Status epilepticus patophysiology epidemiology and outcomes.pdf

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1998;79;73-77Arch. Dis. Child.Rod C Scott, Robert A H Surtees and Brian G R Neville

and outcomesStatus epilepticus: pathophysiology, epidemiology,

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CURRENT TOPIC

Status epilepticus: pathophysiology, epidemiology,

and outcomes

Rod C Scott, Robert A H Surtees, Brian G R Neville

Convulsive status epilepticus (CSE) is the mostcommon neurological medical emergency andcontinues to be associated with significantmorbidity and mortality. Our approach to theepilepsies in childhood has been clarified by thebroad separation into benign and malignantsyndromes. The factors that suggest a pooreroutcome in terms of seizures, cognition, andbehaviour include the presence of multiple sei-

zure types, an additional, particularly cognitivedisability, the presence of identifiable cerebralpathology, a high rate of seizures, an early ageof onset, poor response to antiepileptic drugs,and the occurrence of CSE.1

Convulsive status epilepticus is not a syn-drome in the same sense as febrile convulsions,benign rolandic epilepsy, and infantile poly-morphic epilepsy. These latter disorders have atight age frame, seizure semiology, and areasonably predictable outcome. Episodes ofCSE can occur in each: occasionally in febrileconvulsions, rarely in benign rolandic epilepsy,and often in infantile polymorphic epilepsy.The issue of whether episodes of status epilep-ticus are intrinsically more dangerous in themalignant syndromes needs consideration be-fore we accept global figures for CSE outcome,and we need to separate the immediateoutcome of CSE from the eventual outcome,which may be heavily influenced by the contextor syndrome in which it occurs.

In practical management we are likely towant to stop prolonged seizures as soon as pos-sible, but in theoretical terms it may be impor-tant to know if some causes of CSE are intrin-sically more dangerous. The paediatricdimension to CSE is therefore of manydiVerent causes and occurring in a patient whois less likely to have concomitant cardiovascularor respiratory disease. The hazards and out-

come might be diVerent. This paper reviewsadvances in the pathophysiology and conse-quences of CSE with special reference to agerelated phenomena.

DefinitionStatus epilepticus is a disorder in which themechanisms required for seizure terminationfail. This definition, unfortunately, is not clini-cally useful as these mechanisms have not yetbeen well described. The most widely useddefinition is a seizure or series of seizures thatlast for 30 minutes or more, without full

consciousness being regained between the sei-zures. This gives the impression that status epi-lepticus is always convulsive and is a singleentity. There are, however, as many types ofstatus epilepticus as there are types of seizures,and this definition is now probably outdated.

To show that status epilepticus is a complexdisorder, Shorvon has proposed the followingdefinition. Status epilepticus is a disorder in

which epileptic activity persists for 30 minutesor more, causing a wide spectrum of clinicalsymptoms, and with a highly variable patho-physiological, anatomical, and aetiologicalbasis.2 CSE needs diVerent definitions fordiVerent purposes. Many seizures that last forfive minutes will continue for at least 20minutes, and so treatment is required for mostfive minute seizures. Therefore for emergencytreatment purposes the definition should statea time of five minutes, and means that the childis at risk of having a seizure lasting 20 minutesor more. However, for pathophysiological, epi-demiological, and outcome purposes a defini-tion of seizures persisting for at least 20minutes seems appropriate to identify those atrisk of developing structural brain damage.There is currently no consensus on a defini-tion.

PathophysiologyMuch of the work described in this section hasbeen carried out in human adults and animalmodels, and we must be cautious aboutextrapolating this information into childhood.

SEIZURE INITIATION AND PROLONGATION

Why seizures start and stop is unknown,although it is likely that seizure initiation iscaused by an imbalance between excitatory

and inhibitory neurotransmission, leading tothe initiation of abnormal neural impulses. Theseizure threshold in the immature brainappears to be lower than in the mature brain,but the mechanisms that underlie this suscepti-bility remain unclear. Excitatory synapsesmature earlier than inhibitory synapses andthis, coupled with an increase in the suscepti-bility of excitatory neurotransmitter receptors,increases the likelihood that an excitationinhibition imbalance may occur.3 4

There are other important diVerences be-tween the immature and adult brain. Stimula-tion of GABAAreceptors in the immature brain

Arch Dis Child1998;79:7377 73

Neurosciences Unit,

Institute of ChildHealth, University

College London

Medical School,

30 Guilford Street,

London WC1N 1EH,

UK

R C Scott

R A H SurteesB G R Neville

Correspondence to:

Dr Rod C Scott,

The Wolfson Centre,

Mecklenburgh Square,

London WC1N 2AP, UK.

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results in depolarisation rather thanhyperpolarisation, as occurs in the adult brain.5

The immature cerebral cortex has a highsynaptic density at around 2 months of age andthis may contribute to the development ofhypersynchrony of neural groups.4

The excitatory amino acid neurotransmitterglutamate increases at the site of the seizurefocus at the beginning of seizure activity inadults with temporal lobe epilepsy when meas-ured by in vivo intracerebral microdialysis.6 7 8

It is believed that the same may happen at theonset of generalised seizures. Inhibitory neuro-transmitters such as GABA later increase at theseizure focus and redress the balance betweenexcitation and inhibition.6 GABA also in-creases in the substantia nigra pars reticulata,an area that can modulate a cortical inhibitoryresponse in adult rats, but not in immaturerats.3 Other mechanisms of inhibitory receptormodulation, such as adenosine receptor ago-nism, may also contribute to seizure termina-tion. Thus the increased incidence of CSE inchildhood is probably caused by a combinationof increased seizure susceptibility and de-creased ability to mount an adequate inhibitoryresponse.

SYSTEMIC AND CENTRAL PATHOPHYSIOLOGY

The systemic eVects of CSE are initially domi-nated by the bodys attempt to maintainhomeostasis.9 Blood pressure and centralvenous pressure increase, blood glucose in-creases, and the patient becomestachycardic. 9 10 CSE may also result in electro-lyte imbalance and hyperthermia.11 Cerebralblood flow, blood glucose, and oxygen utilisa-tion increase in the initial phases of a seizure tomaintain cerebral homeostasis. After 30 min-utes homeostatic failure begins and the patientmay need systemic support.9 Cerebral bloodflow, brain glucose, and parenchymal oxygena-tion all decrease and potentially play a part inthe cell damage associated with CSE.9 10 Respi-ratory and metabolic acidosis, electrolyteimbalance (for example, hyperkalaemia),hyperthermia, and rhabdomyolysis may alloccur (table 1).Treatment with drugs withdepressant cardiorespiratory side eVects (forexample, benzodiazepines and barbiturates)may worsen the systemic complications ofCSE.

ELECTROPHYSIOLOGY

About 70-80% of cases of CSE throughout allage groups will have a focal onset but besecondarily generalised. A predictable sequence

of changes in the electroencephalogram (EEG)has been shown in adult humans and in at leastsix animal models.12 CSE starts with localisedepileptic activity followed by isolated general-ised bursts of seizure activity with a normalEEG in between. If the patient does not regainconsciousness between these episodes, thenthey meet the clinical criteria for CSE. The iso-lated ictal discharges merge and become a con-tinuous discharge after about 30 minutes.Discharges then fragment and are interspersedwith flat periods. Ultimately, periodic epilepti-form discharges, which may reflect underlyingmetabolic failure, will occur.9 12

The motor phenomena associated with CSEfollow a similar pattern to the EEG changes.Recurrent seizures will merge into continuousmotor activity, followed by fragmentation ofthe motor activity and myoclonus. If the seizurepersists, then electromechanical dissociationwill ensue.9 12 The prognosis for a goodneurological outcome decreases the further thepatient moves through this continuum.

ROLE OF EXCITOTOXIC AMINO ACIDS IN THE

DEVELOPMENT OF STRUCTURAL BRAIN DAMAGE

SECONDARY TO CSE

Mesial temporal sclerosis is the most common

acquired brain lesion following CSE and mayresult from excitotoxicity. Most work in thisfield has been directed at the eVects ofglutamate. Lucas and Newhouse, 36 years ago,observed that systemic glutamate destroyedretinal cells in rat pups.13 They suggested thatglutamate was directly responsible for the celldeath, although the neurotransmitter role ofglutamate was unknown. Since that time muchanimal model and cell culture work hasattempted to prove this hypothesis and to relateit to status epilepticus.14 Direct application ofglutamate onto hippocampal cultures causesneuronal death, which resembles that seen inthe animal models described in the followingsection.15 This work provides indirect evidencethat CSE can itself cause hippocampal dam-age.

Animal modelConvulsive status epilepticus has been inducedin animal models with the use of convulsantchemicals or by electrical kindling.+ Anti-GABA drugsbicucculine given to

adolescent baboons16 results in neuronal lossin the hippocampus, neocortex, amygdala,thalamus, and cerebellum. The hippocam-pal cell loss resembles that seen in humanswho have died during CSE.17 Allylglycine

Table 1 Systemic and cerebral pathophysiological changes associated with seizures and convulsive status epilepticus

Compensation (< 30 minutes) Decompensation (> 30 minutes)

Increased cerebral blood flow Failure of cerebral autoregulationCerebral energy requirements matched by supply of oxygen and glucose HypoglycaemiaIncreased glucose concentration in the brain HypoxiaIncreased catecholamine release AcidosisIncreased cardiac output Hyponatraemia

Hypo/hyperkalaemiaDisseminated intravascular coagulationLeucocytosisFalling blood pressure

Falling cardiac outputRhabdomyolysis

74 Scott, Surtees,Neville



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can also cause cell death when administeredsystemically.9 18

+ Glutamatergic drugskainic acid is a gluta-mate agonist that has been widely used toinduce status epilepticus. Hippocampaldamage is seen after CSE in rats exposed tointraperitoneal, intra-amgydala, or intraven-tricular kainic acid. This damage is seen insimilar areas of the hippocampus to thatseen in humans who have died during CSE. 2

Other drugs that have been used includeN-methyl-D-aspartate (NMDA), quis-qualate, and pentylenetetrazol.9 18

+ Cholinergic drugspilocarpine and dipipe-ridionethane cause CSE in rats, and result indamage prominent in the neocortex, thala-mus, amygdala, and hippocampus.9

+ Electrical stimulation models have also beendeveloped and show that neuronal deathoccurs in the hippocampus if continuousprotocols are followed.

Thus many diVerent experimental paradigmsresult in similar damage to the hippocampus,and the damage is probably caused by thepresence of status epilepticus itself and not a

direct eV

ect of the drug used to provoke statusepilepticus. Bilateral hippocampal damage mayoccur even with unilateral stimulation.9 18

Rats that have been exposed to kainate afterthey have been rendered epileptic by electricalkindling methods do not appear to develop asmuch hippocampal damage as non-epilepticrats. The kindled animals had a diVerentseizure semiology in that their seizures tendedto be restricted to the limbic system and werelonger lasting.19 CSE induces the production ofheat shock proteins in several brain regions.20

The presence of heat shock proteins canprotect the brain against further stressfulstimuli, which are potentially damaging toneurones.21 The implication is that prolonged

seizures may need to occur in epilepsy naivehuman patients for mesial temporal sclerosis todevelop, and that once it has developed furtherepisodes of CSE may not worsen the mesialtemporal sclerosis.

MECHANISMS BY WHICH GLUTAMATE CAUSES

CELL DEATH

Excess extracellular glutamate may result incell death by causing necrosis,gene determinedcell death, or both.9 The primary receptorinvolved in cytotoxicity related to glutamate isthe NMDA receptor, although other glutamatereceptors may be involved.2 9 1 3 The NMDAreceptor is an ionotropic receptor. Binding of

glutamate and glycine or D

-serine to appropri-ate sites on the receptor results in an influx ofcalcium through the ionophore. Highintracellular calcium concentrations result inthe activation of a large number of calciumdependent processes such as those described inthe following.+ Activation of protein kinase C. This enzyme

is moved from the cytosol to the cell wall,resulting in destruction of the wall. 13

+ Nitric oxide and free radical formation. Cal-cium stimulates constitutive nitric oxidesynthase, causing an increase in intracellularnitric oxide.22 Nitric oxide can inhibit mito-

chondrial respiration directly or indirectlyby forming peroxynitrite free radicals, whichare cytotoxic.13 22

+ Activation of phospholipase A2. This en-zyme breaks down membrane lipids with therelease of arachidonic acid and other fattyacids. One consequence of this membranedestruction can be cell death.13

+ Activation of protease calpain I. The mech-anism by which this enzyme causes cell

death is unclear, but calpain I inhibitors arepartially neuroprotective.13

Glutamate receptor stimulation also results inthe formation of immediate early genes,such asc-fos, fos-B, c-jun, and jun-B. c-fos encodes forFos protein, which has a leucine zipperallowing it to bind and form dimers with simi-lar proteins. These dimers bind to a specificDNA region (AP-1 site), which regulates theexpression of a number of late eVector genes.23

Some of the genes regulated are harmful andsome are potentially neuroprotective. Thusimmediate early genes may play a dual role:induction of gene determined cell death andactivation of brain repair mechanisms.

Metabotropic glutamate receptors are notdirectly associated with an ion channel, andstimulation of these receptors results in theformation of intracellular second messengers.These receptors may also have toxic andprotective functions. The potentially toxiceVects of metabotropic glutamate activationinclude the potentiation of NMDA and otherexcitatory membrane currents, the potentia-tion of intracellular calcium release, a decreasein inhibitory membrane currents, and de-creased GABAergic inhibition. Conversely,potential protective eVects include the inhibi-tion of synaptic glutamate release and de-creased calcium influx.24 Clearly further workrelated to the functions of immediate early

genes and metabotropic glutamate receptors isrequired.

Equal hippocampal damage does not occuracross all ages in rats. Neonatal rats arerelatively resistant to the development ofhippocampal damage after CSE. Maximumvulnerability occurs in P18 to P21 rats, withless vulnerability of hippocampal neurones inadult rats. Changes in humans appear to reflectthe changes seen in rats. Children who developCSE in the neonatal period do not appear todevelop mesial temporal sclerosis, but othersare most vulnerable under the age of 3 years.

Epidemiology, aetiology, and outcome

In terms of outcome it is useful to divide theaetiologies of CSE into febrile and non-febrile.Febrile CSE (status epilepticus associated withfever in a neurologically normal child betweenthe ages of 6 months and 5 years) is consideredto have a good prognosis. There is a very lowincidence of new neurological deficits orcognitive impairment in this group of children,but the risk of subsequent epilepsy appears tobe 21%,25 much higher than the population riskof epilepsy (0.51%). About half of these chil-dren will go on to have complex partialseizures,25 many of whom will have mesial tem-poral sclerosis. The relation between CSE and

Status epilepticus 75



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mesial temporal sclerosis is presumed to becausative, although this is not proved. Up to75% of children with temporal lobe epilepsywill have evidence of mesial temporal sclerosison magnetic resonance imaging,26 27 suggestingthat mesial temporal sclerosis in childhood isnot as rare as previously believed and isprobably underdiagnosed. Approximately 50%of patients with temporal lobe epilepsy second-ary to mesial temporal sclerosis will have a his-

tory of prolonged febrile convulsions inchildhood.2

Outcome from non-febrile CSE is primarilydependent on the aetiology, which is in turndependent on the age of the child.2831 CSElasting longer than one hour has a highermortality than CSE lasting less than onehour.31 The aetiology of non-febrile CSE canbe divided into three groups. (a) idiopathic; (b)acute symptomaticfor example, meningitis,encephalitis, stroke, acute metabolic disorders;and (c) remote symptomaticfor example,underlying acquired, developmental or con-genital CNS disorder; this category alsoincludes CSE occurring in children with

defined epileptic syndromes.Cognitive or persistent neurological deficitsand further seizures occur most frequently withsymptomatic aetiologies and in children underthe age of 3 years. It is possible that theprognosis of an underlying disorder is wors-ened by an episode of CSE, but it may be diY-cult to tease out the significance of the episodeof CSE.29 Recurrent CSE occurs in about 17%of children after an initial episode of CSE.Forty four per cent of these children will haveunderlying chronic brain disorders and 11%will have initially presented with an acutecerebral insult.

Two metabolic disorders that may presentwith CSE deserve special mention as they are

treatable. Pyridoxine dependent epilepsy maypresent in the neonatal period, but it usuallypresents with seizures when the child is a fewmonths old. Treatment with pyridoxine con-trols the seizures. All children under the age of18 months with intractable seizures shouldhave a trial of pyridoxine. Biotinidase defi-ciency is one biochemical defect in biotinresponsive multiple decarboxylase deficiency.Children classically develop seizures, ataxia,skin rash, and alopecia, but may present withseizures alone. Biotin given by mouth is aneVective treatment.

There has been an apparent decrease inmortality since Aicardi and Chevrie32 pub-

lished their review of 239 episodes of CSE in1970. They showed a mortality of 11% and apoor neurological or cognitive outcome in 53%of patients. The hemiconvulsion, hemiplegiaepilepsy syndrome seen in this series is now arare complication of CSE and occurs only inchildren in whom a seizure has lasted morethan one hour. By 1989 the mortality haddecreased to between 3% and 6%.28 30 33 34 Theincidence of prolonged seizures was possiblyhigher when the Aicardi and Chevrie series wasbeing collected as benzodiazepines had notbeen introduced into clinical practice. Achange in definition may also have played a

part. Aicardi and Chevrie required that sei-zures lasted at least one hour, whereas the morerecent studies use 30 minutes as the cut oVpoint. The longer a seizure lasts, the more dif-ficult it becomes to treat, increasing thelikelihood of a poor outcome.2 In a retrospec-tive 10 year review of intensive therapy unitadmissions for CSE the mortality was 8%,although 12% of children had died within oneyear. Thirty three per cent had neurological

sequelae ranging from minor motor problemsto persistent vegetative states.35 All of thesestudies have a bias in their methodology as allthe patients were recruited from hospital basedpopulations.

There are few prospective epidemiologicalstudies attempting to define clearly the inci-dence and outcome of CSE. This is becausethey are diYcult to perform, requiring anetwork between all hospitals in a delineatedarea and many person-hours to ensure datacollection before patient discharge. It is clearthat retrospective work is less accurate, as notekeeping in hospitals is usually not accurateenough to obtain suYciently good data.

DeLorenzo et al in Richmond, Virginia per-formed such a study in which only people livingwithin the city limits were included.36 The hos-pital network went beyond the city limits andtherefore patients presenting outside their areawere identified. The success of this studydepended on a status epilepticus research teambeing on call 24 hours a day, seven days a week.Patients were reported to the team on admis-sion, but the team also identified patients byusing the ICD 9 codes for seizures. The notesof all patients were reviewed by the team. Thetotal incidence of CSE was 41/100 000 resi-dents, but this figure was 147/100 000 ininfants aged 1 month to 1 year. Furtherepisodes of CSE were identified in 35% of

these children. Partial and secondary general-ised seizures accounted for most of theepisodes of CSE in the paediatric age group,although primary generalised CSE occurred in45% of cases. Despite having the highestincidence of CSE, the mortality in children wasonly 2.5%, and non-central nervous systeminfections accounted for all the deaths in thisstudy.36

The child health and education survey is apopulation based birth cohort study in which14 676 children born in a single week in 1970have been followed for 10 years. Thirty seven ofthese children had at least one episode of CSEby the time they were 10 years old. Nineteen

had lengthy febrile convulsions and 18 hadnon-febrile status epilepticus. Two childrendied (5.4%), both of whom presented withnon-febrile CSE. New neurological signs wereidentified in only one child.25 Twenty one percent of children developed non-febrile seizuresafter a prolonged febrile convulsion. Thenational collaborative perinatal project was anepidemiological study carried out in the USA,which showed that 5.4% of children developednon-febrile seizures after a prolonged febrileseizure by 7 years of age.37 Despite the fact thatoutcome seems to be improving, the possibilityof a poor prognosis after CSE is still great

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enough to be of concern. There is a lag periodfrom the time of a prolonged febrile seizure tothe development of complex partial seizures,and therefore these studies probably underesti-mate the risk of subsequent epilepsy and longerfollow up periods are required.

Finally, these studies do not address thequestion of whether mesial temporal damagewhich is not epileptogenic, may cause cogni-tive, especially memory, impairment. Such

damage is apparent in the contralateral tempo-ral lobe of many children and adults investi-gated for surgical treatment of mesial temporalsclerosis.27 There is evidence that such damagemay be of cognitive significance.38

ConclusionsConvulsive status epilepticus continues to beassociated with significant neurological mor-bidity and mortality. It is therefore importantthat the disorder is recognised rapidly andtreatment instituted as soon as possible.Although the outcome is dependent on aetiol-ogy, it is believed that appropriate earlymanagement may reduce some of the morbid-

ity associated with CSE. Future therapeuticand neuroprotective interventions need to beinvestigated in the light of our current under-standing of the mechanisms of seizure termina-tion and neuronal death. The incidence of CSEis highest in childhood and therefore neuropro-tective strategies may ultimately be mostusefully carried out in children.

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19 Kelly ME, McIntyre DC. Hippocampal kindling protectsseveral structures from the neuronal damage resulting fromkainic acid-induced status epilepticus.Brain Res 1994;634:24556.

20 Lowenstein D, Simon R, Sharp F. The pattern of 72 kDaheat shock protein-like immunoreactivity in the rat brainfollowing flurothyl-induced status epilepticus. Brain Res1997;531:17282.

21 Latchman DS. Cell stress genes and neuronal protection.Neuropathol Appl Neurobiol1995;21:4757.

22 Dawson TM, Dawson VL, Snyder SH. A novel neuronalmessenger molecule in brain: the free radical, nitric oxide.

Ann Neurol1992;32:297311.23 Akins PT, Liu PK, Hsu CY. Immediate early gene

expression in response to cerebral ischemia. Friend or foe?Stroke1996;27:16827.

24 Choi D. Glutamate receptors and the induction ofexcitotoxic neuronal death. Progr Brain Res 1994;100:4751.

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27 Cross JH, Connelly A, Jackson GD, Johnson CL, NevilleBG, Gadian DG. Proton magnetic resonance spectroscopyin children with temporal lobe epilepsy. Ann Neurol1996;39:10713.

28 Maytal J. The management of status epilepticus in children.Childrens Hospital Quarterly 1993;3:25563.

29 Shorvon S. The outcome of tonic-clonic status epilepticus.Curr Opin Neurol1994;7:935.

30 Gross-Tsur V, Shinnar S. Convulsive status epilepticus inchildren.Epilepsia 1993;34(suppl 1):S1220.

31 Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinantsof mortality in status epilepticus. Epilepsia 1994;35:2734.

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