status epilepticus - l.s. · pdf filecontinuum (minneap minn) 2013;19(3):767–794....

Status EpilepticusLawrence J. Hirsch, MD, FAAN; Nicolas Gaspard, MD, PhD

ABSTRACTPurpose of Review: This review presents the state of the art in the diagnosis andmanagement of status epilepticus.Recent Findings: In addition to general background, this article presents the mostrecent findings regarding the diagnosis and treatment of status epilepticus, includingthe results of the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) andthe available data on the use of newer antiepileptic and anesthetic drugs in the treat-ment of refractory status epilepticus. It also presents available guidelines such as thosefrom the Neurocritical Care Society.Summary: Despite recent advances, the management of status epilepticus remains achallenge. Rapid treatment, a written treatment protocol, early consideration of non-convulsive seizures, and avoiding overtreatment and medical complications are thekeys to successful management. This article summarizes the current evidence andguidelines.

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INTRODUCTIONStatus epilepticus is a severe neuro-logic condition with significant mor-bidity and mortality. It can occur atany age and requires immediate eval-uation and treatment. A widely ac-cepted practical definition of statusepilepticus is at least 5 minutes ofcontinuous seizure or two or moreseizures between which there is in-complete recovery of consciousness.This definition applies best to childrenover 5 years old and adults1 and wasadopted in recently published studiesand guidelines.2Y4 In younger chil-dren, a threshold of 10 minutes mightbe more appropriate.

ClassificationThe definition of status epilepticus en-compasses a wide variety of clinicalconditions, and several classificationschemes have been proposed. Statusepilepticus can be categorized accord-ing to age at onset, etiology, and clinicaland EEG features (Table 12-1).

EpidemiologyThe incidence of status epilepticus inthe general population was reportedto be between 20 and 40/100,000 peryear in the United States, with a firstpeak before 1 year of age and asecond peak after 60 years of age.5,6

Of all patients with generalized con-vulsive status epilepticus, one-halfhave an acute symptomatic etiologyand more than one-half have not hada prior seizure.

Recent years have seen an increasedawareness of nonconvulsive statusepilepticus in the hospital setting,which affects up to 10% of patients withan altered level of consciousness7 and16% of confused elderly patients.8 Thisprevalence is similar among critically illpatients and even higher after gener-alized convulsive status epilepticus(48% will have nonconvulsive seizureson 24 hours of EEG monitoring), anintracranial hemorrhage, or CNS infec-tion, and in critically ill children.9,10

Other risk factors for nonconvulsive

Address correspondence toDr Lawrence J. Hirsch, YaleUniversity School of Medicine,15 York St, LLCI-714, NewHaven, CT 06510,[email protected].

Relationship Disclosure:Dr Hirsch serves as aconsultant forGlaxoSmithKline, Lundbeck,and Upsher-SmithLaboratories, Inc, andreceives research supportfrom Lundbeck, UCB, andUpsher-Smith Laboratories,Inc. Dr Gaspard has receivedresearch support from theBelgian American EducationalFoundation, Inc; the BelgianNeurological Society; theEpilepsy Foundation; andthe Fulbright Commission forEducation Exchange Betweenthe United States, Belgiumand Luxembourg.

Unlabeled Use of

Products/InvestigationalUse Disclosure:Drs Hirsch and Gasparddiscuss the unlabeled use ofelectroconvulsive therapy,etomidate, felbamate,gabapentin, hypothermia,intravenous immunoglobulins,ketamine, ketogenic diet,lacosamide, levetiracetam,lidocaine, plasma exchange,pregabalin, steroids,topiramate, valproate, andvigabatrin for the treatment ofstatus epilepticus.

* 2013, American Academyof Neurology.

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Review Article

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status epilepticus include remote riskfactors for epilepsy, prior epilepsy,severe alteration of consciousness, oc-ulomotor abnormalities, and periodicdischarges or suppression-burst onEEG.11,12 The majority of seizures thatoccur in the critically ill (about 75% onaverage in the literature13) are non-convulsive and cannot be recognizedwithout EEG, as exemplified by thethree clinical case examples in this ar-ticle. Furthermore, a 30- to 60-minuteEEG will miss all seizures in morethan half of the patients having non-convulsive seizures; therefore, at least24 hours of continuous EEG (cEEG)monitoring is recommended for non-comatose patients, and 48 hours forcomatose patients (as 20% will bemissed with only 24 hours) or thosewith frequent or periodic epileptiformdischarges.10,12

EtiologyCommon causes of status epilepticusare summarized in Table 12-2.14 Be-sides these common etiologies thereare many rare causes of status epi-lepticus.15 Many cases of cryptogenicnew-onset status epilepticus, such asCase 12-1, can be explained after athorough evaluation. In addition, somesubtypes of status epilepticus may be adiagnostic clue to a specific epilepsysyndrome (Table 12-3).

CLINICAL MANIFESTATIONS OFGENERALIZED CONVULSIVESTATUS EPILEPTICUSGeneralized convulsive status epilep-ticus consists of a self-perpetuatinggeneralized tonic-clonic seizure or of aseries of generalized tonic-clonic sei-zures without return to consciousnessin between seizures. Clonic movements

KEY POINTS

h Status epilepticus inadults and in childrenover 5 years old isdefined as at least5 minutes of ictal activityor two or more seizuresbetween which thereis incomplete recoveryof consciousness.

h Nonconvulsive statusepilepticus is the formof status epilepticusmost commonlyencountered in criticallyill patients. It usuallycannot be identifiedwithout an EEG.

h More than one-half ofepisodes of statusepilepticus in adultsoccur in patientswithout prior seizures.

TABLE 12-1 Classification of Status Epilepticus According to Clinicaland EEG Findings

Ictal EEG Activity

Motor Activity Consciousness Generalized Focal/Lateralized

Intense(convulsive)

Markedly toseverelyimpaired

Tonic-clonic

Tonic

Clonic

Myoclonic (withabsence, or in coma)

Hemiconvulsive

Normalto mildlyimpaired

Myoclonic (usuallyin primarygeneralizedepilepsy)

Epilepsia partialiscontinua

Absentor subtle(nonconvulsive)

Markedly toseverelyimpaired

Absence (includingtypical, atypical,and late-onset)

Subtle or purelyelectrographic(in coma)

Complex partial

Subtle or purelyelectrographic(in coma)

Normal tomildlyimpaired

Absence (includingtypical, atypical,and late-onset)

Simple partial(including auracontinua) or mildor intermittentcomplex partial

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are initially violent but become lessprominent and ultimately disappear,even with ongoing electrographic sta-tus epilepticus. The absence of signifi-cant improvement in the level ofconsciousness 20 to 30 minutes afterthe cessation of convulsions shouldraise the concern of postconvulsivenonconvulsive status epilepticus, andan EEG should be performed urgentlyto confirm the diagnosis. Almost halfof these patients will have noncon-vulsive seizures during the first 24 hoursof cEEG.

Physiologic changes in generalizedconvulsive status epilepticus are welldescribed (Figure 12-216,17). Com-pensatory mechanisms occur initiallyand meet the metabolic demand ofthe intense motor and cerebral activ-ity. After 5 to 30 minutes of generalizedconvulsive status epilepticus, homeo-

static compensatory mechanisms can-not answer the metabolic needs, whichcan lead to multiple organ failure.Additional complications include pul-monary embolism, aspiration pneumo-nia, cardiac injury, and hyperthermia.The increase in brain metabolism issupported by compensatory increasesin cerebral blood flow, oxygenation, andglucose levels; however, cerebral auto-regulation progressively fails, and cere-bral blood flow becomes dependent onsystemic blood pressure. Brain oxygen,glucose, and lactate levels ultimatelydrop, and intracranial hypertensionand cerebral edema may ensue.

CLINICAL MANIFESTATIONS OFNONCONVULSIVE STATUSEPILEPTICUSThe clinical manifestations of noncon-vulsive status epilepticus are diverse

KEY POINTS

h If the patient’s level ofconsciousness isnot improving by20 to 30 minutes aftercessation ofmovements, or mentalstatus remains abnormal30 to 60 minutes afterconvulsive activityceases, ongoingnonconvulsive statusepilepticus must beconsidered.

h Prolonged generalizedconvulsive statusepilepticus may leadto cardiorespiratorycollapse, multiple organfailure, and neuronalinjury.

TABLE 12-2 Frequency of Common Etiologies of Status Epilepticus inAdults and Children 91 Month of Agea

Common Etiologies Adults Children

Stroke, including hemorrhagic 20% 10%

Low antiepileptic drug levels 35% 20%

Alcohol withdrawal 15% j

Drug intoxication (theophylline, imipenem,isoniazid, beta-lactams, clozapine, bupropion,4-aminopyridine, cocaine, etc) or withdrawal(benzodiazepine, barbiturate, baclofen)

5% 5%

Anoxic brain injury 15% 5%

Metabolic disturbances (low glucose, calcium,magnesium, or sodium level; high glucoselevel; renal failure; liver failure)

15% 5%

Infection (meningitis, encephalitis,brain abscess, sepsis)

5% 5%

Traumatic brain injury 2.5% 15%

Brain neoplasm 5% 0%

Febrile seizures j 50%

Remote brain injury/congenital malformations 20% 40%

Idiopathic 5% 5%a Modified with permission from DeLorenzo RJ, et al, Neurology.5 B 1996, American Academy ofneurology. www.neurology.org/content/46/4/1029.short?sid=e0855659-4863-46e8-b0c8-0d49dfd06f97.



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and range from severe impairment ofconsciousness to subtle phenomena(Table 12-418). Motor manifestations,if any, often require careful neuro-logic examination to be detected. Pro-longed subjective sensory phenomena(ie, aura continua), negative symptomsor signs (as exemplified by Case 12-2),or changes in cognition or behaviorhave been described in simple partialstatus epilepticus and are often over-looked or mistaken for psychogenic orpsychiatric disorders.

DIAGNOSIS OFNONCONVULSIVE STATUSEPILEPTICUS IN CRITICALLYILL PATIENTSNonconvulsive seizures and status epi-lepticus occur frequently in critically illpatients and correlate with poor out-comes. Therefore, early diagnosis and

treatment of nonconvulsive status epilep-ticus is probably warranted. EEG find-ings in comatose and critically ill patientsdiffer significantly from common patternsseen in healthier patients, and it is oftendifficult to distinguish ictal, interictal,and nonictal patterns in encephalopathicpatients. EEG criteria for nonconvulsivestatus epilepticus (Table 12-519,20) havebeen proposed but not validated. A prac-tical approach is to perform a trial of alow dose of a fast-acting antiepilepticdrug (AED) (Table 12-616). Both clini-cal and electroencephalographic im-provements are required to establish thediagnosis of nonconvulsive status epi-lepticus. As exemplified by Case 12-3,clinical improvement often follows EEGimprovement by several (but usuallyfewer than 24) hours, but is rarely im-mediate.1,21 Lack of improvement doesnot help in establishing or excluding

Case 12-1A 22-year-old man without any significant medical history presented with low-grade fever, headache,and photophobia for 1 week before experiencing a generalized tonic-clonic seizure. In the emergencydepartment, he had several seizures characterized by left facial twitching followed by loss of contactand oral automatisms. He received IV lorazepam and phenytoin, but seizures recurred, and hereceived IV valproate and levetiracetam. He became obtunded. Continuous EEG demonstratedbilateral independent temporal seizures (four seizures per hour) (Figure 12-1). Results of multiple brainMRIs were normal, and his CSF showed mild pleocytosis. He was started on continuous IV midazolam(bolused, then titrated up to 2 mg/kg/h) but experienced breakthrough seizures; continuous IVpropofol was added (bolused, then titrated up to 3.6 mg/kg/h) and led to seizure control. Seizuresrecurred during withdrawal. He was switched to continuous IV pentobarbital (bolused, then titratedup to 2 mg/kg/h) and kept in burst-suppression for 48 hours. He experienced one breakthroughseizure during pentobarbital-induced coma and several withdrawal seizures after pentobarbitaltaper. He was switched to continuous IV midazolam (2.5 mg/kg/h) and ketamine (4.5 mg/kg/h) butdeveloped severe acidosis. He was finally switched to IV phenobarbital (6 mg/kg/d) that led to controlof status epilepticus, 33 days after onset. He remained in the intensive care unit for 2 months butregained a normal mental status, was discharged to a rehabilitation facility, and planned to resumegraduate school. Thorough evaluation identified elevated antibody titers against Mycoplasmapneumoniae (immunoglobulin M [IgM] and IgG, then IgG only).

Comment. This is a typical case of new-onset refractory status epilepticus that mainly affectspreviously healthy young patients and often proves to be very refractory to treatment. It wasattributed to infection with Mycoplasma, an uncommon cause of status epilepticus. This case alsoexemplifies the incremental use of antiepileptic and sedative drugs in refractory nonconvulsive statusepilepticus, and excellent cognitive outcome despite prolonged ‘‘malignant’’ status epilepticus.

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KEY POINT

h Some patients,especially young adultswith normal ornear-normal results ofbrain imaging and anencephalitislike illness,make a meaningful oreven full cognitiverecovery even after veryprolonged refractorystatus epilepticus thatlasted months.


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FIGURE 12-1 Bilateral frontotemporal independent seizures in a patient with Mycoplasma pneumoniae-associatedencephalitis and status epilepticus. AYD, Four 10-second EEG pages demonstrating the onset (arrow) of aright frontotemporal seizure, characterized by rhythmic sharp theta and alpha activity (boxes). EYH, Four

10-second EEG pages demonstrating the onset (arrow) of a left frontotemporal seizure, characterized by rhythmic sharptheta and alpha activity (boxes). High-pass filter is at 1 Hz, low-pass filter is at 70 Hz, and notch filter is off.



the diagnosis of nonconvulsive statusepilepticus.

Brain imaging (including perfusionand metabolic imaging) and intracrani-al monitoring with intracortical EEG,brain tissue oxygen monitoring, andcerebral microdialysis can sometimesclarify the nature or significance ofequivocal EEG patterns by demonstrat-ing changes suggestive of increasedneuronal activity or neuronal metabol-ic stress associated with a specific EEGpattern in a patient.2Y4,22,23

AVAILABLE EVIDENCE ANDGUIDELINES FOR MANAGEMENTAvailable guidelines are limited to theEuropean Federation of NeurologicalSocieties2 and the Neurocritical CareSociety (NCS) guidelines and aremostly consensus-based rather than

evidence-based by necessity, althoughexisting evidence was incorporated.3

Their respective recommendations aresummarized in Table 12-7. The pro-tocol in use at the authors’ institutionis presented in Figure 12-5.

MANAGEMENT OF STATUSEPILEPTICUSInitial management includes early ba-sic life-support measures, monitoringof vital signs, initial evaluation, andemergent/urgent treatment. Althoughurgent evaluation is part of optimalmanagement of status epilepticus, itshould never delay early treatment.

Laboratory TestsSome laboratory tests should beobtained immediately, including testsfor rapidly reversible causes of status

KEY POINT

h The diagnosis ofnonconvulsive statusepilepticus in critically illpatients is sometimesdifficult because of thepresence of equivocal EEGpatterns.A trial of a rapidlyacting IV antiepilepticdrug can be helpful ifthere is improvement inboth the EEG and clinicalexamination, but resultsshould be interpretedwith caution and areoften equivocal. Smallincremental doses oruse of a nonsedatingantiepileptic drug arepreferable as they mayallow observation of aclinical improvementwithout marked sedation.

TABLE 12-3 Diagnostic Implication of Some Subtypes of Status Epilepticus

Subtype of Status Epilepticus Syndrome/Etiology

Myoclonic status epilepticus withoutsignificant alteration of consciousness

Idiopathic generalized epilepsy syndromes (juvenile myoclonicepilepsy, juvenile absence epilepsy, childhood absence epilepsy)

Epilepsy with myoclonic absences

Dravet syndrome

Progressive myoclonus epilepsies

Myoclonic status epilepticus withsignificant alteration of consciousness(myoclonic-absence status epilepticus)

Idiopathic generalized epilepsy syndromes

Epilepsy with myoclonic absences

Jeavons syndrome

Doose syndrome

Syndrome of absence seizures with perioral myoclonia

Dravet syndrome

Angelman syndrome

Diffuse acute encephalopathies (toxic, metabolic,infectious, inflammatory, anoxic)

Typical absence status epilepticus Idiopathic generalized epilepsy syndromes

Atypical absence status epilepticus Symptomatic/cryptogenic generalized epilepsy

Tonic status epilepticus Symptomatic/cryptogenic generalized epilepsy,especially Lennox-Gastaut syndrome

Prolonged complex partial statusepilepticus of frontal origin

Epilepsy with ring chromosome 20 anomaly

Autonomic status epilepticus Panayiotopoulos syndrome (early-onset childhoodepilepsy with occipital paroxysms)


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epilepticus (eg, electrolyte imbal-ances, hypoglycemia) and for identifyingconditions that will influence treat-ment options (eg, hepatic or renalfailure, thrombocytopenia). Troponinlevels and 12-lead ECG are useful inidentifying patients with cardiac dis-ease (eg, myocardial infarction, con-traction band necrosis, arrhythmia, andconduction blocks).

Further studies may be indicateddepending on the clinical context (eg,inborn error of metabolism, furthertoxicologic screen, autoimmune andparaneoplastic disorders, lumbar punc-

ture) and usually can be obtained afterthe urgent treatment period.

EEGEEG is by no means required for thediagnosis and the early management ofgeneralized convulsive status epilepticusand should not delay treatment. It isessential to identify electrographic statusepilepticus in patients who fail to regainconsciousness after a generalized tonic-clonic seizure or generalized convulsivestatus epilepticus, or in patients withnonconvulsive status epilepticus with-out prior overt clinical seizure activity.

FIGURE 12-2 Evolution of brain and systemic pathophysiologic changes during status epilepticus.

GABA = +-aminobutyric acid; NMDA = N-methyl-D-aspartate.

Data from Foreman B, Hirsch LJ, Neurol Clin,16 www.sciencedirect.com/science/article/pii/s073386191100082X and Fountain NB,Lothman EW, J Clin Neurophysiol.17 journals.lww.com/clinicalneurophys/Abstract/1995/07000/Pathophysiology_of_Status_Epilepticus.4.aspx.



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The NCS guidelines strongly advo-cate the use of cEEG as a diagnostic

tool for refractory status epilepticus,as most recurring seizures or episodesof refractory status epilepticus aresubtle or purely electrographic. Theyalso recommend the systematic use ofcEEG in patients at high risk of non-convulsive seizures and nonconvulsivestatus epilepticus (eg, patients incoma or with intracranial hemorrhage;see Table 12-8). The duration of cEEGto identify nonconvulsive seizures ornonconvulsive status epilepticus shouldbe at least 24 hours, in general, becauseup to two-thirds of nonconvulsive seizuresare missed with a routine 30-minuteEEG.24 Monitoring should be extendedto at least 48 hours in comatose patientsor when periodic discharges are pres-ent; in both situations, more than 10%of patients will have their first seizureafter the first 24 hours.12 cEEG shouldbe continued at least 24 hours after statusepilepticus is controlled to excluderecurrence of nonconvulsive seizuresor nonconvulsive status epilepticus.

Brain ImagingLike EEG, brain imaging should not delayurgent treatment of status epilepticus. ACT scan of the head is indicated in allpatients once convulsions have beencontrolled, unless the history offers anobvious explanation for the statusepilepticus. Brain MRI is superior to CTscan for the diagnosis of several condi-tions that may cause status epilepticus,especially encephalitis. Transient MRIchanges mimicking inflammation or is-chemia, including restricted diffusion,may occur during or after prolongedictal activity and should not bemistakenfor irreversible damage or evidence ofbrain lesion.25 They are most oftenlocated in the hippocampus, neo-cortex, corpus callosum, and posteriorthalamus and are best seen in fluid-attenuated inversion recovery (FLAIR)(increased signal) and diffusion-weighted imaging (restricted diffusion).

TABLE 12-4 PossiblePresentations ofNonconvulsiveStatus Epilepticusa

b Behavioral/Cognitive/Sensory

Agitation/aggression

Amnesia

Anorexia

Aphasia/muteness

Catatonia

Coma

Confusion/delirium

Delusions/hallucinations

Echolalia

Laughter

Lethargy

Perseveration

Personality change

Psychosis

Singing

b Autonomic/Vegetative

Abdominal sensation

Apnea/hyperventilation

Brady- and tachyarrhythmia

Chest pain

Flushing

Miosis/mydriasis/hippus

Nausea/vomiting

b Motor

Automatisms

Dystonic posturing

Eye blinking

Eye deviation

Facial twitching

Finger twitching

Nystagmus

Tremulousnessa Modified with permission from Kaplan PW,Neurologist.18 B 2005 Lippincott Williams &Wilkins, Inc. journals.lww.com/theneurologist/Abstract/2005/11000/The_Clinical_Features,_Diagnosis,_and_Prognosis_of.4.aspx.

KEY POINT

h In the intensive careunit, most seizures arenonconvulsive andwould be missed inthe absence of EEGmonitoring.Twenty-four hours ofcontinuous EEG is areasonable screen fornonconvulsive seizuresin noncomatosepatients, but 48 hoursor more may be neededin comatose patients.


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Case 12-2An 84-year-old woman with a history of traumatic brain injury and craniotomy with residual right legweakness and sensory loss was admitted to the hospital for new-onset right arm weakness. She firstnoticed the weakness 5 days before admission. Neurologic examination disclosed ataxia of her rightarm and a right hemianopia. A CT scan revealed a left parietal porencephalic cavity but no acutelesion. She experienced episodes of visual hallucinations, prompting continuous EEG (cEEG), whichrevealed cyclic left posterior quadrant seizures every 5 to 10 minutes (Figure 12-3). She was given IV

FIGURE 12-3 Six 10-second EEG pages demonstrating the onset (arrow) of a left posterior quadrant seizure,characterized by sharply contoured alpha activity (boxes). The patient was having one seizure every 5 to 10minutes, in a cyclic pattern. High-pass filter is at 1 Hz, low-pass filter is at 70 Hz, and notch filter is off.




Although these changes are often re-versible, they may suggest that neuronalinjury is occurring because of theelectrographic seizures or periodicdischarges. Likewise, perfusion andmetabolic imaging studies are some-times useful in identifying ictal activityor its effects when the EEG is equivocal.23

Lumbar PunctureLumbar puncture should be performedwhen an inflammatory or infectiousorigin of the status epilepticus issuspected. Again this should not delay

the treatment of generalized convulsivestatus epilepticus.

TREATMENT OF GENERALIZEDCONVULSIVE STATUSEPILEPTICUSGeneral Aspects ofManagementTreatment of generalized convulsive sta-tus epilepticus should proceed withoutdelay, as early treatment is associatedwith better response and outcome.19,27

In addition to the rapid administrationof a first-line drug, the urgent treatmentof status epilepticus should also aim to

TABLE 12-5 Criteria for the Diagnosis of Nonconvulsive Seizures and Nonconvulsive StatusEpilepticusa,b

Any pattern satisfying any of the primary criteria and lasting Q10 s (for nonconvulsive seizures) or Q30 min(for nonconvulsive status epilepticus)

Primary Criteria

1. Repetitive generalized or focal spikes, sharp waves, spike-and-wave complexes at Q3/s

2. Repetitive generalized or focal spikes, sharp waves, spike-and-wave or sharp-and-slow wave complexesat G3/s and the secondary criterion

3. Sequential, rhythmic, periodic, or quasiperiodic waves at Q1/s and unequivocal evolution in frequency(gradually increasing or decreasing by at least 1/s, eg, 2 to 3/s), morphology, or location (gradual spreadinto or out of a region involving at least two electrodes). Evolution in amplitude alone is not sufficient.

Secondary Criterion

1. Significant improvement in clinical state or appearance of previously absent normal EEG patterns (such asposterior-dominant ‘‘alpha’’ rhythm) temporally coupled to acute administration of a rapidly acting antiepilepticdrug. Resolution of the ‘‘epileptiform’’ discharges leaving diffuse slowing without clinical improvement andwithout appearance of previously absent normal EEG patterns would not satisfy the secondary criterion.

a Modified from Young BG, et al, Neurology.19 B 1996, American Academy of Neurology. www.neurology.org/content/47/1/83.short?sid=1e76acb9-fa82-485b-82dc-2b84738bc64e.

b Reprinted with permission from Chong DJ, et al. J Clin Neurophysiol.20 B 2005 American Clinical Neurophysiology Society.journals.lww.com/clinicalneurophys/Abstract/2005/04000/Which_EEG_Patterns_Warrant_Treatment_in_the.1.aspx.

KEY POINT

h Early recognition ofstatus epilepticus allowsfor prompt treatmentand increases thelikelihood of treatmentsuccess and preventionof further neuronaldamage.

lorazepam and phenytoin, and then IV valproate, which finally stopped her seizures. Sheprogressively improved to her neurologic baseline over 2 days and was discharged from the hospital.

Comment. This case illustrates a presentation of nonconvulsive status epilepticus with purelynegative signs mimicking stroke. The diagnosis would have not been possible without cEEG. Hercondition did not require escalation to sedation, and she responded well to a second trial of anantiepileptic drug. This approach is a good example of nonaggressive but still rapid (once thediagnosis was considered) and effective treatment of nonconvulsive status epilepticus.



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correct metabolic factors that cause orcontribute to status epilepticus. Thisincludes administration of dextrose (withthiamine) when glucose levels are low orunknown, and correction of electrolyteimbalances. Proconvulsive drugs andtoxins should be avoided, discontinued,or even actively removed. Hyperthermiashould be aggressively controlled.

Urgent/Emergent PhaseFirst-line therapy: benzodiazepines.The cornerstone of the emergent phasetreatment is benzodiazepines.

The efficacy of IV lorazepam was es-tablished by three independenttrials.26Y28 In a landmark prehospitalstatus epilepticus treatment trial, sei-zure activity was controlled in 60% of

cases by 2 to 4 mg of lorazepam versus40% with 5 to 10 mg of diazepam and20% with placebo. Importantly, respira-tory depression was twice as commonin the placebo group (22%) comparedto the treated groups (10% with loraz-epam and 11% with diazepam). Theefficacy of lorazepam was further dem-onstrated in a trial comparing it toeither IV diazepam plus phenytoin, orIV phenytoin, or IV phenobarbital.27

Lorazepam resulted in control of statusepilepticus in 65% of cases, the highestpercentage of the four groups.

Recently, the Rapid AnticonvulsantMedication Prior to Arrival Trial (RAM-PART) showed the superiority of IMmidazolam over IV lorazepam in con-trolling generalized convulsive status

TABLE 12-6 Antiepileptic Drug Trial for the Diagnosis of Nonconvulsive Status Epilepticusa

b IndicationRhythmic or periodic focal or generalized epileptiform discharges on EEG with neurologic impairment

b ContraindicationPatients who are heavily sedated/paralyzed

b MonitoringEEG, pulse oximetry, blood pressure, electrocardiography, respiratory rate with dedicated nurse

b Antiepileptic Drug Trial

Sequential small doses of rapidly acting short-duration benzodiazepine such as midazolam at 1 mg ornonsedating IV antiepileptic drug such as levetiracetam, valproate, fosphenytoin, or lacosamide

Between doses, repeated clinical and EEG assessment

Trial is stopped after any of the following:

Persistent resolution of the EEG pattern (and examination repeated)

Definite clinical improvement

Respiratory depression, hypotension, or other adverse effect

A maximum dose is reached (such as 0.2 mg/kg midazolam, although higher may be needed if on chronicbenzodiazepines)

b Interpretation

The test is considered positive if there is resolution of the potentially ictal EEG pattern and either animprovement in the clinical state or the appearance of previously absent normal EEG patterns (eg,posterior-dominant ‘‘alpha’’ rhythm). If EEG improves but patient does not, the result is equivocal.

Non-ictal patterns may disappear after administration of benzodiazepine (always without clinical improvement).

Administration of too high a dose of benzodiazepine might improve the EEG but also leads to sedation,preventing the ability to detect clinical improvement.

A negative or equivocal result does not rule out nonconvulsive status epilepticus.a Modified from Foreman B, Hirsch LJ, Neurol Clin.16 B 2012, with permission from Elsevier. www.neurologic.theclinics.com/article/S0733-8619(11)00082-X/abstract.



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epilepticus (successful in 73% versus63% of patients) when administered byparamedics en route to the hospital.4

The difference was due to the morerapid administration of midazolam andresulted in a lower rate of hospitaliza-tion in the midazolam group. Thesetrials indicate that if IV access isavailable, IV lorazepam is the treatmentof choice for generalized convulsivestatus epilepticus. If IV access is notavailable, IM midazolam is a provenoption, superior to IV lorazepam, al-though intranasal or buccal administra-tion of midazolam (shown to beeffective in multiple trials, and ab-sorbed faster than IM midazolam) orrectal administration of diazepam areappropriate and safe possibilities.

Second-line therapy. If statusepilepticus is not controlled by a firstdose of benzodiazepine, it is recom-mended to administer a second dose.Regardless of whether status epilep-ticus is controlled by benzodiazepines,it is also recommended to immediatelyinitiate a second AED to prevent earlystatus epilepticus recurrence whenthe effect of the benzodiazepines

wears off. Choices include AEDs thatare available in IV form and can berapidly titrated to effective levels, suchas fosphenytoin/phenytoin, valproate,levetiracetam, or lacosamide; pheno-barbital remains an option as well,although it has become less populardue to its adverse effects, especiallyprolonged sedation. In the absence ofpublished evidence to support any dif-ferential efficacy, the choice of treat-ment is guided by the etiology and thepresence of comorbidities. For exam-ple, in patients with idiopathic general-ized epilepsy, valproate is probably thedrug of choice, while phenytoin is con-traindicated because it may aggravatethe condition. In patients with braintumor, it is often better to avoid strongP450 enzyme inducers as they can lowerthe efficacy of steroids and chemother-apeutics. It may be best to avoid certainmedications (ie, phenytoin, carbamaze-pine, lacosamide) if the patient has pre-existing cardiac conduction delay, asthese can all slow cardiac conduction;to avoid topiramate and zonisamide ifthe patient is on propofol, is acidotic, orhas renal stones (exacerbated by these

Case 12-3A 48-year-old man fell from a ladder and experienced a left temporoparietal fracture and epiduralhematoma, and a right-sided subdural hematoma. The hematomas were surgically drained,but he remained comatose with mild withdrawal to noxious stimulation. There were no clinicalseizures or any evidence of subtle seizure activity clinically. Continuous EEG (cEEG) revealed rightfrontotemporal electrographic seizures, which were initially intermittent and then became nearlycontinuous (Figure 12-4 demonstrates two closely occurring seizures characterized by rhythmic deltaactivitywith admixed low-voltage fast frequencies). No clinical signs were present. Hewas initially treatedwith boluses of lorazepam and infusion of levetiracetam that led to transient seizure control. Theaddition of phenytoin and lacosamide led to permanent control. Initially, he showed no clinical signs ofimprovement, but he progressively recovered consciousness over 3 days following seizure control andstarted opening his eyes to verbal stimulation and following commands. He was discharged to arehabilitation facility.

Comment. This case exemplifies the difficulty in the diagnosis and treatment of nonconvulsivestatus epilepticus in patients with acute brain injuries. Without cEEG, it would have been impossibleto make the diagnosis. A trial of antiepileptic drugs resulted in immediate EEG improvement, butclinical improvement was much slower.


KEY POINT

h Results fromrandomized controlledtrials indicate that thefirst-line treatment ofchoice in generalizedconvulsive statusepilepticus is abenzodiazepine: IVlorazepam if IV access isestablished, or IM,nasal, or buccalmidazolam or rectaldiazepam if IV access isnot established.


Status Epilepticus


two carbonic anhydrase inhibitors); andto avoid valproate if the patient hashepatic failure, thrombocytopenia, orother major coagulopathy.

Fosphenytoin/phenytoin is oftenrecommended as a second-line ther-apy. Phenytoin should be infusedslowly, avoiding small veins and under


FIGURE 12-4 Almost-continuous right frontotemporal seizures in a patient with traumatic brain injury andright hemispheric subdural hematoma. AYF, Six 10-second EEG pages demonstrating twoseizures, with respective onset at 3 and 56 seconds (black arrows in Panels A and F). The

ictal pattern is characterized by rhythmic delta activity that fluctuates then evolves to theta activity (boxes inPanels C, D, and E). Although this pattern does not strictly meet the criteria for definite electrographicseizures, it likely represents seizures; in addition, both EEG and clinical improvement was noted after initiationof antiepileptic treatment. High-pass filter is at 1 Hz, low-pass filter is at 70 Hz, and notch filter is off.



cardiovascular monitoring, because ofthe risk of hypotension and arrhyth-mias. Fosphenytoin is the water-solubleprodrug of phenytoin and offers severaladvantages: it can be loaded 3 timesfaster using a peripheral line and is notassociated with a risk of soft-tissuenecrosis with extravasation. It can inducea nonallergic pruritus in up to 50% of

cases because of the phosphate load;this is not an allergic response and canbe minimized by slowing the infusion.

Two small randomized controlledtrials showed that IV valproate is notinferior and may even bemore effectivethan IV phenytoin as a first- or second-line agent.29,30 Some authors, includingthe authors of this article, recommend the

TABLE 12-7 Summary and Comparison of Available Guidelines for the Management ofStatus Epilepticus

Component2010 European Federation ofNeurological Societies Guidelinesa

2012 NeurocriticalCare Society Guidelinesb

Recommendations Evidence Recommendations

Definitionof statusepilepticus

5 min of seizure activity forgeneralized convulsive statusepilepticus

No definition for nonconvulsivestatus epilepticus

Exclude absence status epilepticus

5 min or more of (1)continuous clinical and/orelectrographic seizureactivity or (2) recurrentseizure activity withoutrecovery (returning tobaseline) between seizures

Focus on the acutely ill patientwith impaired mental status

Initialmanagement

Stabilize airway, breathing,circulation

Monitoring and support(arterial oxyhemoglobinsaturation, blood pressure,heart rate)

Lab tests (arterial blood gas,antiepileptic drug [AED] levels,basic metabolic profile,magnesium, complete bloodcount, liver function test, bloodurea nitrogen/creatinine)

Dextrose/thiamine

Determination of the causeof status epilepticus

Stabilize airway, breathing,circulation, peripheral IV access

Monitoring and support (arterialoxyhemoglobin saturation,blood pressure, heart rate)

Lab tests (arterial bloodgas, AED levels, bloodglucose, basic metabolicprofile, magnesium,calcium, complete bloodcount, liver function test,blood urea nitrogen/creatinine)

Dextrose/thiamine

Continuous EEG (cEEG)monitoring

Head CT scan

Consider if appropriate:brain MRI, lumbar puncture,toxicology panel, troponin,coagulation studies, inbornerrors of metabolism

Continued on next page

KEY POINT

h Pruritis duringfosphenytoin infusion isnot an allergic reaction;it is most likely due tothe phosphate load.Slowing the rate ofinfusion may reduceitching.


Status Epilepticus


TABLE 12-7 Summary and Comparison of Available Guidelines for the Management ofStatus Epilepticus (continued )


2012 Neurocritical CareSociety Guidelinesb

Recommendations Evidence Recommendations Strength/Evidence

Initial (emergent/urgent) treatmentfor generalizedconvulsive statusepilepticus andnonconvulsivestatus epilepticus

IV lorazepamorIV diazepamplus IV fosphenytoin/phenytoin

If possible, prehospitaltreatment should beadministered

Level A

Level A

Level A

Benzodiazepines are thetreatment of choice:IV lorazepamorIM midazolamorRectal diazepam

Followed by an IV AED:fosphenytoin/phenytoinorvalproateorphenobarbitalorlevetiracetamormidazolam (continuous)

SR-HQ

I-A

I-A

IIa-A

SR-MQIIa-B

IIa-A

IIb-C

IIb-C

IIb-B

Treatment ofrefractorygeneralizedconvulsive statusepilepticus andsubtle statusepilepticus

Admission to intensivecare unit (ICU)

Continuous IV propofol,thiopental or midazolam

Titrate to burst suppression(propofol or thiopental) orseizure suppression(midazolam)

Simultaneous initiationof chronic medication

If intubation/artificial ventilation isnot justified, furthernonanesthetizingagents may be tried

GPP

GPP

GPP

GPP

GPP

Management in an ICU thatcan provide cEEG

Additional treatment (switchto or start a new AED) preferredover rebolus of AED used initially

Continuous IV midazolam,propofol, or pentobarbital+/j intermittent bolusesorIntermittent IV AED innonintubated patients

Use maintenance AEDs for thetransition from continuous IV.

Titrate to seizure suppressionor burst suppression

Electrographic control for24Y48 h before weaning

SR-VLQ

SR-LQ

SR-VLQ

SR-VLQ

SR-VLQ WR-VLQ

WR-VLQ

In case of status epilepticusrefractory to continuous IVanesthetics, alternative therapiescan be considered but the patientshould be transferred to an ICUthat specializes in the treatmentof status epilepticus and canprovide cEEG monitoring

WR-VLQ




use of high doses of valproate (approx-imately a 40 mg/kg load).3,16 Infusionrates of up to 6 mg/kg/min have beenreported to be safe. Valproate shouldusually be avoided in children below 2

years of age, especially if possibilityexists of an underlying metabolic dis-order, because of the risk of severehepatotoxicity. Otherwise, it is usuallywell tolerated, with minimal sedation

TABLE 12-7 Summary and Comparison of Available Guidelines for the Management ofStatus Epilepticus (continued )


2012 Neurocritical CareSociety Guidelinesb

Recommendations Evidence Recommendations Strength/Evidence

Treatment ofrefractorycomplex partialstatus epilepticus

Postpone anesthesia

No recommendationregarding whichnonanestheticagent should be used

GPP No specific recommendations

Use of cEEG No specificrecommendations

cEEG is usually required for thetreatment of status epilepticus

Indications include:

Recent clinical seizure or statusepilepticus without returnto baseline after 10 min

Coma

Epileptiform or periodicdischarges on initial 30-min EEG

Intracranial hemorrhage

Suspected nonconvulsive seizure

cEEG should be initiated within1 h of status epilepticus onset ifongoing seizures are suspected

Duration of cEEG should be atleast 48 h in comatose patients

ICU EEG reader should havespecialized training in cEEG andquantitative EEG interpretation

SR-VLQ

I-B

I-B

I-B

I-B

I-B

SR-LQ

SR-LQ

SR-LQ

a European Federation of Neurological Societies guidelines used the following definition of evidence:Level A: rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.GPP: good practice pointVclear consensus but lack of evidence.

b Neurocritical Care Society guidelines used the evidence rating system of the American Heart Association/American College of Cardiology guidelines:I: Intervention is useful and effective. Treatment benefits clearly exceed risks.IIa: Evidence/expert opinions suggest intervention is useful/effective. Treatment benefits exceed risk.IIB: Strength of evidence/expert opinion about intervention usefulness/effectiveness is less well established. More data are needed; however, using this treatment when

warranted is not unreasonable.A: Adequate evidence is available from multiple, large, randomized clinical trials or meta-analysesB: Limited evidence is available from less rigorous data, including fewer, smaller, randomized trials, nonrandomized studies, and observational analyses.C: Evidence relies on expert/consensus opinion, case reports, or standard of care.

And the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system:SR = strong recommendation; WR = weak recommendation; HQ = high qualityVfurther research is very unlikely to change our confidence in the estimate of effect; MQ =medium qualityVfurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; LQ = low qualityVfurtherresearch is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; VLQ = very low qualityVany estimate ofeffect is very uncertain.


Status Epilepticus


and cardiorespiratory effect.29,30 Val-proate can cause a reversible, oftenasymptomatic, hyperammonemia.Thrombocytopenia and platelet dys-function may also occur but clinicallysignificant bleeding is unusual, al-though it may be a concern if neuro-surgery is to be performed or if thereis already a bleeding diathesis.

Levetiracetam and lacosamide areboth available in IV form and have

an appealing safety and pharmacokineticprofile. Their use in status epilepticus hasbeen reported in several small retrospec-tive series only, with satisfactory efficacyand excellent safety.31,32 However, arecent retrospective comparison sug-gested that levetiracetam was less ef-fective than valproate.33

Therefore, as a second-line agent,some evidence suggests that valproatemight be superior to phenytoin, and

FIGURE 12-5 Sample status epilepticus treatment algorithm for adults as adopted at Yale-New Haven Hospital.

IV = intravenous; ED = emergency department; IM = intramuscular; O2 = oxygen; HR = heart rate; BP = bloodpressure; EKG = electrocardiogram; CBC= complete blood count; BMP = basic metabolic profile; Ca = calcium;Mg = magnesium; PO4 = phosphate; LFT = liver function test; ABG = arterial blood gas; AED = antiepilepticdrug; HCG = human chorionic gonadotropin; PE = phenytoin equivalent; EEG = electroencephalogram.

Figure courtesy of Amber Castle, PharmD, BCPS Yale-New Haven Hospital, New Haven, CT.



TABLE 12-8 Common Medications Used in Status Epilepticus

Drug Loading Dose Maintenance Dose Level Mechanism(s) of Action

First-Line Agents

Lorazepam 0.1 mg/kg upto 4 mg IVat 2 mg/min

n/a; repeat loadingdose once if needed

n/a +-aminobutyric acid(GABA)agonist

Midazolam 0.2 mg/kg upto 10 mg IM


n/a GABA agonist

Diazepam 0.2 mg/kg upto 20 mg rectallyor 0.1 mg/kg upto 10 mg IV


n/a GABA agonist


Second-Line Agents

Phenytoin 18Y20 mg/kgIV up to50 mg/min(25 mg/min inolder patientsor patients withcardiovascularinstability)

5Y7 mg/kg/d orally/IV,divided every 8 h

Total:15Y20 Hg/mLFree:1.5Y2.5 Hg/mL

Sodium channelmodulation

Fosphenytoin 18Y20 phenytoinequivalents/kg IVup to 150 mg/min

5Y7 phenytoinequivalents/kg/d/IV,divided every 8 h

n/a Sodium channelmodulation

Valproate 20Y40 mg/kg IVup to 3 mg/kg/min(probably safe upto 6 mg/kg/min)

30Y60 mg/kg/d,divided every 6 h

80Y140 Hg/mL Multiple, includingsodium channel modulation,GABA potentiation andglutamate/NMDA inhibition

Levetiracetam 2500Y4000 mg IVup to 500 mg/min

2Y12 g/d orally/IV,divided up toevery 6 h

25Y60 mg/L Synaptic vesicle protein 2A

Lacosamide 400 mg IV over5 min

400Y600 mg/d IV,divided every 12 h

Unknown Sodium channelmodulation

Phenobarbital 20 mg/kg IV up to60 mg/min

1Y4 mg/kg/d orally/IV,divided every 6Y8 h

20Y50 mg/mL GABA potentiation


Status Epilepticus


Clearance Protein Binding Removed by Dialysis Adverse Reactions/Comments

Hepatic 85% No Sedation, respiratory depression,arrhythmia and hypotension, although lesslikely tooccur than if SE is left undertreated.

Hepatic; activemetaboliteexcreted renally

97% No Sedation, respiratory depression,hypotension, though less thanif leaving untreated.

Hepatic 98% No Sedation, respiratory depression,hypotension, though less thanif leaving untreated.

Clearance Protein Binding Removed by DialysisAdverse Reactions, Comments,and Interactions

Hepatic 90% G5% Cardiorespiratory depression, arrhythmia,hypotension, metabolic acidosis (dilutedin propylene glycol), infusion site injuryInteractions: Phenytoin is a CYP1A2,CYP2C9, and CYP3A4 inducer.

Hepatic 90% G5% Cardiorespiratory depression, arrhythmia,hypotension, nonallergic pruritusInteractions: Fosphenytoin is a CYP1A2,CYP2C9, and CYP3A4 inducer.

Hepatic 80%Y90% G20% Hyperammonemia, thrombocytopenia,pancreatitis, hepatic toxicity inchildren G2 y

Renal (67%)and hepatic (33%)

G10% 50% No major adverse reaction

Hepatic (60%)and renal (40%)

G15% 50% No major adverse reaction, but mayprolong PR interval

Hepatic (75%)and renal (25%)

20%Y45% Yes Sedation, respiratory depressionInteractions: Phenobarbital is aCYP1A2, CYP2C9, and CYP3A4 inducerand may aggravate valproate-inducedhyperammonemia.




TABLE 12-8 Common Medications Used in Status Epilepticus (continued )


Third-Line Agents

Midazolam 0.2 mg/kg IV every5 min until seizurescontrolled or maximumdose of 2 mg/kg

0.1Y2.9 mg/kg/hcontinuous IV

n/a; titrate todesired levelof EEGsuppression

GABA potentiation

Propofol 2 mg/kg IV every5 min until seizurescontrolled ormaximumdose 10 mg/kg

2Y15 mg/kg/hcontinuous IV(Limit to 5 mg/kg/hfor treatment 948 h)


GABA agonist,glutamate/NMDAinhibition and calciumchannel modulation

Pentobarbital 5 mg/kg IV up to50 mg/min every5 min until seizurescontrolled

1Y10 mg/kg/hcontinuous IV


GABA potentiation

Ketamine 1.5 mg/kg IVevery 5 min untilseizures controlledor maximumdose 4.5 mg/kg



Glutamate/NMDAinhibition

Etomidate 0.3 mg/kg IVevery 5 min untilseizures controlled


Unknown GABA potentiation

Lidocaine 1Y5 mg/kg(usually 100 mg)IV every 5 minuntil seizurescontrolled

Up to 6 mg/kg/hcontinuous IV

G5 mg/L Sodium channelmodulation

Drug Starting Dose Subsequent Dosing Level Mechanism(s) of Action

Oral Agents

Topiramate 100 mg every12 h

400Y800 mg/dorally, dividedevery 8Y12 ha

Unknown Sodium channel modulation,GABA potentiation, glutamate/!-amino-3-hydroxy-5-methylisoxazole-4-propionicacid inhibition, and carbonicanhydrase inhibition

Gabapentin 300 mg every8 h orally

1800Y3600 mg/dorally, dividedevery 6Y8 h

Unknown Calcium channel modulation

Pregabalin 75 mg every12 h orally

150Y600 mg/d orally,divided every 12 h

Unknown Calcium channel modulation

Vigabatrin 500 mg every8 h orally

Up to 1 g every 8 horally

Unknown GABA potentiation


Status Epilepticus



Hepatic; activemetabolitesexcreted renally

90% No Sedation, respiratory depression,hypotension

Hepatic 90% No Sedation, respiratory depression,hypotension, propofol infusionsyndrome

Hepatic 45%Y70% No Sedation, respiratory depression, hypotension,ileus, gastric stasis, metabolic acidosis (dilutedin propylene glycol), thrombocytopenia,immunosuppression

Hepatic; activemetabolitesexcreted renally

45% Unknown Hypertension, possible raise inintracranial pressure

Hepatic 75% Unknown Adrenal insufficiency, nonepilepticmyoclonus

Hepatic 60%Y80% No Cardiac arrhythmiaInteractions: Lidocaine interacts withantiarrhythmic agents.


Renal (70%)and hepatic(30%)

15%Y40% Yes Metabolic acidosis; topiramate maypotentiate GABA agonists, is a weakCYP2C19 and CYP3A4 inhibitor, andmay aggravate valproate-inducedhyperammonemia.

Renal G3% Yes No major adverse reaction

Renal 0% Yes No major adverse reaction

Renal 0% Yes, but dosageadjustment unknown

No major adverse reactionassociated with short-term use




perhaps levetiracetam. The place oflacosamide is still uncertain.

Failure of second-line therapy andrefractory status epilepticus. Severalcriteria, including the failure of 2 or 3drugs and duration typically more than30 minutes, have been proposed todefine refractory status epilepticus. Awidely accepted definition, adoptedin the NCS guidelines, considers thatrefractory status epilepticus is statusepilepticus that fails to respond to twoAEDs. Using this definition, refractorystatus epilepticus occurs in up to 40%of cases of status epilepticus.27,34

Predictors of refractory status epi-lepticus include encephalitis andnonstructural causes (especially hypoxic-ischemic encephalopathy), delayeddiagnosis and treatment, and subtlestatus epilepticus.19,34,35

In animal models, the acute phase ofstatus epilepticus is sensitive to +-

aminobutyric acid (GABA) agonists. How-ever, internalization of GABA receptorsstarts to occur as early as 5 minutes afteronset, while glutamate N-methyl-D-aspar-tate (NMDA) receptors are progressivelyoverexpressed. This leads to the mainte-nance phase during which GABA ago-nists are less effective, while NMDAantagonists, initially not effective, becomemore effective.36Y38

Given the need for early control ingeneralized convulsive status epilep-ticus, it is usually recommended thatfailure of one first-line and one second-line drug should immediately promptmore aggressive treatment (ie, therapeu-tic coma), with initial bolus or bolusesfollowed by continuous infusion of ananesthetic dose of an AED.

Three commonly used drugs areavailable for this purpose: midazolam,propofol, and pentobarbital (or itsprodrug, thiopental, in Europe). Very

TABLE 12-8 Common Medications Used in Status Epilepticus (continued )


Felbamate 400 mg every8 h orally

Up to 1200 mgevery 8 h orally

40Y1002g/mL

GABA potentiation andglutamate/NMDA inhibition

Magnesiumsulfate

2Y4 g IV over2 h

2 g IV every 8 hor 0.5Y2 g/hcontinuous IV

92.0 mEq/L(up to 7.0mEq/L)

Glutamate/NMDA inhibitionand calcium channelmodulation

Immune Therapies Starting Dose Maintenance Dose Level Mechanism(s) of Action

Methylprednisolone 1 g/d during 3 d 1 mg/kg/d then taper n/a Renal

IV immunoglobulin 0.4 g/kg/d for 5 d NA n/a n/a

Plasmapheresis 1 session every otherday for 5 to 7 d

Unknown n/a n/a

IV = intravenous; n/a = not applicable; IM = intramuscular; NMDA = N-methyl-D-aspartate.a Doses up to 1200Y1600 mg have been used and are recommended in the Neurocritical Care Society guidelines.

KEY POINT

h Evidence from smallrandomizedcontrolled trialssuggests that IV valpro-ate is not inferior and isperhaps superior tophenytoin.


Status Epilepticus


little evidence is available regardingthe choice of drug.

A systematic review of all publishedcase series between 1980 and 2001 con-cluded the following: (1) midazolam wasassociated with a higher rate of break-through seizures; (2) hypotension wasmore frequent with pentobarbital; and(3) the rates of both withdrawal seizuresduring emergence from drug-inducedcoma and mortality were similar (approx-imately 50%)with all threemedications.39

The observed differences could havebeen fully explained by treatment goalsrather than the agent used. Similarly, aretrospective series found no differencein outcome between the three drugs.40

A prospective trial attempted tocompare propofol to pentobarbital/thiopental. Only 24 patients were en-rolled when the trial was stopped prema-turely because of slow enrollment. Therewere no significant differences in terms of

mortality or efficacy.41 Severe adverseevents occurred in both arms of the trial,and the duration of mechanical venti-lation was longer in patients treatedwith pentobarbital.

The use of pentobarbital, the crite-rion standard for treatment of refractorystatus epilepticus, is also associated witha significant risk of immunosuppression.

Prolonged infusion of propofol canlead to acidosis, multiple organ failure,and rhabdomyolysis, a condition knownas propofol infusion syndrome. Riskfactors for propofol infusion syn-drome include prolonged administra-tion (more than 48 hours) at high dose(more than 5 mg/kg/h), young age, andacute neurologic illness.

Altogether, these data suggest thatall three drugs are acceptable alterna-tives for the treatment of refractorystatus epilepticus, as stated in bothavailable guidelines. Midazolam might

KEY POINT

h Continuous IV propofolmay be a poor option inchildren with statusepilepticus because ofthe risk of the propofolinfusion syndrome,although proper dosingmay allow safe use.


Renal (50%)and hepatic(50%)

20%Y25% Unknown A plastic anemia, hepatic failureInteractions: Felbamate is a weakCYP3A4 inducer and CYP2C19 inhibitorand is potentially interactive withphenobarbital, phenytoin, and valproate.

Renal No Varies with dialysisbath magnesiumconcentration

Hypotension, cardiac arrhythmia

Clearance Protein Binding Removed by Dialysis Interactions

990% No No Methylprednisolone may causesteroid-induced gluconeogenesis whichmay lower the efficacy of the ketogenic diet.

n/a n/a No None

n/a n/a n/a Plasmapheresis can cause the possibleclearing of antiepileptic drugs.



have the best combined efficacy andsafety profile, but this needs to be con-firmed in a prospective, controlled trialbefore clear recommendations canbe made.

Data regarding the depth and dura-tion of sedation are still inconclusive.40,42

Therefore, the authors prefer to at-tempt to control seizures first (referredto as ‘‘seizure suppression’’) withoutachieving suppression-burst, regardlessof the agent chosen, in an attempt tominimize adverse effects. It should alsobe noted that seizures sometimes arisefrom a suppression-burst background,and even from an isoelectric back-ground in some patients.

Recommendations on the durationof anesthesia are mainly based on

expert opinions. The NCS guidelinesrecommend at least 24 to 48 hours ofelectrographic control before slowlywithdrawing the anesthetic drug,which is usually done over 24 hours.This further emphasizes the need forcEEG in the treatment of refractorystatus epilepticus.

Breakthrough seizures are usuallymanaged by the administration of anextra bolus and an increase in themaintenance infusion rate.

Finally, initiation or continuation ofat least one (typically multiple) stan-dard AED in addition to the anestheticagent is also recommended in orderto decrease the risk of recurrent sei-zures and status epilepticus when theanesthetic drug is tapered.

KEY POINTS

h Seizures can arise fromsuppression-burst andeven from suppressedbackground.

h Uncertainty existsregarding the agent tobe used and thedepth and duration ofanesthesia requiredfor the treatment ofrefractory statusepilepticus.

TABLE 12-9 Nonpharmacologic Approaches Used in Status Epilepticus

NonpharmacologicApproaches Dose Duration

Mechanism(s)of Action Interactions

Adverse Reactions/Comments

Electroconvulsivetherapy

1 sessiondaily for3Y8 d

Unknown, butup to 2 wk

Unknown None, althoughdoses ofanticonvulsantsshould bedecreasedprior toelectroconvulsivetherapy foroptimal response

Adverse reactionsattributable to ashort generalanesthesia; memoryloss and mood effectdifficult to ascertainin patients withstatus epilepticus;requires lowering ofthe dose of currentanticonvulsant drugs.

Hypothermia n/a Unknown, butusually 24 h

Decrease brainmetabolismwhich istheoreticallyneuroprotective

None Acid, base, andelectrolytedisturbances;coagulation disordersand thrombosis;infections; cardiacarrhythmia; bowelischemia; paralyticileus

Resective surgery n/a n/a n/a None

Ketogenic diet n/a n/a n/a None Acidosis,immunosuppression,nephrolithiasis

n/a = not applicable.


Status Epilepticus


Malignant and super-refractorystatus epilepticus. Status epilepticusthat does not permanently respond toa course of anesthetic drug has beenreferred to by some authors as ‘‘ma-lignant’’43 or ‘‘super-refractory’’ statusepilepticus,44 which represents up to20% of cases of refractory status epi-lepticus and is more common in youn-ger patients with encephalitis.34,43

Therapeutic options include a secondtrial of the same anesthetic drug;switching to another anesthetic drug;combining multiple anesthetic drugsand AEDs, including ketamine; and otherapproaches such as immune therapies(eg, steroids, plasma exchange, or IVIg), ketogenic diet, hypothermia, neu-rosurgery, and electroconvulsive ther-apy (Table 12-9). Details of thesetreatments can be found in recent com-prehensive reviews.16,44

Suggested doses, mechanisms ofaction, common side effects, and in-teractions of the most commonly usedmedications for the treatment of sta-tus epilepticus are summarized inTable 12-8.

TREATMENT OFNONCONVULSIVE STATUSEPILEPTICUSThe treatment algorithm detailedabove applies mainly to the treatmentof generalized convulsive status epi-lepticus. The approach to refractorynonconvulsive status epilepticus dif-fers from refractory generalized con-vulsive status epilepticus, as thenonconvulsive form carries a lower riskof severe acute systemic complications.It is probably safer to postpone the useof anesthetic agents and to try first,either sequentially or additively, othernonsedating AEDs. Older and newerdrugs are acceptable options, includingAEDs that cannot be administeredparenterally. Their use, however, is sup-ported only by small case series.

TREATMENT OF REFRACTORYSTATUS EPILEPTICUS ANDMYOCLONIC STATUSEPILEPTICUS AFTERCARDIAC ARRESTEarlier studies showed that myoclonicstatus epilepticus is one of the strongestpredictors of poor outcome in pa-tients with postanoxic coma,45 buttheir results may not be applicable topatients treated with therapeutic hy-pothermia. In some instances, patientswith postanoxic refractory status epilep-ticus (including myoclonic status epilep-ticus) undergoing hypothermia can havegood outcomes, especially if the EEGbackground is reactive, somatosensoryevoked potentials are present, and therefractory status epilepticus or myo-clonic status epilepticus is treated.46

NEUROPATHOLOGICCHANGES AFTER PROLONGEDNONCONVULSIVE STATUSEPILEPTICUSAnimal models have shown that per-manent cerebral damage in statusepilepticus may occur either as a resultof systemic metabolic disturbances (eg,hypoxia, hypoglycemia) or as the directconsequence of the electrical dischargeitself,47 and may aggravate an underly-ing brain injury.48 In humans, serumlevels of neuron-specific enolase, amarker of neuronal damage, are ele-vated after nonconvulsive seizures andstatus epilepticus.23 More recently, itwas also shown that subjects present-ing with acute seizures after traumaticbrain injury developed greater hippo-campal atrophy than a matched groupwithout seizures, especially on the sideof seizure activity.49 These and otherfindings20 indicate that prolonged ictalactivity, complicated or not by systemicfactors and with or without motor activ-ity, can cause irreversible brain damage,especially in the acutely injured brain.

KEY POINT

h The treatment ofnonconvulsive statusepilepticus has not yetbeen specifically studiedin a prospective,randomized trial. It isrecommended byexperts and in theEuropean Federation ofNeurological Societies’published set ofguidelines to adopt asimilar but lessaggressive course thanfor the treatment ofgeneralized convulsivestatus epilepticus.In particular,recommendationsemphasize to postponeanesthesia.



OUTCOMEThe mortality rate for adults whopresent with a first episode of statusepilepticus is about 20% but dependsgreatly on, and is in fact often due to,the underlying etiology.50 Negativeprognostic factors include older age,longer duration, subtle status epilep-ticus after generalized convulsive sta-tus epilepticus, female sex, and thepresence of comorbidities.51 Between20% and 50% of survivors will have sig-nificant functional disability.51 Worseoutcome is more common in patientswith acute brain injury and after refrac-tory status epilepticus, although mean-ingful recovery is possible even afterprolonged status epilepticus, as exem-plified in Case 12-1.52,53

CONCLUSIONSStatus epilepticus is a serious medicalcondition with significant morbidityand mortality and requires urgent med-ical evaluation and treatment. The last2 decades have seen major advances inthe definition of the first line of treat-ment. The more widespread admin-istration of IM midazolam (or othernon-IV route of administration54) enroute to the hospital will likely de-crease the number of refractory statusepilepticus cases admitted to the hos-pital. However, further prospective tri-als are needed to define the optimaltherapy for the remaining refractorycases. Likewise, treatment of noncon-vulsive status epilepticus, especially incritically ill patients, should be studied.Other avenues of research includethe mechanisms of secondary neuro-nal injury, long-term consequences ofthe various subtypes of status epilep-ticus, and the role of potentially neu-roprotective interventions.

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