Updates in the Management

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Updates in the Management

of Seizures and Status Epilepticus

in Critically Ill Patients

Karine J. Abou Khaled, MD,Lawrence J. Hirsch, MD*

Department of Neurology, Comprehensive Epilepsy Center, Columbia University,

7th floor, 710 West 168th Street, New York, NY 10032, USA

Seizures and status epilepticus (SE) in the intensive care setting can be

seen in two main groups of patients: patients admitted to the intensive

care unit (ICU) because of continuous or repetitive seizures requiring

aggressive treatment, and patients admitted for medical or surgical reasonswho develop seizures during the course of their ICU stay. This article is a re-

vision and update of a previously published in Critical Care Clinics in 2006

[1], which provided recent concepts of seizures and SE in the adult ICU.

This revision follows the structure of the original article and starts with

a brief review of SE epidemiology, definition, classification, etiologies, diag-

nosis, and prognosis. Then, the systemic and neurologic effects of seizures

and SE are discussed. Finally, the authors propose strategic therapeutic

steps and focus on the treatment of seizures and SE in patients with specific

organ failures or after organ transplantation.

Epidemiology and definition

SE remains a serious, life-threatening emergency. De Lorenzo and

colleagues [2] estimated that it affects 152,000 individuals in the United

States per year and causes 42,000 deaths. The first attempt to define SE

was in 1962, when the tenth European Conference on Epileptology and

Clinical Neurophysiology defined SE as a condition characterized by an

epileptic seizure which is so frequently repeated or so prolonged as to create

This is an updated version of an article that originally appeared in Critical Care Clinics,

volume 22, issue 4.

* Corresponding author.

E-mail address: [email protected] (L.J. Hirsch).

0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.ncl.2008.03.017 neurologic.theclinics.com

Neurol Clin 26 (2008) 385408
mailto:[email protected]://www.neurologic.theclinics.com/http://www.neurologic.theclinics.com/mailto:[email protected]


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a fixed and lasting epileptic condition [3]. The International Classification

of Epileptic Seizures, along with a general consensus, described SE as any

seizure lasting more than 30 minutes or intermittent seizures from whichthe patient did not regain consciousness lasting for more than 30 minutes

[3]. The rationale for choosing 30 minutes was based on the minimum dura-

tion thought to result in neuronal injury in animal models. Bleck [4] defined

SE as continuous or repeated seizures lasting more than 20 minutes. More

recently, Lowenstein and colleagues [5] suggested that defining SE based

on the theoretic onset of neuronal injury is of questionable value because

of the complexity of this relation in human beings. They suggested that

we should not wait 10 minutes or longer before instituting a treatment pro-

tocol for SE [5]. Treiman and colleagues [6] defined overt convulsive SE astwo or more generalized convulsions without full recovery of consciousness

between seizures, or continuous convulsive activity for more than 10 min-

utes. For practical purposes, SE should be considered if a seizure persists

more than 5 minutes because very few single seizures last this long.

Classification of status epilepticus

In 1967, Gastaut [3] first distinguished two major types of SE based

exclusively on seizure semiology. The first type is generalized SE, which issubdivided into two groups: (1) generalized convulsive SE (GCSE), which

is tonic-clonic SE or grand mal SE, tonic SE, clonic SE, or myoclonic SE;

and (2) nonconvulsive generalized SE, including petit mal status. The second

type is partial SE, which is subdivided into two groups: simple partial SE

(eg, somatomotor or aphasic SE) and complex partial SE. Gastaut sepa-

rately distinguished a unilateral SE, seen only in infants and very young chil-

dren, and erratic SE, seen in neonates.

There is no recent consensus on further classification of nonconvulsive

status epilepticus (NCSE). In clinical practice, it is often impossible to dif-ferentiate between NCSE of generalized onset and NCSE of partial onset

with bilateral spread. The authors divide SE into convulsive SE and

NCSE or subtle SE. The authors reserve the term absence SE for patients

with idiopathic primary generalized epilepsy. There are two distinct clinical

scenarios involving NCSE: that in ambulatory patients with confusion who

have a good prognosis and often respond quickly and dramatically to treat-

ment in the emergency department, and that in comatose or stuporous

patients who have a more guarded prognosis and rarely awaken rapidly

with treatment. The latter situation is discussed further in this article.

Etiologies

Seizures in the ICU can arise from various etiologies. Etiologies differ

among centers, patient population, and age. Box 1 summarizes these by cat-

egories. Lowenstein and Alldredge [7] evaluated 154 patients treated for

386 ABOU KHALED & HIRSCH


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generalized SE, 93% of whom had an onset preceding hospital admission.

The two leading etiologies were anticonvulsant drug withdrawal or noncom-

pliance (almost all were noncompliant with their prescribed regimen) andalcohol-related. These results were similar to what was found by Aminoff

and Simon [8]. Other etiologies included stroke, drug toxicities, central ner-

vous system infection, tumor, and metabolic etiologies. A remote neurologic

cause was found in 70% of the overt SE group and 34% of the subtle SE group

in the Veterans Affairs cooperative study [6]. In another study, the leading

etiologies for adult SE cases were low antiepileptic drug (AEDs) levels

Box 1. Etiologies of seizures in critically ill patients

Exacerbation of preexisting epilepsyAED withdrawal

Acute neurologic insult

Cerebrovascular disease: infarct, hemorrhage (including

subarachnoid, subdural, parenchymal, intraventricular),

vasculitis

Infection: meningitis, encephalitis, brain abscess

Head trauma

AnoxiaBrain tumors

Demyelinating disorders

Supratentorial neurosurgical procedure

Acute systemic insult

Electrolytes imbalances: hyponatremia, hypocalcemia,

hypomagnesemia, hypophosphatemia (especially in

alcoholics)

Hypoglycemia; hyperglycemia with hyperosmolar state; both can

cause focal seizures as wellVitamin deficiency: pyridoxine

Illicit drug use, especially cocaine

Toxins

Hypertensive encephalopathy/eclampsia/posterior reversible

encephalopathy syndrome

Hypotension

Organ failure: renal, hepatic

Multisystem illness, such as systemic lupus erythematosus

Medications: side effects/toxicity (see Box 2), withdrawal(benzodiazepines, barbiturates)

Alcohol related

Systemic infection/sepsis

387MANAGEMENT OF SEIZURES AND STATUS EPILEPTICUS


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(34%), followed by remote symptomatic events (25%), and stroke (22%) [2].

In a series of patients with NCSE, Towne and associates [9] identified hypoxia

or anoxia as the most frequent etiology (42%) followed by cerebrovascularaccident (22%). Neuroinfectious etiologies are more common, in places

such as India particularly neurocysticercosis and tuberculosis [10,11].

Treatment of the underlying cause may be crucial to managing seizures

successfully, especially when caused by a toxic or metabolic origin. It is

often difficult, however, to identify a single etiology because of the presence

of multiple factors lowering the seizure threshold, including the acute med-

ical or neurologic process, medications, renal or hepatic failure, infection,

fever, hypoxia, metabolic abnormalities, or alkalosis. Because of this com-

plexity, it is difficult to define the incidence of drug-induced seizures inICU patients. Imipenem commonly is cited for its association with seizures.

One study found that imipenem use was associated with an increased risk

for seizures, but most of these occurred when the patient was not taking

imipenem [12]. This finding highlighted the possibility that imipenem was

a confounding variable, a marker of severity of illness and infection, rather

than a contributor to the seizures. Box 2 lists the major categories of med-

ications that have been incriminated in contributing to seizures.

Box 2. Medications associated with decreased seizure threshold

Antidepressants, mostly bupropion and maprotiline

Neuroleptics, mostly phenothiazines and clozapine

Lithium

Baclofen

Withdrawal of AEDs

Phenytoin at supratherapeutic levels (including very high free

levels)Theophylline

Analgesics: meperidine, fentanyl, and tramadol

Opioid withdrawal

Benzodiazepine withdrawal

Barbiturate withdrawal

Antibiotics: b-lactams (cefazolin), carbapenems (imipenem),

quinolones, isoniazid (treat with vitamin B6), metronidazole

Antiarrhythmic medications: mexiletine, lidocaine, digoxin

Radiographic contrast agentsImmunomodulators: cyclosporine, tacrolimus, interferons

Chemotherapeutic agents: alkylating agents, such as

chlorambucil and busulfan

Data from Refs. [110112].



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Diagnosis

NCSE is underdiagnosed. It can present in many ways, including mild

personality changes, lethargy, agitation, blinking, confusion, facial twitch-

ing, automatisms, and coma [13,14]. After convulsive SE, nonconvulsive sei-

zures may continue, even after clinical seizures have ceased. In the

Richmond study, 14% of subjects with convulsive SE who stopped seizing

clinically showed persistent electrographic SE on electroencephalogram

(EEG), and 48% had intermittent electrographic seizures [15]. Nonconvul-

sive seizures have been reported in 34% of neurologic ICU patients [16],

16% of severe head trauma patients [17], and 8% of comatose patients

who had no prior seizures or subtle clinical evidence of seizures [9]. In the

authors series of 570 consecutive in-patients undergoing continuous EEG

Monitoring at Columbia, 110 (19%) had seizures, and 101 of these 110 sub-

jects (92%) had purely nonconvulsive seizures that could be detected only by

EEG. Only half of these subjects had their first seizure within the first hour

of recording; even a prolonged routine EEG would not have identified the

nonconvulsive seizures in half the subjects. The authors concluded that 24

hours was a reasonable screen for nonconvulsive seizures in noncomatose

patients (95% of noncomatose patients had their first seizure by 24 hours),

but that 48 hours or more may be needed in comatose patients (only 80%

had their first seizure by 24 hours) [18].

Prognosis

The overall mortality after SE is similar in the two largest known United

States studies: 21% in Rochester, Minnesota [19], and 22% in Richmond,

Virginia [20] (but higher in the elderly population, 38%) [21]. Towne and col-

leagues [22] reported 1-month outcome of 253 adult patients with SE and

showed that the mortality rate of patients with prolonged SE (O60 minutes)was 32%, compared with 2.7% in patients whose SE was 30 to 59 minutes.

Mortality was increased in patients older than 70 years of age. Recently,

Koubeissi and Alshekhlee [23] found an overall in-hospital mortality of

3.45% in a study of 11,580 hospitalized patient cohort with GCSE in the

United States. Of those who survived, about 20% of patients were discharged

to rehabilitation facilities and 76% discharged home. Mechanical ventilation

was associated with tripled mortality compared with those who did not re-

quire it. This study also confirmed that advancing age was associated with

higher mortality rate, as demonstrated by the Richmond study in 1996 [20].Conflicting data exist regarding mortality and morbidity of NCSE, de-

pending primarily on patient selection. The highest reported mortality rates

have been 52% [9,24]. Shneker and Fountain [25] found that 18% of pa-

tients with NCSE died. Patients in the acute medical group (defined as acute

neurologic or systemic problems or both) had significantly higher mortality

rates (27%) than patients in the cryptogenic (18%) or epilepsy (3%) group.



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Worse outcome also was associated in patients with severely impaired men-

tal status.

Sequelae of status epilepticus

Cerebral changes

Lothman and colleagues [26] developed and characterized the self-

sustaining limbic SE electrogenic animal model using continuous hippocampal

stimulation. As SE progresses, the animals show fewer motor manifesta-

tions, despite ongoing electrographic seizure activity. Self-sustaining limbic

SE stops spontaneously after several hours, and the animals graduallyrecover to normal alertness. Approximately 9 months later, they begin

to have spontaneous recurrent partial seizures that persist for more than

1 year. This model suggests that acute SE can lead to long-term epilepsy.

Recurrent spontaneous seizures are frequent sequelae of GCSE and are

present after induced SE in several animal models. In a rat model of low

dose pilocarpine-induced NCSE, Krsek and colleagues [27] found long-

term motor deficits and histologic damage 2 months after NCSE. In the

rats with NCSE, they also noted disturbances in social behavior, and im-

pairment of gamma-aminobutyric acid (GABA) ergic mediated inhibitionin the hippocampus.

What about sequelae of recurrent seizures in humans? Biological markers

such as serum neuron-specific enolase (a glycolytic enzyme found primarily

within neurons), are being investigated as markers of neuronal injury. In

the animal literature, neuron-specific enolase correlates with the amount of

histologic injury in rats after lithium-pilocarpineinduced SE [28]. Elevated

levels of serum neuron-specific enolase have been documented in patients after

nonconvulsive SE, including in cases without any demonstrable acute brain

injury [2932]. The subtype of SE that was associated with the highest serumneuron-specific enolase levels was subclinical SE in critically ill patients [30].

These acute seizure-related changes can also be shown by different mag-

netic resonance neuroimaging modalities. There are several reported cases of

SE with clear development of acute hippocampal swelling on MRI, followed

by later hippocampal atrophy and abnormal signal, evidence of mesial tem-

poral sclerosis [3335]. Pathologic and histologic changes also have been

shown. DeGiorgio and colleagues [36] used a case-control approach and

cell-density quantification to analyze changes in the hippocampus of five

patients who died after GCSE. They found significant pyramidal cell lossin these patients compared with a control group. Changes attributable

directly to the occurrence of GCSE are difficult to determine because path-

ologic alterations could have been present as a result of prior history of

repetitive seizures or other acute processes. Chronic sequelae result from

cell loss or altered physiology or synaptic connectivity. Focal or diffuse cor-

tical damage has been described. The latter accounts for general cognitive



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changes, whereas hippocampal neuronal loss can explain the subsequent

deficits in memory that are sometimes seen [37].

Changes in systemic physiology

The first 30 minutes of GCSE are dominated by sympathetic overdrive,

probably mediated by increased circulating catecholamines, following which

physiologic changes begin to normalize or move in the opposite direction as

a result of failure of homeostatic mechanisms [38]. The most important

physiologic perturbations are fever, blood pressure changes, cardiac

arrhythmias, pulmonary vascular pressure changes, and alterations in blood

chemistries.

Fever is common secondary to sustained muscle activity. Clinicians

should be cautious and rule out infection before attributing fever to

SE, especially if associated with increased white blood cells in blood

or cerebrospinal fluid. Meldrum and colleagues [39] found that

increased temperature correlated with severity of cerebellar injury

and found that neuromuscular blockade prevented both.

Systemic blood pressure increases early in SE, but tends to fall to normal

or below normal later in GCSE.

Cardiac arrhythmias can be life threatening in SE. Boggs and associates[40] reported specific electrocardiogram (ECG) abnormalities not pres-

ent at baseline in 58.3% of patients in SE. The most frequently ob-

served abnormalities were ischemic changes. They also found that

patients with ECG abnormalities had a higher mortality (37% versus

12% in patients without ECG changes). Excessive endogenous epi-

nephrine release has been implicated in cardiac contraction band ne-

crosis. Manno and colleagues [41] reviewed the cardiac pathologic

slides of 11 patients who died during an episode of SE and found con-

traction band necrosis in 8 of them, compared with 5 of 22 controlpatients (P!.05).

Pulmonary arterial pressures increase in SE and pulmonary edema might

occur in the setting of sympathetic hyperactivity [38].

Blood chemistry changes observed in SE include the following:

Severe metabolic acidosis may be seen secondary to excess anaerobic

metabolic activity.

Hyperkalemia may be seen secondary to acidosis and muscle necrosis.

Hyperglycemia resulting from increased catecholamines, but with pro-

longed SE increased insulin secretion may result in hypoglycemia,Increased creatine kinase levels resulting from rhabdomyolysis can be

seen after prolonged convulsions and might lead to acute renal failure.

Increased prolactin level 10 to 20 minutes after a suspected event has

been documented to be useful in differentiating epileptic from

nonepileptic convulsions, but there is no evidence of the level being

useful in SE [42].



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Leukocytosis from demargination, but this should not be attributed to

SE unless infectious etiologies are ruled out.

In a series of 138 patients who had cerebrospinal fluid analysis during SE,Barry and Hauser [43] found that 22.5% had abnormal cerebrospinal

fluid white blood cell count or differential. The highest white blood cell

count in patients with no acute insult was 28 per mm3. A mild transient

increase in protein content also may be observed, possibly reflecting

breakdown of the blood-brain barrier [8].

Treatment of acute seizures and status epilepticus

Management of SE should begin within 5 minutes of seizure activity orafter two seizures without full recovery in between. In the setting of acute

brain injury, treatment usually should be initiated after a single self-limited

seizure, at least for the short-term, and especially in patients with increased

intracranial pressure or patients in whom an episode of marked hyperten-

sion and tachycardia would be dangerous. General supportive measures

for seizures and SE are reviewed first. Subsequently, specific treatments

and choice of AEDs are reviewed. Treatment in special situations, including

organ failure and immunosuppression, conditions commonly encountered

in the ICU, is also addressed.

General supportive measures

General supportive measures begin with basic life support measures and

adequate monitoring of vital signs and ECG. A proposed timetable and

treatment protocol is represented in Table 1.

Blood pressure should be monitored closely, especially if seizures persist

for more than 30 minutes, at which point cerebral autoregulation starts to

fail and cerebral perfusion becomes increasingly dependent on systemic blood

pressure. At this point, intravenous drugs, such as propofol, benzodiazepines,and barbiturates, frequently are introduced, and intravenous fluid resuscita-

tion and vasopressors may become necessary. Refractory GCSE and the use

of agents such as midazolam, propofol, and pentobarbital generally mandate

securing the airway and instituting mechanical ventilation.

The treatment should aim to correct all underlying potential causes and

stop the seizures simultaneously. In at least half of cases of SE, there is some

acute etiology that warrants attention. Depending on the clinical presenta-

tion, additional tests might be necessary when the patient is stabilized,

including lumbar puncture and head CT or MRI, to rule out acute struc-tural or potentially treatable etiologies.

Pharmacologic therapy

Early initiation of therapeutic intervention is much more important than

the choice of agent used. Mazarati and colleagues [44] showed in animal



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Table 1

Status epilepticus: adult treatment protocol, Columbia University Comprehensive Epilepsy

Center 2006

Time, minutes Action

05 Diagnose; give oxygen; ABCs; obtain IV access; begin ECG monitoring;

draw blood for Chem-7, magnesium, calcium, phosphate, CBC, LFTs,

AED levels, ABG, troponin; toxicology screen (urine and blood).

610 Thiamine 100 mg IV; 50 mL of D50 IV unless adequate glucose known.

Lorazepam 4 mg IV over 2 mins; if still seizing, repeat 1 in 5 mins.

If no rapid IV access, give diazepam 20 mg PR or midazolam 10 mg

intranasally, buccally or IMa

1020 If seizures persist, begin fosphenytoin 20 mg/kg IV at 150 mg/min, with

blood pressure and ECG monitoring. This step can be skipped initially,

especially if proceeding to midazolam or propofol, or performed

simultaneously with the next step; if done simultaneously,

administration rate can be slowed. IV valproate is a reasonable

alternative to fosphenytoin at this point as well (dosing below).

1060 If seizures persist, give one of the following (intubation usually necessary

except for valproate): CIV midazolam: Load: 0.2 mg/kg; repeat

0.2 mg/kg0.4 mg/kg boluses every 5 minutes until seizures stop, up to

a maximum total loading dose of 2 mg/kg. Initial CIV rate: 0.1 mg/kg

per hr. CIV dose range: 0.05 mg/kg2.9 mg/kg per hr, titrate to EEG

seizure control or burst suppression. If still seizing, add or switch to

propofol or pentobarbital.

or

CIV propofol: Load: 1 mg/kg2 mg/kg; repeat 1 mg/kg2 mg/kg boluses

every 35 minutes until seizures stop, up to maximum total loading dose

of 10 mg/kg. Initial cIV rate: 2 mg/kg per hr. CIV dose range: 1 mg/kg

15 mg/kg per hr titrate to EEG seizure control or burst suppression. If

still seizing, add or switch to midazolam or pentobarbital. Avoid using

O5 mg/kg per hr for multiple days to minimize risk of propofol infusion

syndrome. Follow CPK, triglycerides, acid-base status closely.

or

IV valproate: 30 mg/kg40 mg/kg over approximately 10 minutes. If still

seizing, additional 20 mg/kg over approximately 5 minutes. If stillseizing, add or switch to CIV midazolam or propofol.

or

IV Phenobarbital: 20 mg/kg IV at 50 mg100 mg per min. If still seizing,

add or switch to CIV midazolam, propofol, or pentobarbital.

O 60 minutes CIV Pentobarbital. Load: 5 mg/kg at up to 50 mg per min; repeat 5 mg/kg

boluses until seizures stop. Initial CIV rate: 1 mg/kg per hr. CIV-dose

range: 0.5 mg/kg10 mg/kg per hr; traditionally titrated to suppression-

burst on EEG but titrating to seizure suppression is reasonable as well.

Begin EEG monitoring ASAP if patient does not rapidly awaken, or if any

CIV treatment is used.

Abbreviations: ABCs, stabilize airway, breathing and circulation; ABG, arterial blood gas;

ASAP, as soon as possible; CBC, complete blood cell count; CIV, continuous intravenous;

CPK, creatine kinase; IV, intravenously; IM, initramuscularly; LFT, liver function test; PR,

per rectum.a The IV solution of diazepam can be given rectally if Diastat is not available; the IV

solution of midazolam can be given by any of these routes.



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experiments that the efficacy of phenytoin decreased dramatically with time,

and proposed that the failure of diazepam and phenytoin to abort self-

sustaining SE during its maintenance phase implies that seizures evolve cer-tain mechanisms that cause refractoriness to antiepileptic drugs. Although

phenytoin and benzodiazepines become less effective, glutamate antagonists,

such as ketamine (an N-methyl-D-aspartate or NMDA antagonist), are

ineffective initially, but become effective in later stages in animals. In human

beings, intervention within the first 30 minutes of seizure onset was associ-

ated with 80% response to first-line drugs. The response rate declined with

longer intervals to treat, such that more than 60% of the patients who were

in SE for more than 2 hours before initiation of treatment failed to respond

to the first-line treatment [7]. AEDs should be selected in considerationof the patients prior history, medications, allergies, hemodynamic status,

and hepatic and renal function, and the physicians experience and

preference.

Only a few randomized, controlled trials have compared treatment strat-

egies in SE. The most important one was the Veterans Affairs (VA) Status

Epilepticus Cooperative Study [6], which compared the efficacy of four

drugs for the treatment of GCSE. A total of 518 subjects were randomly

assigned to receive phenobarbital (15 mg/kg), phenytoin (18 mg/kg), diaze-

pam (0.15 mg/kg) plus phenytoin (18 mg/kg), or lorazepam (0.1 mg/kg). Thefirst regimen chosen was successful in 55.5% of subjects with overt status,

but only 14.9% of subjects with subtle SE (coma and ictal discharges on

EEG with or without subtle movements). In subjects with overt status,

intravenous lorazepam was most effective. It stopped SE in 65% of the

cases; phenobarbital, 58%; diazepam plus phenytoin, 56%; and phenytoin

alone, 44%. The only statistically significant differences were between phe-

nytoin alone and lorazepam. Hypotension requiring treatment occurred

more often in subjects with subtle SE, but there were no differences between

the medications. Overall mortality was twice as high for subjects whose SEwas not controlled with the first drug as for subjects who had successful

response to the first regimen. In the VA cooperative study, subjects who

failed the first treatment rarely responded to the second (7%) or third

(2.3%), raising the question of the efficacy of a second and third drug [6,45].

Lorazepam has many advantages over other drugs. It can be given

quickly and has a duration of antiseizure effect of 12 to 24 hours [46]. Lep-

pik and colleagues [46] compared lorazepam with diazepam for the treat-

ment of SE in 78 subjects enrolled in a double-blind, randomized trial.

Time of onset of the two drugs was almost the same. Seizures were con-trolled in 89% of the episodes treated with lorazepam and in 76% treated

with diazepam. These results, combined with the more recent and more

definitive VA cooperative study, have led to intravenous lorazepam

(0.1 mg/kg) becoming a clear drug of choice for initial treatment of SE.

Phenytoin or fosphenytoin is the most frequently recommended agent

used following benzodiazepines [12,47], but recent data indicate that IV



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valproate may be as good and perhaps even better [10,11]. A phenytoin load

of 18 mg/kg to 20 mg/kg intravenously is recommended. Phenytoin solution

is highly caustic to veins and may cause tissue necrosis in case of extravasa-tion, limiting the rate of administration to a maximum of 50 mg/min. Fast

administration carries the risk of hypotension and cardiac arrhythmias and

requires close monitoring of blood pressure and ECG. Fosphenytoin

sodium is a phenytoin prodrug, preferred over phenytoin because of its

water solubility, allowing faster administration with less risk of venous irri-

tation. It is rapidly dephosphorylated in the bloodstream to phenytoin, with

a half-life of 10 to 15 minutes, reaching therapeutic free phenytoin levels

slightly faster than intravenous phenytoin. Cardiac complications and hypo-

tension still can occur with fosphenytoin (owing to the phenytoin).Free phenytoin levels should be monitored with a goal of 1.5 mg/mL to 2.5

mg/mL, which is equivalent to a total phenytoin level of 15mg/mL to 25mg/mL

in the presence of normal protein binding [13]. Free levels may be excessively

high in the presence of low albumin or coadministration of highly protein

bound drugs (eg, valproic acid), and this may confuse the clinical presentation

by worsening encephalopathy or paradoxically exacerbating seizures. An-

other common problem in ICU patients who are receiving parenteral nutrition

is decreased enteral phenytoin absorption and blood levels after conversion of

intravenous phenytoin to oral phenytoin, with subsequent poor seizure con-trol. In a study by Bauer [48], phenytoin serum levels decreased an average

of 71.6% when parenteral nutrition was given concurrently. This problem

may be overcome if parenteral nutrition is withheld temporarily before and

after administration of oral phenytoin to these patients.

An alternative as second-line therapy is phenobarbital, with a loading

dose of 15 mg/kg to 20 mg/kg. Maximum rate is 50 mg to 100 mg per min-

ute. Recommended serum levels in SE are greater than 30 mg/mL. It has

a prolonged half-life in adults, ranging from 50 to 150 hours, and is a power-

ful sedative that may contribute to coma and mask the evolution of the neu-rologic examination in critically ill patients. In addition, Phenobarbital may

cause respiratory depression and hypotension via vasodilation and cardiac

depression. The main advantages are intravenous availability, prolonged

effect, and good efficacy in controlling SE.

Interest in valproic acid (VPA) for the treatment of SE has increased with

the availability of an intravenous formulation. It is highly bound to plasma

protein, similar to phenytoin, with similar caveats about its use. It differs

from older generation AEDs in being an enzyme inhibitor, rather than

inducer; one must be vigilant for increased levels or effect of concomitantP-450-metabolized medications. There is a dramatic fall of its level after

addition of antibiotics, such as meropenem or amikacin, possibly owing

to accelerated renal excretion [49].

Valproate has broad-spectrum activity against all types of seizures, in-

cluding postanoxic myoclonus. A major advantage is not causing sedation

or hypotension, which renders it a drug of choice in patients with a do



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not intubate status or phenytoin allergy (although it has not been approved

by the United States Food and Drug Administration for use in SE). Intra-

venous VPA has been used in open-label studies with seizure control inapproximately 80% of cases [50,51]. Giroud and colleagues [51] found

that intravenous VPA stopped SE in 19 of 23 patients within 20 minutes.

Sinha and Naritoku [52] reviewed hospital records of 13 elderly patients

with SE and cardiovascular instability who received intravenous valproate

therapy. A loading dose of valproate of 25.1 plus or minus 5 mg/kg (range

14.7 mg/kg32.7 mg/kg), at a rate of 36.6 plus or minus 25.1 mg per minute

(range 6.3 mg100 mg per minute), was used. There were no significant

changes in blood pressure, pulse, or increases of vasopressor dosages. All

patients died as a result of their underlying medical illness or withdrawalof life support. Peters and Pohlmann-Eden [53] reported a series of 102 adult

patients who received standardized high-dose intravenous VPA in various

situations, including 35 patients who were in SE; 85.6% had interruption

of clinical seizure activity within less than 15 minutes, followed by freedom

from seizure during intravenous therapy for at least 12 hours. Subgroup

analysis showed efficacy of intravenous VPA in 27 of 35 patients

with SE (77.1%). None had serious side effects, including sedation or hypo-

tension. Adverse effects from valproate include hyperammonemic encepha-

lopathy, pancreatitis, parkinsonism, rare liver failure, and not-so-rarethrombocytopenia, which is usually dose related and benign. Other types

of VPA-associated bleeding diatheses have been observed, including platelet

dysfunction and hypofibrinogenemia.

Two recent prospective, randomized trials compared the efficacy and tol-

erance of IV valproate to IV phenytoin (PHT) in patients with SE. In one of

the studies, Agarwal and colleagues [10] randomized 100 subjects in SE who

had persistant seizures after IV diazepam to either IV VPA or IV PHT

(20 mg/kg load for both). No difference in efficacy or tolerance was detected

between the two drugs. The other study by Misra and colleagues [11] wasa randomized controlled trial that compared IV VPA (30 mg/kg given

over 15 minutes) and IV PHT (18 mg/kg) as first line treatment for convul-

sive SE (no benzodiazepines were used before this); if the given drug failed,

they were switched over to the other agent. The investigators found that

VPA was more effective in controlling the SE, both as the initial drug

(66% versus 42%, P .046), and even more dramatically as the second

drug (79% versus 25 %, P .004).

If seizures persist, intubation becomes required if not performed yet, and

continuous intravenous drugs become necessary to control the SE. Onlya few agents are available for control of refractory SE, and no consensus

has been reached regarding the degree or duration of the required EEG sup-

pression. In a retrospective review, Rossetti and colleagues [54] showed that

achievement of burst suppression on EEG did not correlate with a better

outcome. Further studies are needed to evaluate the relationships between

the depth of burst suppression, duration of therapy, and outcomes. Claassen



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and colleagues [55] did a systematic review of the literature on use of pento-

barbital, propofol, and midazolam in refractory SE and found that most

patients already had been treated with phenytoin, benzodiazepines, and phe-nobarbital before continuous intravenous therapy. Duration of infusion was

longest with midazolam and shortest with pentobarbital. Continuous EEG

monitoring was performed significantly less often in patients treated with

pentobarbital (27%) than in patients treated with midazolam or propofol,

possibly explaining its seemingly higher efficacy. Continuous EEG is

recommended because most seizures in patients with refractory SE are non-

convulsive and unnoticeable at the bedside [18]. Commonly used therapies

for refractory SE include the following.

Barbiturates

Acting on GABA receptors, effects of barbiturates include cerebral and

respiratory depression, myocardial depression, vasodilation, hypotension,

and ileus. Administration of continuous intravenous barbiturates requires

support with mechanical ventilation, intravenous fluids and vasopressors,

and continuous EEG monitoring (or frequent prolonged checks if continu-

ous EEG is unavailable) to identify breakthrough seizures and to assess the

level of suppression.

Thiopental is one the preferred drugs for treating SE in the ICU in theUnited Kingdom after failure of the initial treatment [56]. The recommended

dose is 2 mg/kg to 4 mg/kg bolus, followed by infusion of 3 mg/kg to 5 mg/kg

per hour, although higher doses commonly are used. Thiopental is metabo-

lized by the liver and should be withdrawn slowly 24 hours after resolution

of electrographic seizures. At serum levels less than 30 mg/L, the elimination

half-life is 3 to 11 hours, but this may increase to 60 hours with higher serum

levels and result in a prolonged recovery time.

Pentobarbital has a slower action than thiopental, but cerebral concen-

trations are maintained longer. The loading dose is 5 mg/kg and shouldbe repeated until seizures stop, with a maximum bolus rate of 25 mg to

50 mg per minute. Infusion rates are 0.5 mg/kg to 10 mg/kg per hour, tra-

ditionally titrated to burst suppression on EEG. In some patients, seizures

still can occur from a suppression-burst background, and in other patients

seizures are fully controlled without reaching suppression burst. The half-

life is longer than thiopental (2030 hours). On drug withdrawal, seizures

may recur. Although not clearly investigated, several paroxysmal or periodic

patterns on the ictal-interictal continuum have been observed on EEG dur-

ing pentobarbital withdrawal; these patterns sometimes resolve without in-tervention as the withdrawal of barbiturate continues.

Benzodiazepines

Midazolam, which also acts on the GABA-A receptor, is increasingly

used as an alternative to intravenous barbiturates because it is shorter acting

and causes fewer hemodynamic disturbances. The recommended loading



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dose is 0.2 mg/kg, and boluses should be repeated every 5 minutes until

seizures stop, up to a maximum total loading dose of about 2 mg/kg. The

initial rate is 0.1 mg/kg per hour with a continuous dose range: 0.05 mg/kg to 2.9 mg/kg per hour (this is higher than in older literature, and even

higher doses are occasionally used). The elimination half-life is 1.5 to 3.5

hours initially; with prolonged use, there may be tolerance, tachyphylaxis,

and significant prolongation of half-life, up to days. Naritoku and Sinha

[57] reported slow clearance of midazolam in two patients after several

days of continuous therapy, probably related to accumulation of midazolam

in peripheral compartments (adipose tissue) with subsequent redistribution

back to the central compartment. The time to stop SE is usually well under

1 hour, with a duration of effect lasting minutes to hours. Respiratory de-pression and hypotension are common side effects.

Propofol

Also a GABA-A receptor agonist, propofol has a rapid onset of action of

less than 3 minutes, quick redistribution into body compartments, and easy

reversibility, which has led to widespread use for the sedation of critically ill

patients. The recommended dose is a bolus of 1 mg/kg to 2 mg/kg, followed

by a continuous infusion of 1 mg/kg to 15 mg/kg per hour with a recommen-

ded maximum dosage of 5 mg/kg per hour if maintained for days. There isno consensus regarding total duration of induced coma when seizures are

controlled, but 12 to 24 hours seems to be the most commonly used dura-

tion. Side effects include respiratory depression, hypotension, bradycardia,

and the more recently recognized propofol infusion syndrome, consisting

of metabolic acidosis, cardiac failure, rhabdomyolysis, hypotension, and

death. In 2001, the United States Food and Drug Administration commu-

nicated that pediatric ICU patients given propofol for sedation had higher

death rates that patients who received other standard anesthetic agents. In

recent years, case reports regarding propofol infusion syndrome in adultsalso have emerged. Risk factors were mostly prolonged infusion (O48

hours), high doses (O5 mg/kg per hour) [58,59], severe head injury [60],

lean mass, and concurrent use of catecholamines or steroids [59]. It has

been suggested that concomitant use of propofol with catecholamines may

precipitate this syndrome. Cray [61] proposed that either propofol or its

lipid soluent affects cellular metabolism, causing a biochemical break in

the respiratory chain that leads to lactic acidosis and multiple organ dys-

function. It is prudent to avoid prolonged use of propofol (O48 hours) at

higher doses (O5 mg/kg per hour), and once used creatine kinase and lacticacid should be followed closely. Rossetti and colleagues [62] used concom-

itant intravenous clonazepam and propofol at the lowest effective dose. In

their group of 31 patients with refractory SE, none had evidence of propofol

infusion syndrome, and only one had isolated hyperlipidemia. Overall mor-

tality was 22%, which is low for patients with refractory SE, and there were

no neurologic sequelae in 20 of the 25 patients who survived. This was the



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first published series of SE patients treated with propofol in which there was

not a very high mortality rate.

Other antiepileptic drugs

There has been increasing use of levetiracetam in ICU patients. Levetir-

acetam, the mechanism of action of which is not well understood but in-

volves binding to the synaptic vesicle protein SV2A, has the advantages of

rapid titration, no drug interactions, and a good safety profile. It is less

than 10% protein bound, with a plasma half-life of 6 to 8 hours. The liver

does not metabolize levetiracetam, thus making it an excellent choice in pa-

tients with hepatic failure. Dosage should be reduced in the presence of renal

impairment, and supplemental doses should be given after dialysis (approx-imately 50% of the pool of levetiracetam in the body is removed during

a standard 4-hour hemodialysis procedure) [63,64]. The recent introduction

of the intravenous formulation makes it use more ideal in the ICU. Intrave-

nous levetiracetam with a mean loading dose of 944 mg was studied by-

Knake and colleagues [65] in 18 subjects with benzodiazepine-refractory

focal SE. SE was controlled in all subjects, with only 2 of the 18 subjects

requiring additional antiepileptic drugs following the IV levetiracetam.

No severe adverse effects were noted.

Topiramate, administered via the nasogastric route, is reported to be ef-fective in aborting SE [66], possibly owing to the multiple mechanisms of

action. There is evidence of a neuroprotective effect of topiramate, with

attenuation of seizure-induced neuronal injury noted in experimental SE

[67]. Several other oral AEDs have been used for refractory seizures or

SE in the ICU, but there are no comparative data to help select one over

the other. If topiramate or zonisamide is used, one should remain vigilant

for metabolic acidosis (particularly in combination with propofol) because

they are both carbonic anhydrase inhibitors. If carbamazepine or oxcarba-

zepine is used, one should be attentive to hyponatremia.Ketamine is an anesthetic and NMDA receptor antagonist that has been

used in refractory SE with success in animal models [6870]. Borris and

associates [68] showed that in contrast to its failure to control early SE,

ketamine is more effective in treatment of prolonged SE, the opposite of

phenobarbital, in an animal model of SE (rats who underwent electrical

stimulation of the hippocampus). There is evidence that it also may be an

agonist at the GABA-A receptor [70], that it has neuroprotective effects,

and that it does not compromise the hemodynamic status of ICU patients.

Few cases have been reported in human beings [71,72], but no clear evidencesupports its use in SE at this point. Severe neurotoxicity has been reported

secondary to NMDA-receptor antagonism, so further studies and caution

are needed before its widespread use in SE.

The efficacy of isoflurane, an inhalational anesthetic agent, in aborting sei-

zures in nine patients with refractory SE was shown in an article by Kofke and

colleagues [73], who also noted that seizures tended to recur on



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discontinuation. They recommended its use only when other agents have

failed. Mirsattari and colleagues [74] described seven patients with refractory

SE, who received isoflurane with or without desflurane with a goal of burstsuppression on EEG to control SE. Four patients had good outcomes, and

three died; all experienced hypotension. Other complications included atelec-

tasis and ileus.

Steroids, intravenous immunoglobulins, plasmapheresis, and adrenocor-

ticotropic hormone all have been reported to help control seizures, mostly in

the pediatric population or as part of syndromes known to involve immune

mechanisms. More research is needed to clarify the indications and conse-

quences of each of these therapies [75].

Extensively used in cardiology, lidocaines main advantages are a short half-life and a relative lack of respiratory and cerebral depressant effects. It is 65%

protein bound with a distribution half-life of less than 10 minutes in adults and

rapid hepatic metabolism. Pascual and colleagues [76] reported 42 episodes of

SE treated with a lidocaine intravenous bolus dose of 1.5 mg/kg to 2 mg/kg

over 2 minutes; 31 responded to the first injection, but seizures recurred in 19.

Eleven were nonresponders to the first and second bolus. Effects are thought

to be temporary because of its rapid clearance. It is useful as a short-term

AED, particularly in patients with preexisting respiratory disease as an alterna-

tive to benzodiazepines. Toxic effects include hypotension, sedation, and otherneurologic side effects such as hallucinations or exacerbation of seizures.

Acute seizures in special intensive care situations

Seizures and liver disease

The reported incidence of seizures in liver failure ranges from 2% to 33%

[77]. Postulated pathophysiologic factors include hyperammonemia, abnor-

mal glutamine metabolism, cerebral ischemia, cerebral edema, accumulation

of toxins, or associated biochemical abnormalities such as hyponatremia,hypomagnesemia, and renal failure [7880]. Elevation of endogenous benzo-

diazepines may lower the incidence of seizures in hepatic failure.

Ficker and colleagues [79] reviewed EEGs of 118 patients with hepatic

encephalopathy and identified epileptiform abnormalities in 15%. Twelve

patients had clinical seizures, and most of them died or deteriorated. There

are rare reports of SE [80]. It is important to detect subclinical ictal activity

in these patients because seizures increase cerebral oxygen requirements and

may worsen brain edema and prognosis. Ellis and colleagues [78] evaluated

42 subjects in grade III or IV hepatic encephalopathy using a bedside cere-bral function and activity monitor (two-channel, five-lead EEG designed to

study background activity, not seizures). Twenty subjects were given phe-

nytoin, and 22 acted as controls. Subclinical seizure activity was reported

in 3 (15%) and 10 (45%) subjects of the treated and control groups.

Autopsy examinations available in 19 subjects showed signs of cerebral

edema in only 22% of the phenytoin-treated subjects, compared with 70%



17/24

of the controls (P!.033). This study emphasizes the importance of contin-

uous brain monitoring in the critically ill, as outlined earlier, although we

recommend performing EEG with a full set of electrodes to allow accuratediagnosis and differentiation of seizures from other patterns, such as tripha-

sic waves, artifact, and high-voltage slowing. Even with a full set of elec-

trodes and board-certified electroencephalographers, this differentiation

can be challenging or impossible [37,8183].

The overall therapeutic approach of seizures and SE in these patients

does not differ from others except that special considerations should be

made with the use of AEDs metabolized by the liver. The degree of hepatic

failure might affect the AEDs metabolism; in early hepatitis, there may be

increased blood flow to the liver with relatively normal hepatic function,a situation that may increase hepatic clearance of the drugs. In more

advanced hepatic failure with necrosis, hepatocellular tissue decreases, and

serum levels of drugs cleared by the liver may increase [84]. Hypoalbumine-

mia, also encountered in malnutrition and infectious, renal, or neoplastic

diseases, can lead to increased free unbound blood levels of some AEDs

that are highly bound to protein, such as phenytoin and VPA. Monitoring

free levels of these drugs, especially phenytoin, avoids toxicity (which can in-

clude worsening encephalopathy and myoclonus). Other AEDs favored in

this situation would be drugs with low or no protein binding effect orwith primarily renal metabolism, such as gabapentin, pregabalin, and leve-

tiracetam; an intravenous form of levetiracetam is now available. In a study

in animal models, Gibbs and colleagues [85] showed that levetiracetam has

neuroprotective effect against mitochondrial dysfunction and oxidative

stress seen after SE. This effect also has been reported with topiramate

[67,86], but further studies are needed for both of these agents.

Seizures and renal disease

Acute renal failure is associated with uremic encephalopathy andseizures, which may result from metabolic abnormalities, such as hyponatre-

mia, calcium disorders, uremia, hypertensive encephalopathy, or dysequili-

brium syndrome seen with hemodialysis. The incidence of seizures in

patients undergoing hemodialysis for renal failure has been estimated at

2% to 10% [8789].

Treatment of these patients may be problematic because of alteration of

AED pharmacokinetics in uremia, decreased albumin, and dialysis effects.

AEDs predominantly eliminated by the kidneys, such as gabapentin, pregaba-

lin, and levetiracetam in particular, but also topiramate and phenobarbital,should be used at much lower doses in renal failure. Some carbonic anhydrase

inhibitors, such as zonisamide and topiramate are relatively contraindicated

in patients at risk of nephrolithiasis or when the etiology of the renal failure

is unknown because they increase renal bicarbonate loss and stone formation.

As far as dialysis effects, drugs that are highly protein bound (phenytoin, val-

proate, tiagabine; moderately high binding with carbamazepine) are not



18/24

dialyzed significantly (although the unbound portion is higher than usual in

these patients, so the effect is unpredictable) and do not usually need to be re-

placed. Some AEDs are moderately affected (lamotrigine, 55% proteinbound, 20% dialyzable) and might require predialysis and postdialysis level

monitoring to make necessary adjustments (postdialysis supplementation).

AEDs requiring replacement after dialysis are gabapentin, pregabalin, etho-

suximide, levetiracetam, phenobarbital, and topiramate. In general, the

serum concentration of these AEDs decreases by 50% after dialysis.

Seizures in transplant patients

Seizures in transplant patients are frequent and may arise from metabolic

abnormalities such as hyponatremia, hyperglycemia or hypoglycemia, neu-rotoxicity from immunosuppressive agents or other medications (eg, high-

dose intravenous antibiotics), infections including brain abscess, cerebral

edema, cerebral infarction, or postanoxic encephalopathy secondary to

hypovolemia or septic shock [90,91]. The incidence of seizures in transplant

patients varies depending on the transplanted organ (Table 2), but the true

proportion is likely underestimated because none of the studies done so far

used continuous EEG in these patients to rule out nonconvulsive seizures.

Some of the reports include encephalopathy as a neurologic complication

after transplant without clarifying EEG findings.One third of liver transplant patients are believed to have seizures [92,93].

Wijdicks and colleagues [105] reviewed 630 orthotopic liver transplant recip-

ients and found generalized tonic clonic seizures in 28 (4%), none of whom

had history of seizures before the transplant. Most seizures in critically ill

patients are now known to be nonconvulsive [13,17,18,106]; this is likely

an underestimation of the prevalence of seizures in these patients. Most sei-

zures occurred in the postoperative period, usually on days 4 to 6. Phenytoin

effectively treated clinical seizures in all 28 patients and was successfully dis-

continued in all survivors shortly thereafter. One possible explanation forthis timing of seizures is that there is withdrawal from endogenous benzodi-

azepines in the post transplant setting as hepatic clearance dramatically in-

creases. Immunosuppressant drug neurotoxicity is the most commonly cited

etiology, particularly toxicity associated with the calcineurin inhibitors cy-

closporine and tacrolimus. These agents are linked to a wide spectrum of

Table 2

Seizures after transplantion

Organ transplanted Incidence of seizures

Liver 25% [92]30% [93]

Kidney 1% [94]5% [95]31% [96]

Heart 2% [108,109]6.5% [97]15% [98]

Lung 22% [99]27% [100]

Bone marrow 3% [101]7.5% [102]12.5% [103]

Pancreas 13% [104]



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neurologic abnormalities, particularly in liver transplant patients, including

tremor, visual hallucinations, speech difficulties, cortical blindness, posterior

cerebral edema (also known as posterior reversible encephalopathy syn-drome), and seizures. Factors that may promote the development of serious

complications include advanced liver failure, hypertension, hypocholestero-

lemia, elevated cyclosporine or tacrolimus blood levels, and hypomagnese-

mia. Nonconvulsive SE should be considered in the differential diagnosis

of delirium and agitation in the post-transplant period, and continuous

EEG monitoring should be obtained. (A 30- to 60-minute EEG would de-

tect only one third to one half of cases with nonconvulsive seizures

[18,106].) In cardiac transplant patients, certain AEDs should be used

with caution because of the risks of arrhythmias (phenytoin, carbamaze-pine), hyponatremia (carbamazepine, oxcarbamazepine), and cardiovascu-

lar depression (phenobarbital).

Anticonvulsant use is valuable in the short-term, but data are unclear

regarding duration of treatment. This should be decided on a case-by-case

basis depending on the etiology and the radiologic and electrographic find-

ings. If there is an acute symptomatic explanation for seizures that has been

corrected, there is no indication for prolonged AED use. In liver transplant

patients, phenytoin may be needed for rapid seizure control, and levetirace-

tam also may be used as discussed earlier. Gabapentin, pregabalin, and top-iramate are other agents that can be advanced relatively quickly.

Medication interactions constitute another concern in the transplant

population. Phenytoin decreases absorption of cyclosporine [107], and all

hepatic enzyme inducers (including phenytoin, carbamazepine, and pheno-

barbital) can increase the clearance of cyclosporine, methylprednisolone,

and many other medications dramatically.

Summary

Seizures occur in critically ill patients in various conditions. In all situations,

it is crucial to identify potential causes or contributors, particularly reversible

factors, such as metabolic disturbances, fever, hypoxia, and medications. For

SE, it is imperative to begin treatment as soon as possible and to treat until suc-

cess is verified with EEG or the patient returns to normal mental status.

Nonconvulsive seizures are underdiagnosed. Most seizures in critically ill

patients are nonconvulsive and can be detected only with EEG monitoring.

The authors recommend continuous EEG monitoring in critically ill patients

with alteration of mental status, especially if there is concurrent acute braininjury, prior epilepsy, a prior clinical seizure or SE, fluctuating mental status,

coma, abnormal eye movements, or subtle twitching. Nonconvulsive seizures

are associated with neuronal metabolic stress, increased edema and mass ef-

fect, and worse clinical outcome. Future studies are needed to determine

whether greater use of EEG monitoring and early or more aggressive treat-

ment of nonconvulsive seizures would improve the outcome of these patients.



20/24

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