50 Status epilepticusHelen I Opdam

Status epilepticus (SE) is a medical emergency requir-ing prompt intervention to prevent the development of irreversible brain damage.

DEFINITION AND CLASSIFICATION

The duration of seizure activity required to define SE has not been universally agreed upon. Most authors have defined SE as more than 30 minutes duration of either a single seizure, or intermittent seizures with no regaining of consciousness between seizures.1–4 This definition is most useful for epidemiological research5 and is based on experimental studies that show irre-versible neuronal damage occurs after 30 minutes of seizure activity.6

There is general acceptance of an operational defini-tion of SE as 5 minutes of continuous seizure activity, or two or more discrete seizures with no intervening recovery of consciousness. It has arisen from the need to rapidly initiate treatment for SE and the observation that seizures persisting beyond this duration are unlikely to remit spontaneously.7 Promulgation of this definition and resultant earlier treatment may be responsible for a decline in the incidence of SE.5

Refractory SE is defined as failure of initial therapy, such as benzodiazepines and phenytoin, usually neces-sitating treatment with agents that induce general anaesthesia.8–10 Refractory SE develops in about one in five patients presenting with an SE episode and is asso-ciated with a worse prognosis.9,11

Continuation or recurrence of SE beyond 24 hours of anaesthetic therapy has been termed ‘super- refractory SE’.12

SE is commonly separated into two categories:

• Generalised convulsive SE (GCSE): seizures are primary or secondarily generalised and the patient has generalised tonic and/or clonic convulsive movements with loss of consciousness.

• Non-convulsive SE (NCSE): there is altered conscious-ness and electroencephalography (EEG) evidence of seizures without convulsive movements. NCSE is a heterogeneous disorder with multiple sub-types. NCSE may evolve from GCSE when electri-cal seizure activity continues with loss of motor manifestations.

The incidence of SE is U-shaped, being greatest under 1 year and over 60 years of age.5

PATHOPHYSIOLOGY

Ongoing or recurrent seizures result from failure of normal seizure terminating mechanisms and pre-dominance of excitation causing seizure activity to persist. The major inhibitory mechanism in the brain is γ-aminobutyric acid A (GABAA) receptor-mediated inhibition. With ongoing seizure activity GABAA recep-tors undergo cellular internalisation and subsequent degradation, leading to loss of endogenous inhibition and sustainability of seizures. This reduction in synap-tic GABAA receptors explains the progressive phar-macoresistance to GABAergic anticonvulsants such as benzodiazepines.13

Excitatory mechanisms are predominantly via glutamine acting on N-methyl-D-aspartate (NMDA) receptors. NMDA receptors increase on synapses during ongoing epileptic activity, facilitating neuronal excitability and persistence of seizures. This in contrast explains the efficacy of NMDA antagonists, even late in the course of SE.

The pathophysiological effects of seizures on the brain are thought to result from both direct excito-toxic neuronal injury and secondary injury due to sys-temic complications such as hypotension, hypoxia and hyperthermia. Ongoing excitation leads to neuronal injury and death, predominantly through mitochon-drial dysfunction. Experimental models and anecdotal human evidence suggest also that SE is epilep-togenic, although the mechanisms of this are not well understood.13

AETIOLOGY

Status epilepticus may occur de novo (approximately 60% of presentations) or less commonly in a previously diagnosed epileptic.5 In the situation where refractory SE does not have a clear cause, more unusual condi-tions should be considered as their diagnosis may lead to a specific therapy. These include autoimmune condi-tions, mitochondrial diseases and unusual infections.14 The aetiologies of SE are given in Box 50.1.2,5,14,15

Generalised convulsive status epilepticus (GCSE) 561

sequence of EEG changes during untreated GCSE. Ini-tially, discrete electrographic seizures merge to a waxing and waning pattern of seizure activity, fol-lowed by continuous monomorphic discharges, which become interspersed with increasing periods of electro-graphic silence and, eventually, periodic epileptiform discharges on a relatively flat background.16 The pres-ence of any of these EEG patterns should suggest the diagnosis of GCSE.

ENDOCRINE AND METABOLIC EFFECTS

Early in GCSE there is a marked increase in plasma catecholamines, producing systemic physiological changes that resolve if SE is stopped early (Box 50.2). However, if seizures continue, many of these early physiological changes reverse and the resultant hypo-tension and hypoglycaemia may exacerbate neurologi-cal injury.18

Hyperthermia is due to both muscle activity and central sympathetic drive, and thus may still occur when paralysing agents prevent motor activity. In early SE, both cerebral metabolic activity and cerebral blood flow (CBF) are increased. In late SE, although cerebral metabolic activity remains high, CBF may fall owing to hypotension and loss of cerebral autoregulation leading to cerebral ischaemia.

PSEUDOSEIZURES

An important differential diagnosis of generalised con-vulsive epilepsy is pseudoseizures.19 These can occur in patients with or without a history of epilepsy. Clinical features suggestive of pseudoseizures are listed in Box 50.3. “Distinction between the two may be extremely difficult, and can be made with complete certainty only using EEG monitoring.” Pseudostatus, misdiagnosed as true SE, is often refractory to initial therapy and can lead to patients receiving general anaesthesia and mechanical ventilation.

GENERALISED CONVULSIVE STATUS EPILEPTICUS  (GCSE)

GCSE is the most common and most dangerous type of SE and accounts for approximately 75%.2 It encom-passes a broad spectrum of clinical presentations, from overt generalised tonic–clonic seizures to subtle convul-sive movements in a profoundly comatose patient.16

CLINICAL

Typically, early in the evolution of seizures, patients are unresponsive with obvious tonic (sustained contrac-tions) and/or clonic (rhythmic jerking) movements (overt GCSE). Motor manifestations may be symmetri-cal or asymmetrical.

With time, the clinical manifestations may become subtle, and patients have only small-amplitude twitch-ing movements of the face, hands, or feet, or nystag-moid jerking of the eyes (late or subtle GCSE).16

Later still some patients will have no observable repetitive motor activity and the detection of ongoing seizures requires EEG (electrical GCSE). Most authors classify this as a form of NCSE.7,17 Such patients are still at risk of CNS injury and require prompt treatment.

EEG CHANGES

Just as there is a progression from overt to increasingly subtle motor manifestations, there is also a predictable

Box 50.1  Causes of status epilepticus in adults2,4,14,15

Low antiepileptic drug levels – poor compliance, recent dose reduction  or  discontinuation  (most  common  cause  in patients with epilepsy)

Stroke – vascular occlusion or haemorrhageMetabolic disturbances – electrolyte abnormalities (hyponat-

raemia,  hypocalcaemia,  hypomagnesaemia,  hypophos-phataemia), hyperglycaemia, hypoglycaemia

Organ failure – uraemia, hepatic encephalopathyCNS infection – bacterial meningitis, viral encephalitis, cer-

ebral toxoplasmosis, tuberculosis, otherCerebral hypoxia/anoxiaAlcohol – withdrawal or intoxicationHead traumaDrug toxicity – cephalosporins, isoniazid, tranexamic acid, 

tacrolimus, cyclosporine, tricyclic antidepressants, olanza-pine,  phenothiazines,  theophylline,  cocaine,  ampheta-mine, antiepileptic drugs, other

CNS tumours – primary or secondaryTemporally  remote  causes  (previous  CNS  injury)  –  stroke, 

trauma, tumour, meningitisHypertensive encephalopathy, eclampsiaImmunological disorders – paraneoplastic syndromes, Hashi-

moto’s encephalopathy, anti-NMDA receptor encephalitis (may  have  associated  ovarian  tumour),  cerebral  lupus, thrombotic thrombocytopenic purpura, other

Mitochondrial diseases

Box 50.2  Physiological changes in generalised convulsive status epilepticus18

HypoxiaRespiratory acidosisLactic acidosisHyperpyrexiaHypertension (early)/hypotension (late)Hyperglycaemia (early)/hypoglycaemia (late)TachycardiaCardiac arrhythmiasBlood leucocytosisCSF pleocytosis, increased CSF proteinIntracranial hypertensionNeurogenic pulmonary oedemaAspiration pneumonitisRhabdomyolysis

562 Status epilepticus

consciousness, which includes confusion, agitation, bizarre or aggressive behaviour and coma.20 More recently other possible classification systems have been proposed.20,25–27

The most important factor in determining outcome in NCSE is the underlying cause.4,20,21

NCSE is often mistaken for other conditions, result-ing in a delay in diagnosis and treatment. A high index of suspicion must therefore be present to trigger inves-tigation with an EEG.

The differential diagnosis of NCSE includes:

• metabolic encephalopathy• drug intoxication• cerebrovascular disease• psychiatric syndromes (dissociative reactions, acute

psychosis)• post-ictal confusion.

EPILEPTIFORM ENCEPHALOPATHIES

In many advanced coma stages, the EEG exhibits con-tinuous or periodic EEG abnormalities, but in such situ-ations it is unclear whether the abnormal discharges are responsible for, or contribute to, the altered conscious-ness or are merely a reflection of a severe cerebral insult.27

Some consider myoclonic SE that follows an anoxic insult as part of this category, rather than as a form of NCSE.27

INVESTIGATIONS

Not all of the investigations listed in Box 50.4 need to be performed in every patient. The selection of tests depends on both the patient’s history and the presentation.

NEUROIMAGING

Most patients with SE should have a computed tomog-raphy (CT) scan of the brain performed, although this

NON-CONVULSIVE STATUS EPILEPTICUS  (NCSE)

This accounts for approximately 25% of SE, though its incidence is probably underestimated because of failure to recognise and diagnose the condition.

The diagnosis of NCSE generally requires a change in behaviour and/or responsiveness from baseline for at least 30 minutes, no overt seizure activity and an EEG with epileptiform discharges.20 A response to intrave-nous antiepileptic drugs (e.g. benzodiazepines), with clinical improvement and resolution or improvement in EEG epileptic activity, is helpful in confirming the diagnosis.21

The diagnosis of NCSE should be considered in any patient with an unexplained altered conscious state, particularly those with CNS injury, metabolic distur-bance, hepatic encephalopathy or sepsis. Series where EEG has been performed in critically ill patients with an unexplained depressed conscious state have found a high incidence of NCSE (8–18%).22–24 EEG monitoring is required in patients with GCSE who do not recover consciousness after resolution of overt convulsive activ-ity; in one study more than 14% of such patients had NCSE.17

NCSE is a heterogeneous disorder with multiple subtypes and published reports often describe diverse cohorts of patients. Although attempts have been made to define and classify this disorder, there is yet no uni-versally accepted definition or classification.20,25

Traditionally NCSE is divided into absence status epilepticus (ASE) and complex partial status epilepticus (CPSE).21 ASE is associated with bilateral diffuse syn-chronous seizures and may be ‘typical’ as characterised by generalised 3 Hz spike-wave EEG activity during periods of altered behaviour, or responsiveness that occurs in children with idiopathic generalised epilepsy who are otherwise normal.21 Atypical ASE is a hetero-geneous syndrome occurring in patients with mental retardation and epilepsy with multiple seizure types.

CPSE may present with a wide variety of clinical features and a variable degree of impairment of

Box 50.3  Features suggestive of pseudoseizures

Lack of stereotyped seizures, with behavioural manifestations varying from event to event

Lack of sustained convulsive activity – ‘on–off’ appearanceIncrease in movement if restraint is appliedAbolition  of  motor  movements  with  reassurance  or 

suggestionResistance to eye opening and gaze aversionPoor response to treatment, refractory status epilepticusAbsence of pupillary dilatationNormal tendon reflexes and plantar responses immediately 

after convulsionLack  of  metabolic  consequences  despite  some  hours  of 

apparent fitting

Box 50.4  Investigations in status epilepticus

Initial studiesBlood  glucose,  electrolytes  (sodium,  potassium,  calcium, 

magnesium), ureaArterial blood gasesAnticonvulsant drug levelsFull blood countUrinalysisFurther investigations after stabilisationLiver function tests, lactate, creatine kinaseToxicology screenLumbar punctureElectroencephalogramBrain imaging with computed tomography or magnetic reso-

nance imaging

Drugs for status epilepticus 563

may not always be necessary if another episode of SE occurs in a patient with established epilepsy who has previously been thoroughly evaluated. Magnetic resonance imaging (MRI) may occasionally reveal abnormalities not visualised on CT scans and should be considered for non-emergency imaging. Imaging should be performed only after control of SE and patient stabilisation.28

LUMBAR PUNCTURE

In any patient, especially in young children with fever and SE, CNS infection and lumbar puncture along with blood cultures should be considered.29 Meningitis is an uncommon cause of SE in adults and, unless the suspicion of CNS infection is high, brain imaging should be performed before a lumbar puncture. Con-traindications to lumbar puncture include intracranial hypertension, mass lesion and hydrocephalus. If men-ingitis is suspected and a lumbar puncture cannot be performed expediently, antibiotics should be adminis-tered immediately rather than delayed. Approximately 20% of patients have a modest CSF white cell count pleocytosis after SE and such patients should be treated for suspected meningitis until the diagnosis is excluded.1

MANAGEMENT

GENERALISED CONVULSIVE STATUS   EPILEPTICUS  (GCSE)

An accurate history should be obtained, with particu-lar emphasis on eye-witness accounts of the onset and nature of the seizures, and a full physical exami-nation performed. However, neither should delay initial emergency management. Rapid control of sei-zures is crucial to prevent brain injury and the devel-opment of refractory SE. There is evidence that the longer SE goes untreated the harder it is to control with drugs.8,9,30,31

Management of SE involves termination of seizures, treating precipitating causes and underlying condi-tions, and prevention of complications and recurrence of seizures.

Few controlled data are available to support the use of any particular agents. One of the few randomised, double-blind clinical trials for treatment of GCSE found that lorazepam, phenobarbital or diazepam followed by phenytoin are all acceptable as initial treatment, but that phenytoin alone was not as effective as lorazepam.31 Another randomised controlled trial in the pre-hospital setting found intravenous lorazepam and diazepam to be equally effective and superior to placebo in terminat-ing GCSE.32

There are few data to guide the treatment of refrac-tory SE, for which anaesthetising agents such as thio-pental, propofol or midazolam infusions are commonly used. A randomised controlled trial of propofol versus

barbiturates was terminated after 3 years with only 24 of the required 150 patients recruited.33

The EEG goal of treatment for refractory SE remains controversial, with some advocating EEG background suppression (isoelectric) and others suppression of sei-zures regardless of the EEG background activity.7,9,10,34

Various protocols for SE management have been suggested.1,7,9,34 One approach is outlined in Box 50.5.

NON-CONVULSIVE STATUS EPILEPTICUS  (NCSE)

Patients with NCSE are a heterogeneous group and as such there is a variable response to treatment.25 Prognosis is most closely related to the underlying aetiology.20,21

Clinical response to intravenous benzodiazepine is predictive of a good outcome.35

There is considerable debate as to whether NCSE presents the same degree of risk of neurological injury as GCSE.36 Prompt treatment is generally recommended and the use of additional non-anaesthetising anticon-vulsants, such as levetiracetam, phenobarbital and val-proate, has been suggested prior to embarking upon general anaesthesia.7,21,37

The potential side-effects of aggressive treatment (hypotension, immunosuppression) need to be bal-anced against the potential neurological morbidity of NCSE.38 Particularly in elderly patients, aggressive treatment and anaesthesia may be associated with more risk than benefit and result in a worse outcome.20,38,39

DRUGS FOR STATUS EPILEPTICUS

BENZODIAZEPINES

Benzodiazepines are fast-acting antiseizure drugs and are therefore preferred as initial therapy. They act mainly by enhancing the neuroinhibitory effects of γ-aminobutyric acidA (GABAA). The efficacy of benzo-diazepines diminishes with duration of SE as a result of a reduction in synaptic GABAA receptors with pro-longed seizures.13

Diazepam is a highly lipid-soluble drug with rapid CNS penetration, but then redistribution resulting in a short duration of action. It can be administered either intravenously or by the rectal route. Rectal administra-tion can be achieved using a specially formulated rectal gel, or the intravenous preparation can be diluted with an equal amount of saline and flushed into the rectum. Rectal administration should be considered when vas-cular access is delayed and may be particularly useful in the pre-hospital setting.

Lorazepam has a longer duration of action and has a lower incidence of seizure recurrence when used as a single agent.31 A double-blind, randomised comparison of intravenous diazepam, lorazepam and placebo in SE in the pre-hospital setting found both benzodiazepines to be associated with greater cessation of seizures and lower requirement for intubation than placebo. There

564 Status epilepticus

dose to maintain seizure control.34 There is a wide variation in recommended infusion rates, from 0.05–0.4 mg/kg per hour7 to 0.2–2.9 mg/kg per hour.10

Clonazepam has a longer duration of action than diazepam and is given by intravenous bolus. Early reports suggested that it has better efficacy and fewer side-effects than diazepam, though there are no pub-lished comparisons.

PHENYTOIN

Phenytoin is useful for maintaining a prolonged anti-seizure effect after rapid termination of seizures with a benzodiazepine, or when benzodiazepines fail. When used alone as initial therapy phenytoin is not as effica-cious as benzodiazepines for terminating seizures.31

The recommended intravenous loading dose is 20 mg/kg. The common practice of giving a standard

was a trend toward lorazepam being more efficacious than diazepam.32

Midazolam has a short duration of action and, unlike other benzodiazepines, can be administered via intramuscular, buccal and intranasal routes. These alternative routes of administration may be more convenient, acceptable and efficacious than diazepam administered by the rectal route.40,41 A recent study found that intramuscular midazolam was as safe and efficacious as intravenous lorazepam and resulted in faster and more reliable administration in the pre-hospital setting.42

Midazolam administered by intravenous bolus and infusion may terminate seizures when other agents have failed. It may also have fewer side effects than alternative agents available for the treatment of refrac-tory SE.43 A limiting factor in its use is tachyphylaxis, which may necessitate a several-fold increase in the

Box 50.5  Protocol for management of SE

††In refractory SE, consider giving pyridoxine for children <18 months or if isoniazid toxicity is suspected in adults.

†High infusion rates for prolonged periods require caution.

*If i.v. access is not obtainable, consider rectal diazepam, buccal/sublingual or intranasal or i.m. midazolam, i.m. fosphenytoin.

1.  Assess A, B, C, GCS2.  Give O2 and consider need for intubation/ventilation3.  Monitor blood pressure, ECG, pulse oximetry4.  Obtain i.v. access and draw blood for investigations5.  If patient is hypoglycaemic, or if blood glucose estimation 

is not available, give glucose:adults:  give  thiamine  100 mg  i.v.  and  50 mL  of  50% 

glucose i.v.children: give 2 mL/kg of 25% glucose i.v.

6.  Seizure control:A.  Give benzodiazepine,* for example:

diazepam:  0.2 mg/kg  i.v.  at  5 mg/min  up  to  total dose of 20 mg;

lorazepam:  0.1 mg/kg  i.v.  at  2 mg/min  up  to  total dose of 10 mg;

clonazepam:  0.01–0.02 mg/kg  i.v.  at  0.5 mg/min up to total dose of 4 mg.

If  diazepam  stops  the  seizures,  phenytoin  should  be given next to prevent recurrence.

Repeat dose every 2–5 min  if  required. Note:  risk of respiratory depression with cumulative doses.

B.  If seizures persist, give phenytoin:phenytoin:  15–20 mg/kg  (adults  ≤50 mg/min;  chil-

dren ≤1 mg/kg/min) or fosphenytoin 15–20 pheny-toin  equivalents  (PE) mg/kg  i.v.  (adults ≤150 mg/min; children ≤3 mg/kg per min).

Additional doses of 5 mg/kg i.v., to a maximum dose of 30 mg/kg can be given for persistent seizures.

Monitor blood pressure and the ECG during infusion. If hypotension or arrhythmias develop, stop or slow the rate of the infusion.

C.  If seizures persist (refractory SE), intubate and ventilate patient. Give either:thiopental:  slow  bolus  3–5 mg/kg  i.v.,  followed  by 

infusion 1–5 mg/kg per h, orpropofol: slow bolus 1–2 mg/kg i.v., followed by infu-

sion 2–5 mg/kg per h,† or

midazolam:  slow bolus 0.1–0.2 mg/kg,  followed by infusion 0.1–1.0 mg/kg per h.

Titrate doses based on clinical and electrographic evi-dence of seizures, targeting electrographic suppres-sion  of  seizures  or  EEG  background  suppression (isoelectric).

Monitor  BP  and  maintain  normotension  by  reducing infusion rate and/or giving fluids/pressor agents.

D.  Insert  nasogastric  tube  and  administer  usual  anticon-vulsant medications if patient is receiving treatment for pre-existing epilepsy.

E.  Beware of ongoing unrecognised seizures.Use EEG monitoring until seizures are controlled and 

then  for 1–2 hours after seizures stop. Continue  to monitor the EEG continuously, or for periods of more than 30 minutes every 2 hours, during  the mainte-nance phase.

Avoid muscle relaxants (use continuous EEG if giving repeated doses of muscle relaxants).

F.  Discontinue midazolam or thiopental, or start reducing propofol,  approximately  12  hours  after  resolution  of seizures. Use continuous EEG monitoring and observe for further clinical and/or electrographic seizure activ-ity. If seizures recur, reinstate the infusion and repeat this  step  at  12–24-hour  intervals  or  longer  if  the patient’s seizures remain refractory.

In addition:Look for and treat cause and precipitant.††

Look for and treat complications: hypotension, hyperthermia, and rhabdomyolysis.

Drugs for status epilepticus 565

BARBITURATES

Phenobarbital is a potent anticonvulsant with a long duration of action. The usual dose is 15–20 mg/kg intravenously. It has equal efficacy to benzodiazepines and phenytoin when used first-line, but may cause greater depression of respiration, blood pressure and consciousness and therefore is often used only if these agents fail. However, many would advocate alternative and more aggressive measures for treatment of refrac-tory SE at this point as the likelihood of phenobarbital controlling seizures when these other agents have failed is small.10

Thiopental is an intravenous anaesthetic agent used for refractory SE. A dose of 3–5 mg/kg is usually given for intubation, followed by repeated doses of 0.5–1 mg/kg until seizures are controlled. Following bolus intra-venous administration, the drug is rapidly redistrib-uted into peripheral fat stores and an infusion of 1–5 mg/kg per hour is required for ongoing suppres-sion of seizures. Once lipid stores are saturated the duration of action is prolonged and recovery may take hours to days. Prolonged therapy requires the use of EEG monitoring to ensure that the seizures remain sup-pressed and to allow titration to the lowest dose that achieves the EEG target of seizure and/or EEG back-ground suppression. Side-effects include hypotension, myocardial depression and immunosuppression with increased risk of infection.

Pentobarbital (the first metabolite of thiopental) is available in the USA as the alternative to thiopental.

Compared with other agents used in refractory SE (midazolam and propofol), barbiturates may result in a lower frequency of short-term treatment failure and breakthrough seizures, but result in more hypotension and slower recovery from anaesthesia.50

PROPOFOL

Propofol (2,6-diisopropylphenol) is an anaesthetic agent that has become increasingly popular for the treatment of refractory SE. It is administered as an intravenous bolus followed by infusion and intubation and ventilation are required.

Compared with high-dose barbiturates (pentobarbi-tal) in adult patients with refractory SE, propofol has been found to control seizures more quickly and, because of its shorter duration of action, allows earlier re-emergence from anaesthesia.51 However, seizures tend to recur with sudden discontinuation of propofol, necessitating recommencement of the infusion and a more gradual tapering of the dose, such that both drugs ultimately may result in a similar duration of ventila-tion and ICU stay.51

There is concern that prolonged high-dose propofol use (e.g. >5 mg/kg per hour) may result in myocardial failure, hypoxia, metabolic acidosis, lipaemia, rhab-domyolysis and death (propofol infusion syndrome).52 Early reports were in children and later adults and its

loading dose of 1000 mg of phenytoin may provide inadequate therapy for some adults.

When phenytoin is infused at the maximal adult rec-ommended rate of 50 mg/min, hypotension occurs in up to 50% of patients and cardiac rhythm disturbance occurs in 2%. These adverse effects are more common in older patients and those with cardiac disease and are due to the phenytoin itself as well as the propylene glycol diluent. Blood pressure and the ECG should be monitored during infusion of phenytoin and the infu-sion slowed or stopped if cardiovascular complications occur.

Intramuscular administration of phenytoin is not recommended as absorption is erratic and it can cause local tissue reactions.

Fosphenytoin, a new water-soluble prodrug of phenytoin, is converted to phenytoin by endogenous phosphatases.44 Doses of fosphenytoin are expressed as phenytoin equivalents (PE). Fosphenytoin can be administered at rates of up to 150 PE mg/min, since it is not formulated with propylene glycol, allowing ther-apeutic serum concentrations of fosphenytoin to be attained within 10 minutes. However, this may not nec-essarily result in more rapid CNS penetration and onset of action.45

Systemic side-effects are similar for phenytoin and fosphenytoin, although reactions at the infusion site are less common with fosphenytoin.44

Fosphenytoin can also be administered intramuscu-larly, although absorption is slower than with intrave-nous administration, and this route should be used only when intravenous access is not possible.

SODIUM VALPROATE

There are reports of intravenous valproate being used to treat both GCSE and NCSE in adults and chil-dren. It is non-sedating and it appears to be well toler-ated with few reports of hypotension or respiratory depression.46

It may be particularly useful as a second- or third-line drug in situations where it is not possible, or it is pre-ferable to avoid the use of sedating anaesthetic agents and the associated requirement for intubation.47

An initial dose of 10 mg/kg followed by continuous infusion or divided doses up to 20-40 mg/kg daily is recommended.7,48

LEVETIRACETAM

Although the data are mostly uncontrolled and retro-spective, there is some evidence for the use of levetira-cetam as second- or third-line therapy and in situations where it is desirable to avoid intubation, such as in NCSE and treatment of the elderly.8,37,47,49 Levetiracetam may have particular utility in controlling seizures after hypoxic brain injury.8

Levetiracetam may be given intravenously in bolus doses of between 1000 and 3000 mg.

566 Status epilepticus

presentation, and duration of SE.15,57 Refractory SE is associated with a worse prognosis and very pro-longed ‘super-refractory’ SE an even higher mortality. However, where no underlying irreversible brain damage is present, good recovery is possible even after weeks of SE.9,12

Children have a much lower mortality of 3%58 whereas those aged over 65 years have a mortality rate of 30%.3,4

SE that is precipitated by low antiepileptic drug levels, alcohol abuse or systemic infection has a very low mortality, whereas SE secondary to an acute CNS insult such as stroke or infection has a higher mortal-ity.3,5 SE associated with hypoxic brain injury is most often fatal.59 NCSE detected in comatose critically ill patients, despite recognition and treatment, has a poor outcome.24,39

Consequences of SE include brain damage result-ing in permanent neurological deficits and also the development of focal epilepsy (epileptogenesis). Multi-organ failure and death can result from uncontrolled seizures, the underlying illness or complications of treatment.

STATUS EPILEPTICUS  IN CHILDREN58–61

Most paediatric cases of SE occur in young children, with 80% occurring in those below 4 years of age.58 The vast majority of cases are convulsive and generalised.28

The distribution of causes is highly age-dependent, with febrile SE and that due to acute neurological disease (e.g. CNS infection) being more common in chil-dren under 4 years. Remote symptomatic causes and SE in a child with previously diagnosed epilepsy are more common in older children.58 The most frequent aetiolo-gies of SE in children are listed in Box 50.7.28,29,58

The likelihood of bacterial meningitis is much higher in febrile children presenting with a first-ever episode of SE (12%) as opposed to a brief seizure (1%) and a high index of suspicion is required to investigate and treat for meningitis.58

Treatment of SE in children is essentially the same as in adults.60

use requires caution. There are series, however, of pro-longed high-dose propofol use in adults with SE without major adverse effects.53

NEUROMUSCULAR-BLOCKING AGENTS

Paralysis is indicated if uncontrolled fitting causes dif-ficulty with providing adequate ventilation or severe lactic acidosis. Neuromuscular blockade should be used only if continuous EEG monitoring is available, as the clinical expression of seizure activity is abolished.

OTHER AGENTS OF POTENTIAL USE  IN REFRACTORY SE

Ketamine acts as an antagonist at the NMDA receptor and may have a role in the treatment of prolonged refractory SE.12

Intravenous lacosamide is a new anticonvulsant drug available in intravenous and oral formulations that may be an option for treatment of established SE after failure of standard therapy, or when standard agents are considered unsuitable. Evidence exists mainly in the form of limited case series.54

Pregabalin appears to be an interesting option as add-on treatment in refractory NCSE and may lessen the requirement for ICU treatment.55

Magnesium is the drug of choice in eclamptic sei-zures and also is effective in seizures due to hypomag-nesaemia, but there is little evidence to support its use in other forms of SE.12

SURGERY

Surgery has occasionally been used in refractory SE with procedures based on standard epilepsy surgery techniques. Some success has been reported with focal resections, subpial transection, corpus callosotomy, hemispherectomy and vagus nerve stimulation.12,56

INTENSIVE CARE MONITORING

Monitoring using ECG, intra-arterial and central venous catheters, capnography and pulse oximetry should be considered in patients with, or at risk of, cardiorespira-tory compromise. Indications for EEG monitoring are listed in Box 50.6.17 Cerebral function monitors are useful in titrating doses of anaesthetic agents to EEG background suppression, but may not have sufficient sensitivity to detect seizure activity. Intracranial pres-sure monitoring should be considered if elevated intracranial pressure is present owing to the underlying brain pathology.

OUTCOME

The prognosis of patients with SE is related to age, aetiology, degree of impairment of consciousness at

Box 50.6  Indications for EEG monitoring17

Refractory  SE,  to  aid  the  titration  of  anticonvulsant  anaes-thetic  drugs  (minimizing  dose  and  toxicity)  and  ensure suppression of seizure activity*

Patients receiving neuromuscular blockade*Patients who continue  to have a poor conscious state after 

apparent cessation of seizuresSuspected non-convulsive status epilepticus in a patient with 

an altered conscious stateSuspected pseudoseizures

*Continuous or regular intermittent EEG monitoring recommended.

567Status epilepticus in children

The underlying cause is the main determinant of mortality, which is negligible for prolonged febrile seizures and 12–16% for acute symptomatic causes.61 Similarly, the risk of subsequent epilepsy is low in neu-rologically normal children but higher than 50% in those with acute or remote symptomatic causes.61

Box 50.7  Causes of status epilepticus in children28,29,58

Febrile  –  previously  neurologically  normal,  temp.  >38°C, CNS infection excluded

Acute symptomatic – meningitis, encephalitis, cerebrovascu-lar  disease,  trauma,  metabolic  derangement,  hypoxia, sepsis, drug-related

Remote symptomatic causes – previous traumatic brain injury or insult, CNS malformation, cerebral palsy

Progressive neurological conditions – tumours, degenerative, autoimmune diseases

Cryptogenic

http://www.expertconsult.comAccess the complete references list online at 

7. Meierkord H, Boon P, Engelsen B, et al. EFNS guide-line on the management of status epilepticus in adults. Eur J Neurol 2010;17(3):348–55.

8. Holtkamp M. Treatment strategies for refractory status epilepticus. Curr Opin Crit Care 2011;17(2): 94–100.

9. Rossetti AO, Lowenstein DH. Management of refrac-tory status epilepticus in adults: still more questions than answers. Lancet Neurol 2011;10(10):922–30.

12. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134(Pt 10):2802–18.

13. Chen JW, Wasterlain CG. Status epilepticus: patho-physiology and management in adults. Lancet Neurol 2006;5(3):246–56.

14. Tan RY, Neligan A, Shorvon SD. The uncommon causes of status epilepticus: a systematic review. Epi-lepsy Res 2010;91(2-3):111–22.

20. Meierkord H, Holtkamp M. Non-convulsive status epilepticus in adults: clinical forms and treatment. Lancet Neurol 2007;6(4):329–39.

60. Abend NS, Gutierrez-Colina AM, Dlugos DJ. Medical treatment of pediatric status epilepticus. Semin Pediatr Neurol 2010;17(3):169–75.

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