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Current Anaesthesia & Critical Care (2007) 18, 86–93

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The management of tonic–clonic statusepilepticus (TCSE)

Chris Turner

Department of Neurology, National Hospital for Neurology and Neurosurgery,Queen Square, London WC1N 3BG, UK

KEYWORDSEpilepsy;Tonic–clonic;Status

ee front matter & 2007acc.2007.03.005

ess: ctwork@btinternet

Summary Tonic–clonic status epilepticus (TCSE) can be defined as a condition inwhich prolonged or recurrent tonic–clonic seizures (TCS) persist for 30min or more.The earlier the treatment is initiated the more easily it is resolved. It is mostcommon in children, mentally handicapped, and those with structural cerebralpathology especially in the frontal lobes. In known epileptics, TCSE can beprecipitated by drug withdrawal or non-compliance, inter-current illness, alcoholand drug toxicity, metabolic derangement, or progression of an underlyingpathology. The principles of management include rapid cessation of the seizure toprevent primary neuronal injury diagnosis and treatment of the underlyingcondition, and prevention of relapse with appropriate anticonvulsant therapy.& 2007 Elsevier Ltd. All rights reserved.

Introduction

Tonic–clonic status epilepticus (TCSE) can bedefined as a condition in which prolonged orrecurrent tonic–clonic seizures (TCS) persist for30min or more.1 Most TCS last less than 2min, andmany seizures that continue up to 30min stillself-terminate spontaneously.2 Treatment of thepremonitory stages is more likely to be successfulthan treatment in the later stages and thereforetreatment should commence as soon as it isapparent that the seizure is persisting for morethan 5min.

The annual incidence of TCSE is 18–28/100,000persons.3 It is most common in children, mentally

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handicapped, and those with structural cerebralpathology especially in the frontal lobes. In knownepileptics, TCSE can be precipitated by drug with-drawal, inter-current illness, metabolic derange-ment, or progression of the underlying pathology. Itis more common in secondary rather than primaryepilepsies, i.e. due to tumours or infections. Adultpatients with chronic epilepsy have a lifetime riskof 5% of developing TCSE. TCSE accounts for 3.5% ofadmissions to a neurological intensive therapy unit(ITU). Mortality of TCSE is 20% although most ofthese patients die from the condition underlyingthe TCSE rather than the seizures or its treatment.Permanent neurological deficits can occur withTCSE especially in young children, and the risks ofmorbidity are higher the longer the duration ofthe TCSE.

d.

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Table 2 Outcomes from both hospital and com-munity based studies of TCSE.

Aetiology Hospital 1980s(% poor

Community1989–1991 (% poor

The management of tonic–clonic status epilepticus 87

Aetiologies of TCSE

TCSE is caused by a variety of aetiologieswhich have not changed over the past few decades.There have been two major studies in San Franciscoin the 1970s and 1980s in an urban hospitalsetting4,5 and one community-based study inRichmond, Virginia.6 The most common causes inthe hospital studies were non-compliance withantiepileptic drugs (AEDs), alcohol-related TCSE,drug toxicity, tumours, and trauma (see Table 1).The community-based study suggested thatrefractory epilepsy, metabolic disorders, and car-diac arrest are as common but also demons-trated that non-compliance with medication isconsistently the single highest aetiological causeof TCSE.

outcome)(n ¼ 157)

outcome)(n ¼ 253)

AEDs non-compliance

10 7

ETOH-related

7 8

Drug toxicity 30 15CNSinfection

35 1

Cerebraltumour

35 38

Trauma 1 21Refractoryepilepsy

22 —

Stroke 50 35Metabolicdisorders

35 32

Cardiacarrest/anoxia

80 60

Unknown 60 18

Determinants of outcome of TCSE

It was Cranford et al.7 in the 1970s who emphasizedthe importance of aetiology in determining theoutcome of TCSE. The community- and hospital-based studies described above also investigatedoutcome and related it to aetiology and otherdeterminants such as age. Table 2 demonstratesthat in both studies there were better outcomes inpatients where non-compliance with AEDs was theprimary cause and there were consistently worseoutcomes when stroke and anoxia were the mainaetiological factors.4–6

Several studies have correlated TCSE with along duration with poor outcome, althoughthis is difficult to dissociate from aetiology, i.e.certain aetiologies are associated with longerduration of TCSE.8,9 In the hospital-based study,

Table 1 Causes of TCSE (see Refs.4–6).

Aetiology Hospital 1980s (%)(n ¼ 157)

H(n

AEDs non-compliance 26 26ETOH-related 24 15Drug toxicity 10 10CNS infection 8 4Cerebral tumour 6 4Trauma 5 3Refractory epilepsy 5 —

Stroke 4 15Metabolic disorders 4 8Cardiac arrest/anoxia 4 4Unknown 5 18

the patients with good outcome had TCSE for 2.4 hand those with a bad outcome for 11 h and thiswas related to aetiology.5 In the community-based study, poor outcome was associated withduration of TCSE greater than 1 h, and age andanoxic aetiology were independent (of durationof TCSE) risks for poor outcome.10 In 12% ofpatients, TCSE is the first manifestation of chronicepilepsy.11

ospital 1970s (%)¼ 98)

Community 1989–1991 (%)(n ¼ 253)

2282252

161515122

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Treatment of TCSE

The aims of managing a patient in TCSE are:

(1)

to abort the seizure to prevent primary neuro-nal injury,

(2)

to diagnose and initiate treatment of theunderlying condition,

(3)

to prevent secondary neuronal injury fromsystemic changes associated with of a pro-longed seizure,

(4)

to prevent relapse.

Prevention of neuronal damage is an importantprimary end-point although there still remains debateabout the time at which a convulsive seizure causesneuronal damage. There are probably many factorsincluding the underlying aetiology, age of the patient,and genetic factors involved in neuronal survival.2,12

General considerations in management

It is useful to consider the management of TCSE instages:

1st stage (0–10min)

�

‘‘ABC’’ of resuscitation—the airway should becleared and maintained but fingers should not beused to clear oral debris, � oxygen via face mask mandatory as hypoxia is

often severe.

2nd stage (0–60min)

�

monitoring of vital signs including capillary bloodsugar, � emergency AEDs (see below), � treat medical complications e.g. severe acidosis,

rhabdomyolysis, hyperthermia,

� IV access, � emergency investigations (see below).

3rd stage (0–90min)

�

Establish aetiology and treat e.g. IV glucose forhypoglycaemia, IV thiamine for Wernicke’s en-cephalopathy, drug reintroduction when re-cently withdrawn.

4th stage (30–90min)

�

transfer to ITU, � initiate intracranial pressure (ICP) monitoring

where appropriate,

�

initiate long-term anticonvulsant, � sedate and intubate as needed.

Emergency investigationsBlood: FBC, urea and electrolytes, liver functiontests, calcium, phosphate, magnesium, CRP, clot-ting, glucose, anticonvulsant levels, and toxicologyscreen (where appropriate).

Establishing the aetiologyThis depends on the age of the patient and thepresence or absence of established epilepsy.Imaging (either CT or MRI) and a lumbar punctureare often required to rule out new structural orinfective causes. If TCSE is due to drug withdrawal,then immediate reintroduction of the drug shouldbe performed that often results in termination ofthe seizures.

Medical complications of TCSEThese include hypoxia, hypotension, raised ICP,pulmonary oedema, and hypertension, cardiacarrhythmias, rhabdomyolysis, hyperthermia, cardi-ac failure, lactic acidosis, hypoglycaemia, electro-lyte imbalance, acute hepatic and renal failure,and disseminated intravascular coagulation. Aspecial note of magnesium should be made. Thereis no evidence that supraphysiological levels ofmagnesium has any benefit to TCSE and mayactually cause muscle paralysis, making detectionof seizures more difficult or even cause significanthypotension. However, in patients with eclampsiaand in susceptible groups, e.g. alcoholics orpatients on HIV medications, then a low magnesiumshould be treated with 2–4 g over 20min. This mayhelp seizure and arrhythmia control.

EEG MonitoringIn prolonged TCSE or in comatose patients, muscleactivity can be difficult to detect, and thereforeEEG monitoring can help to identify ongoingactivity. Often patients have electrographic evi-dence of seizure activity but no overt clinicalseizures by the time they reach ITU followingtreatment with benzodiazepines and phenytoin.Burst suppression provides an arbitrary physiologi-cal target for the titration of barbiturates or otheranaesthetic drugs during EEG monitoring. Drugdosing is set to produce interburst suppressionbetween 2 and 30 s. There is still debate whetherburst suppression needs to be electrically achievedas it often requires high doses of AEDs which areassociated with significant cardiorespiratory com-promise.

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The management of tonic–clonic status epilepticus 89

ICP monitoringWhen the aetiology of the TCSE has caused asignificant rise in ICP, then monitoring may behelpful. Its treatment depends on the underlyingcause, although for lesions with a significantinflammatory component, e.g. neoplasms, dexa-methasone at 4mg qds can be used. Mannitolinfusions are only useful for temporary reduction inICP in tentorial coning, while a definitive procedureis performed, such as neurosurgical decompression.

Long-term anticonvulsant therapyThis should be commenced in conjunction withemergency treatment. The choice of drug dependson previous drugs used, the type of epilepsy, andthe clinical setting. If phenytoin or phenobarbitonehas been used in the emergency setting then theycan be continued via a nasogastric tube guided byserum levels.

Emergency anticonvulsant treatment ofTCSE

Emergency treatment of TCSE is performed to avoidcerebral damage and the associated medicalcomplications of TCSE. In the initial stages of TCSE,there are compensatory mechanisms which in-crease cerebral perfusion. These fail after60–90min due to loss of cerebral autoregulationand hypotension. At this time, intracellular calciumlevels rise and cause neuronal cell death. There arefour main stages of escalating treatment which arepartly based on clinical experience and partly onsmall clinical trials. The largest of these was theVeteran’s Association cooperative clinical trial.13

This trial has enabled more rational, evidence-based decisions to be made and has confirmedintravenous lorazepam as the initial treatment ofchoice for TCSE.13,14

Stage 1 (premonitory stage)

In patients with established epilepsy, TCSE rarelyoccurs without warning. This usually takes the formof increasing seizure frequency or severity. Urgentdrug manipulation will usually prevent the subse-quent development into TCSE. If a regular AED hasbeen stopped or reduced, then it should bereinstated immediately. If the patient is sufferingfrom clusters of seizures, then regular oral cloba-zam at 5–10mg bd can be added until the patientsregular AEDs can be optimized. If the seizures areprolonged and very frequent, then rectal diazepamhas been the drug of choice used by general

practitioners and patients and their families forseveral years. A dose of 0.5–1mg/kg of rectaldiazepam achieves therapeutic serum concentra-tions within 1 h and has been demonstrated to beeffective at stopping acute seizures with minimalside-effects. Rectal administration is not toleratedby some patients especially children. Midazolamhas the advantage that it can be administered byintranasal, buccal, and intramuscular routes. Manypatients use 10mg in 2ml of buccal preparation.The prompt treatment of the seizure will make iteasier to gain seizure control. If the patient is athome, then missed or reduced medication shouldbe given if possible.

Stage 2 early TCSE (0–30min)

If the seizure does not respond to administration ofdiazepam then the patient needs admitting to ahospital setting as an emergency. Intravenouslorazepam at 0.07mg/kg, to a maximum of 4mg,is the drug of choice because of its prolonged action(greater than 4 h compared to IV diazepam at20min). This can be repeated once if seizureactivity does not stop after a further 5–10min. Inmost patients, this therapy will be successful and24 h in-patient observation should follow.

Stage 3 established TCSE (30–60min)

This stage is defined as continuous or serial TCSwithout regaining of consciousness for greater than30min in spite of benzodiazepine treatment. Atthis point, physiological cerebral decompensationoccurs and the patient should be managed in a highdependency unit at a minimum. There are threecommon pharmacotherapeutic options which allinvolve an IV loading dose and oral or IV main-tenance. The loading doses are:

(1)

sub-anaesthetic phenobarbitone (10mg/kg), (2) phenytoin (15–20mg/kg), (3) fosphenytoin (a phenytoin prodrug).

It is common practice to follow a failure of IVphenytoin to control seizures with sub-anaestheticdoses of phenobarbitone. Data from the Veteranstrial13 suggest that there are diminishing responsesfor further drug addition prior to full anaesthesia iflorazepam fails in the initial stages; however, theside-effects of anaesthetic drugs and risks ofintubation and intensive care management mustbe weighed against prolongation of the seizure. TheIV loading dose of phenobarbitone can be given in

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under 10min and so many practitioners still use thisprior to intubation.

Continuous benzodiazepine or chlormethiazoleinfusions on wards are now not recommendedbecause of potential cardiorespiratory depression.

Uncontrolled studies with intravenous sodiumvalproate of 15mg/kg followed by 1mg/kg/h hasbeen used with limited experience and somesuccess.

Stage 4 refractory TCSE (after 60min)

Full anaesthesia is required at this stage which canbe barbiturate or non-barbiturate. There has beenlittle formal evaluation of the several drugs thatare used in TCSE. The intravenous barbiturate,thiopentone, is most commonly used in the UK. Theintravenous non-barbiturates, propofol and mida-zolam, are also being increasingly used. Pentobar-bitone is not available in the UK but is usedelsewhere.

Once the patient has been seizure-free for12–24 h and there are adequate serum levels ofone or several maintenance anticonvulsants, thenthe anaesthetic can be weaned off slowly.

AEDs used in TCSE

Diazepam

Diazepam has been extensively studied and hasbeen found to be highly effective in a wide rangeof types of TCSE. It has a rapid onset of action andcan be given rectally or intravenously in thepremonitory phase. Adequate cerebral levelsare reached within 1min of intravenous adminis-tration whereas rectal diazepam levels peak at20min. It is then redistributed rapidly and there-fore has a short duration of action (approxi-mately 20min). Repeated dosing leads to accumu-lation and can lead to sudden unexpected cardior-espiratory collapse and CNS depression. Suddenapnoea can occur especially after repeated or toorapid administration. It is metabolized by thehepatic microsomal enzymes system and thereforehepatic impairment can lead to toxicity morerapidly.

Bolus IV administration should be given notexceeding 2–5mg/min. Diazepam suppositoriesshould not be used as absorption is too slow butthe intravenous form, ‘‘diazemuls’’, can be admi-nistered rectally. In adults, 10–20mg is recom-mended in TCSE, and a further 10mg can be givenat 15min intervals up to a total of 40mg.

Midazolam

Midazolam is given as a water-soluble preparation,but after absorption is lipophilic at physiological pHand can therefore be administered by intranasal,buccal, and intramuscular administration and sub-sequently rapidly crosses the blood brain barrier. Ithas recently been demonstrated that 10mg in 2mlmidazolam squirted around the buccal mucosa is aseffective as 10mg rectal diazepam in children.Maximum serum concentrations are reached at30min although the pharmacodynamic responsemay be quicker. Midazolam has very short distribu-tion and elimination half-lives and therefore has avery short half-life with a tendency to cause seizurerelapse. Its smaller distribution volume makes itthe drug of choice for infusions because of thereduction of accumulation in tissues, although in anITU setting, hepatic impairment can prolong itshalf-life and accumulation. It has the same toxiceffects as diazepam, i.e. cardiorespiratory collapseand CNS depression.

In the acute setting of TCSE, it can be given IM,intranasal, rectally, or buccally at 10mg andrepeated once after 15min. If an infusion isrequired for refractory status, then a loading doseof 0.15mg/kg followed by an infusion of0.05–0.4mg/kg/h can be given.

Lorazepam

Lorazepam has a smaller volume of distribution andis less lipid soluble than diazepam. Its pharmaco-kinetics result in a slower onset of action but it hasa longer duration of action (over 4 h). Lorazepam isindicated in the acute stages of TCSE only becauseof its lack of lipid accumulation, strong cerebralbinding, and long duration of action due to itsdistribution half-life which make it a better drugthan diazepam in the acute setting. It has beensubjected to large clinical trials in adults, children,and the newborn. Lorazepam is excellent atcontrolling seizures in the early stages but its maindisadvantage is that tolerance develops rapidly. Itusually is effective for 12 h in preventing seizures,but repeated doses are less effective making itunsuitable for long-term therapy. Lorazepam hassedative side-effects but is less likely to causecardiorespiratory collapse because of its relativelipid insolubility and its lack of accumulation.

Lorazepam is usually administered by IV injectionand because it is slow to distribute its rate ofadministration is not important. The typical adultdose is 0.07mg/kg to a maximum of 4mg. This can

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The management of tonic–clonic status epilepticus 91

be repeated after 20min if there has been noeffect.

Phenytoin

Phenytoin is the drug of choice in established TCSE.There is extensive experience with its use, and itslong duration of action makes it particularlyeffective and it can be continued as maintenancetherapy. It causes relatively little CNS/respiratorydepression although hypotension is more common.The initial infusion is usually given over 30min andthe onset of action is slow. It is therefore oftenadministered with a short-acting drug with rapidonset, i.e. a benzodiazepine. The saturable first-order kinetics often do not cause a problem in anacute setting but levels should be monitored.Phenytoin can precipitate at low pH, e.g. in 5%glucose, and should therefore be given in normalsaline. The high pH of phenytoin can lead tothrombophlebitis if it extravasates and thereforecaution is required. The adult loading dose is15–20mg/kg and the rate of infusion should notexceed 50mg/min. A common mistake is to give alower dose and therefore inadequate therapy. Oralor IV maintenance doses can be continued at5–6mg/kg/day.

Fosphenytoin

In order to overcome some of the properties ofphenytoin, a water-soluble pro-drug called fo-sphenytoin was developed. This is inactive, but ismetabolized to phenytoin with a half-life of8–15min; 5mg of fosphenytoin is equimolar with1mg phenytoin. Fosphenytoin is more expensivebut causes less thrombophlebitis, less hypotension,is easier to administer, and has greater tolerability.Since it is water soluble, it can be given as an IMinjection, although there is limited experience withthis route of administration. ECG monitoring ismandatory during administration of fosphenytoin orphenytoin.

Phenobarbitone

Phenobarbitone is another drug of choice for thetreatment of established stage 3 TCSE. It is highlyeffective, has a rapid onset of action, andprolonged anticonvulsant effects. It is stable andnon-reactive, and has convenient pharmacoki-netics. There is wide clinical experience with itsuses and side-effects. It has stronger anticonvul-sant effects than other barbiturates. It may alsohave cerebrally protective actions. Acute tolerance

is rare and once seizures are controlled they do nottend to recur.

The main disadvantages of phenobarbitone aresedation, respiratory depression, and hypotension,although these tend to only occur with rapidlyrising levels and very high doses. It is eliminatedslowly and therefore monitoring of levels is vital forchronic use.

The intravenous loading dose is 10mg/kg at100mg/min, followed by maintenance of 1–4mg/kg/day. After loading, maintenance can be given byoral, IV, or IM routes.

Thiopentone

Thiopentone is traditionally used as the barbiturateanaesthetic in TCSE. It is an effective anticonvul-sant and may have cerebral protective properties.At anticonvulsant doses, intubation and usuallyventilation are required due to its sedative proper-ties. Hypotension is also common and may requireinotropes. It has saturable kinetics and tends toaccumulate resulting in prolonged sedation afterthe drug is stopped. It can also cause pancreatitisand hepatic dysfunction.

There are few formal clinical trials of thiopen-tone in TCSE in spite of its use for over 40 years. Italso requires intensive monitoring. Thiopentone isusually given as a 100–250mg bolus over 20 s andfurther 50mg boluses every 2–3min until seizuresare controlled. Intravenous infusion is then con-tinued at the minimum dose required to controlclinical and electrographic seizure activity, which isusually 3–5mg/kg/h. The serum levels should beused to monitor maintenance therapy. The doseshould be lowered with persistent hypotension.Thiopentone should be continued for at least 12 hafter seizure control. There is some evidence thatco-loading with phenobarbitone at the onset helpsseizure control.

Propofol

There is a current trend for non-barbiturateanaesthesia to be used in TCSE and propofol isperhaps the most popular. There is limited butgrowing evidence of its use in TCSE. Propofol is ahighly effective and non-toxic anaesthetic. It isanticonvulsant by potentiating GABA receptors.Propofol also has neuroexcitatory side-effectspossibly through subcortical disinhibition and canlead to myoclonus, opisthotonos, abnormal move-ments, and muscle rigidity. These can be mistakenfor seizures. Seizures have been demonstrated onpropofol withdrawal and are due to a rebound

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phenomenon.15 Propofol is extremely lipid solubleand has a high volume of distribution. It actsextremely rapidly in TCSE but causes profoundcerebral and respiratory depression and thereforepatients usually require ventilation. Cardiovascularside-effects are usually relatively mild. Long-termadministration causes severe lipaemia and mayresult in acidosis and rhabdomyolysis. In TCSE, aninitial bolus of 1–2mg/kg is given followed by aninfusion of 1–15mg/kg guided by EEG activity. Thisdose can then be slowly tapered over 24 h following12 h of seizure control.

Treatment of non-convulsive statusepilepticus (NCSE)

Most seizure types, other than TCS, can occurwithout spontaneous cessation. These includecomplex and simple partial epilepsies, absencestatus epilepticus and status epilepticus in coma.Most NCSE occurs in the context of patients withlearning difficulties. They are two importantqualities to NCSE: firstly they can be difficult todiagnose and secondly there is great uncertaintyover optimum management. The diagnosis is madeon clinical grounds and EEG. In adults, new onsetNCSE can occur in the context of encephalitis,metabolic derangement, or any other focal acuteprecipitant. In patients with known epilepsy, anyprolonged change in personality, post-ictal confu-sion, or psychosis should prompt EEG. NCSE canfollow TCSE and is an important cause of persistentcoma. The EEG may demonstrate regular repetitivedischarges but may be difficult to differentiatefrom encephalopathy. The presence of periodic orrhythmic discharges coinciding with clinical seizureactivity and response to anticonvulsants can behelpful. Animal models suggest that neuronaldamage does occur during NCSE; however, it isgenerally accepted that for humans the neuronalloss is probably minimal relative to the underlyingcondition causing NCSE.

Complex partial status epilepticus (CPSE)

This is a relatively common form of NCSE in adults.The EEG findings are often non-specific and thediagnosis is made clinically. The aggressiveness ofmanagement depends on the prognosis of theunderlying condition and whether treatment willimprove prognosis.16 CPSE in a known epileptic isprobably more benign than in a patient with anacute precipitant. The potential side-effects rarelywarrant IV treatment and oral clobazam has provento be effective. Most CPSE is self-limiting, however,

IV therapy may be required if the episode isprolonged.

NCSE in coma

This occurs in 8% of the patients in coma and istherefore important to recognize. The diagnosis isoften debatable as burst-suppression, period dis-charges, and encephalopathic triphasic dischargesare often seen in cortical damage/dysfunction andmay not represent seizure activity. There are fourrecognized groups of patients.

(1)

Patients who have had TCSE often developminimal or no motor activity but ongoingelectrical activity. This should be treatedaggressively with anaesthesia and maintenanceAEDs.

(2)

Subtle motor activity, usually in the context ofhypoxic brain injury, has a poor prognosis andwarrants aggressive management with AEDs asthe little evidence that is available suggeststhat treatment improves prognosis.

(3)

Electrographic status with no clinical signs isvery difficult to interpret. These patients havea poor prognosis and therefore aggressive AEDtreatment is recommended.

(4)

In patients who have abnormal repetitivemovements but no EEG activity, there is noindication to treat the movements.

References

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13. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C,Rowan AJ, et al. A comparison of four treatments for

generalized convulsive status epilepticus. Veterans AffairsStatus Epilepticus Cooperative Study Group. N Engl J Med1998;339(12):792–8.

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