory idiopathic or febrile CSE, it should aim to achieve complete seizure control and return to baseline status. However, this may not be a reasonable objective in children with acute symptomatic or progressive aetiologies with breakthrough seizures on every attempt to withdraw the high-dose suppressive therapy, in whom subsequent epilepsy and significant morbidity is almost the rule. In these cases, the realization that a seizure-free state is unlikely can lead to a shorter duration of suppressive therapy with eventually the same outcome but fewer complications.

The neuroprotective and antiepileptogenic role of several AEDs has been investigated in animals but none has been found to completely protect against neuronal injury nor to prevent the development of spontaneous recurrent seizures.[142],[143],[144],[145],[146]

c) Identification and treatment of causal or precipitating factors

Management of CSE includes identification and treatment of the underlying cause. In the absence of an obvious aetiology, blood glucose, blood gases and electrolytes (including sodium, calcium and magnesium) should be tested and any metabolic derangement should be corrected. However, the diagnostic assessment should not delay treatment and clinicians should be able to diagnose CSE on clinical grounds alone.

In general, an EEG, neuroimaging or other laboratory studies are not needed before the initiation of anticonvulsant therapy. If available, indications for emergency EEG include:[147]

  • Clinical impression of pseudoseizures presenting as CSE
  • Unexplained altered awareness or no improvement or return to baseline of mental status after controlling overt convulsive movements (to exclude ongoing seizure electroencephalographic activity).
  • Neuromuscular paralysis.
  • High-dose suppressive therapy for refractory CSE.


The incidence of bacterial meningitis among young children with CSE and fever is reported to be 12-17%, which is siginificantly higher than the 1.2% incidence in those with short seizures and fever.[14] However, central nervous system infections are an overlooked cause of CSE in infants and young children with fever, as the classical symptoms and signs of bacterial meningitis may be absent in this age group. Therefore, a high index of suspicion for meningitis in the child with CSE with fever is paramount and lumbar puncture and early parenteral antibiotics are advisable.[148] Conversely, the possibility of cerebrospinal fluid pleocytosis as a direct consequence of CSE has been reported both in adults[149],[150] and children.[151]

Finally, clinicians should be familiar with the causes of intractable seizures or CSE in their geographic setting (i.e. tuberculous meningitis, malaria or neurocysticercosis are important causes of CSE in some parts of the world).[147]

Thus, CSE is a common and potentially dangerous disorder that deserves appropriate treatment following a guideline. Recent advances in functional neuroimaging, genomic investigation and prospective human data are likely to increase our knowledge of seizure induced injury, which will hopefully lead to improved algorithms for prevention and treatment of CSE.

 
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    Abstract
    Introduction
    Definition
    Epidemiology
    Pathophysiology
    CSE and Brain Damage
    CSE and the Imma...
    Clinical Charact...
    Outcome
    Recurrence
    Management
    References
    Article Figures
    Article Tables

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