DEFINITIONS AND EPIDEMIOLOGY Seizures—transient signs, symptoms, or both that are due to abnormal 

excessive or synchronous neuronal activity in the brain—can be either partial (focal) or generalized. Partial or focal 
seizures are limited to a particular region of the brain, and their clinical manifestations reflect the function of that 
brain area. In generalized seizures, rapid spread from brain areas with widespread cortical and subcortical 
connections produces loss of consciousness from the onset. The earliest manifestations of a seizure offer the best 
clue to its origin. Thus, patients with seizures beginning in the medial temporal lobe may experience a stereotyped 
odor followed by alteration in consciousness and automatisms, whereas patients with seizures begin- ning in the 
motor cortex experience contralateral jerk- 

Treatment of Acute and Remote 

Symptomatic Seizures Barbara S. 
Koppel, MD 
Corresponding author Barbara S. Koppel, MD New York Medical College Department of Neurology, Metropolitan Hospital 
Center, Room 7C5, 1901 First Avenue, New York, NY 10029, USA. E-mail: bsk0909@aol.com Current Treatment Options in 
Neurology 2009, 11:231–241 Current Medicine Group LLC ISSN 1092-8480 Copyright © 2009 by Current Medicine Group 
LLC 

Opinion statement 
In  principle,  the  use  of  anticonvulsant  drugs  does  not  differ  between  acute  and  remote  symptomatic  seizures,  but 
control  of  acute  symptomatic  seizures  requires  simultaneous  treatment  of  the  underlying  etiology.  Prevention  of 
remote  seizures  when  the risk is known to be high has been the subject of intense efforts at anti- epileptogenesis, but 
the  optimal  duration  of  treatment  after  an  injury  is  not  yet  known.  Appropriate  evaluation  of  a  seizure  depends  on 
individual  circumstances,  but  findings  on  examination,  laboratory  tests  (serum  electrolytes,  magnesium,  glu-  cose, 
assessment  of  hepatic  and  renal  function),  and brain imaging (CT scan or MRI) are necessary to determine the most 
likely  cause.  Lumbar  puncture  is  always  required  when  there  is  suspicion  of  meningitis  or  encephalitis.  Preferred 
medica-  tions  for  treatment  of  acute  symptomatic  seizures  or  status  epilepticus  are  those  available  for  intravenous 
use,  such  as  benzodiazepines,  fosphenytoin or phenyt- oin, valproate, levetiracetam, and phenobarbital. Diazepam is 
also  available  as  a  gel  for  rectal  administration.  Seizures  that  occur  in  patients  with  epilepsy  because  of  missed 
antiepileptic  drugs  or  inadequate  serum  levels  should  be  treated  with  additional  doses  of  their regular medications; 
loading  doses  can  be  administered with minimal toxicity in tolerant patients. Surgery is rarely necessary in the acute 
setting  except  for  intracerebral  lesions  with  rapidly  rising  intracranial  pressure  and  impending  herniation.  After 
seizures are controlled, the provoking condition must also be determined and treated. 

Introduction 
ing  or  posturing  of  the  limbs.  Sometimes  a  focal  origin  can  be  inferred  by  transient  focal  weakness  or  unilateral 
Babinski  response  immediately  after  the  ictus.  Imaging  and  focal  epileptiform  discharges  on  electroencephalog- 
raphy (EEG) can also help in determining the site and cause of seizures. 
Seizures  occur  by  age  80  in  up  to  10%  of  the  US  population.  Symptomatic  seizures  are  secondary  to  an 
identifiable  condition,  in  contrast  to  idiopathic  seizures.  Table  1 lists diseases that lead to symptomatic seizures [1]. 
These  are  subdivided  into  early  or  acute  (occur-  ring  within  1  to  2  weeks  in  the setting of an illness that is actively 
affecting  brain  function, such as anoxia, meningitis, or metabolic encephalopathy) or remote (occurring after a latent 
period of epileptogenesis that 
 
232 Epilepsy 
Table 1. Causes of acute and remote symptomatic seizures* 
Structural causes 
Cerebrovascular disease Hemorrhage (intracranial, intraventricular or subarachnoid, subdural, epidural, and following venous 
thrombosis 
or vasculitis) Ischemia (cortical, acute, or previous) Indirect or small-territory disease (hypertensive encephalopathy, eclampsia, 
posterior reversible encephalopathy 
syndrome, vasculitis, or collagen-vascular disease) Trauma (penetrating > contusion; rare after concussion) Infection 
Abscess (bacterial, parasitic [especially cysticercosis and malaria], toxoplasma, fungal [especially aspergillus]) Viral (especially 
herpes simplex or zoster in an immunosuppressed patient, HIV alone [either early or late], West Nile virus, 
rarely progressive multifocal leukoencephalopathy) Meningitis (remote only with sequelae of infection, such as focal deficit or 
developmental delay) Tumor (primary or metastatic) Demyelination 
Acute disseminated encephalomyelitis Multiple sclerosis (rare, but occurs with acute plaque abutting cortex) Congenital 
malformations 
Tuberous sclerosis, Sturge-Weber, fetal alcohol syndrome, migration disorders; prenatal infection such as 
rubella, toxoplasmosis Intracranial surgery Metabolic or toxic causes Hypoxia, global ischemia, hypoglycemia, or 
hyperglycemia (seizures may be focal or myoclonic) Hepatic or renal failure Electrolyte imbalance (hyponatremia, 
hypomagnesemia, hypophosphatemia, hypocalcemia) Drug intoxication or overdose (cocaine, amphetamine, phencyclidine, 
γ-hydroxybutyric acid [GHB]), Ecstasy, methylphe- 
nidate, anticonvulsants (with level ≥ 2 × upper limit of therapeutic) Antidepressants including tricyclics, bupropion in doses > 
450 mg/d Drug or alcohol withdrawal (anticonvulsants, sedative/anxiolytic, hypnotic, marijuana?) Neurotoxins (pesticides, 
organophosphates used as military poisons) Sepsis Autoimmune disorders, especially those affecting central nervous system, 
such as lupus, Wegener’s granulomatosis Vitamin deficiency (pyridoxine, thiamine?) Medications Antibiotics (penicillin, 
quinolones, isoniazid, metronidazole) Antiarrhythmics (lidocaine, mexiletine, digoxin) Bronchodilators (theophylline, 
metaproterenol sulfate [overdose]) Antipsychotics/antidepressants/mood stabilizers (lithium, bupropion, maprotiline, clozapine, 
phenothiazines in high doses) Antispasticity (baclofen) Analgesics (meperidine, tramadol [high doses], fentanyl) 
Immunosuppressants (cyclosporine, tacrolimus, interferons) Chemotherapeutics (chlorambucil, busulfan) Radiographic contrast 
with iodine, especially when used for intracranial angiography 
*In order of frequency. 
 
Treatment of Acute and Remote Symptomatic Seizures Koppel 233 
may last for years). If they recur, the latter are referred to as remote symptomatic epilepsy; if isolated, they are called 
remote  symptomatic  seizure.  In  a  series  of  cases  of  symptomatic  epilepsy,  the  brain  injuries  most  com-  monly 
responsible  were  stroke  (21%),  trauma  (7%),  or  tumor  (11%) [1]. In certain populations such as patients with AIDS 
or patients from endemic areas, infections such as neurocysticercosis or toxoplasmosis cause the majority of seizures 
[1]. 
Prolonged  or  repeated  symptomatic  seizures  can  lead  to  long-term  pathologic  changes  that  may  cause 
spontaneous  seizures  and  memory  dysfunction,  so  every  effort  should  be  made  to  control  these  seizures.  In  addi- 
tion, seizures and postictal clouding of consciousness can obscure the baseline mental status. 
Generalized  tonic-clonic  and  myoclonic  seizures  are  often  symptomatic  of  metabolic  abnormalities,  alco-  hol 
abuse  or  withdrawal,  toxins, medication overdose, hypoxia, hypoglycemia, or meningitis/encephalitis. Gen- eralized 
seizures  occurring  in  the  setting  of  fluctuating  consciousness  or  encephalopathy  and  accompanied  by  motor  signs 
such  as  asterixis,  myoclonus,  and  tremor  are  usually  due  to  metabolic  derangement.  Patients  who  also  exhibit 
delirium,  tachycardia,  and  hallucinations  usually  have  illicit  drug  or  alcohol  intoxication  or  withdrawal.  Focal 
signatures  to  the  seizure  can  sometimes  occur  in  generalized  conditions  such  as  hyperglycemia,  hepatic 
encephalopathy, or cocaine toxicity. 
Status  epilepticus  (SE)  refers  to  repeated  seizures  lasting  more  than  30  minutes  without  regaining  normal 
consciousness.  Newer  models  take  into account the probability that seizures lasting more than 5 minutes will evolve 
to  SE.  SE  occurs  at  a  rate  of  18  to  41  episodes  per  100,000  people  per  year.  Acute  symptomatic  seizures  are 
responsible  for  50%  to  70%  of  episodes,  remote  symptomatic  seizures  are  involved  in  20%  to  30%, and the others 
are  idiopathic  or  cryptogenic  [2••]  (Table  2).  Rates  of  SE  are  higher  in  critical care units because of the underlying 
conditions  [3•].  SE  may  evolve  to  non-  convulsive  status  epilepticus (NCSE), with more subtle motor signs such as 
twitching  of  eyelids,  nystagmoid  eye  jerks,  and  irregular  tremor  of  the  fingers  or  toes.  EEG  patterns  may  evolve 
from  spike-wave  discharges  to  peri-  odic epileptiform discharges, burst suppression, slowing, amplitude depression, 
and  irregular  sharp  waves.  The  mortality  rate  for  NCSE  is  39%  in  comatose  patients  and  18%  overall;  these  rates 
reflect  the underlying etiol- ogy, as mortality is only 3% in patients with preexist- ing epilepsy [2••]. Similarly, SE is 
easier to manage in patients with preexisting epilepsy. 
CAUSES OF SYMPTOMATIC SEIZURES Cerebrovascular disease Stroke causes remote epilepsy in 11% of 
patients and is the leading cause of seizures in the elderly, account- ing for 55% of seizures in people over 65 years 
of age. 
Table 2. Causes of status epilepticus 
Cause  %  Antiepileptic  failure  to  maintain  level  20  Prior  cortical  injury  15  New  stroke  (any  type)  15  Alcohol  withdrawal  or 
intoxication  10  Metabolic  or  electrolyte  derangement  10  Cryptogenic  10  CNS  infection  (acute)  5  Tumor  5  Drug  toxicity 
(therapeutic or illicit) < 5 Hypoxic-ischemic injury < 5 Idiopathic epilepsy, new or old < 5 
CNS—central nervous system. 
Seizures  occur  at  a  rate  of  up  to  8% both early and late following a stroke, with much higher rates (up to 27%) after 
venous  infarct  [4•],  followed  by  subarachnoid  hemorrhage  (18%),  ischemic strokes, whether embolic or thrombotic 
(15%  of  patients  with  large  volumes  of  damage  in  cortical  regions),  and  intracranial  hemor-  rhage  (12%)  [1,5•]. 
Sludging in sickle cell disease also increases the risk of seizure [6]. 
Even  in  early  seizures,  the  stroke  usually  precedes  the  seizure,  but  if  seizure  is  the  presenting  symptom,  the 
stroke  must  be  addressed  with  appropriate  anticoagulant,  antithrombotic,  thrombolytic,  surgical,  or  other  therapy. 
Hemorrhagically transformed ischemic strokes had the highest rate of early seizure in the series by Alberti et al. [5•]. 
Predictors  of  a  first  seizure  include  the  presence  of  multiple  lesions,  including  prior  strokes,  on  the  initial CT scan 
(OR,  3.6),  along  with  cortical  or  supratentorial  location  (OR,  2.5)  [7].  After early seizures, the risk of later seizures 
is 43%, so short-term anticonvulsant use can be considered [8]. 
After  a  remote  poststroke  seizure,  the  risk  of  a  sec-  ond  seizure  is  54%  to  66%  [8].  Most  anticonvulsants  are 
effective  in  controlling  this  type  of  late  epilepsy  [9,  Class  I].  Venous  thrombosis, being more difficult to control, is 
an  exception  [10],  but  in  one  study  the  OR  for  seizure  in  this  group  was  lowered  to  0.006  by  acute  use  of  an 
unspecified  antiepileptic  drug  (AED)  [11,  Class  I].  EEG  should  not  be  used  to  predict  seizures,  as  up  to  17%  of 
strokes  demonstrate  epileptiform  activ-  ity,  but  a  seizure  actually occurs in only 2%. Some of the first generation of 
anticonvulsants,  though  effective,  have  adverse  neurocognitive  and  cerebellar  effects  that  may  interfere  with 
rehabilitation  efforts  [12,  Class  I],  and  many  protein-bound,  hepatic  enzyme–inducing  anticonvulsants  make 
anticoagulation  difficult.  As  yet, anticonvulsants such as topiramate and gabapentin have not shown neuroprotective 
effects in humans. 
 
234 Epilepsy 
Seizures emerging during thrombolysis are considered a good sign of restoration of blood flow [13]. 
Seizures  occur  more  commonly  when  blood  is  pres-  ent,  whether  parenchymal,  subarachnoid,  or  subdural. 
Monitoring  of 102 patients with intracranial hemor- rhage found seizures in one third, but half of these seizures were 
purely  electrographic  [14].  The  rate  of  seizures  after  subarachnoid  hemorrhage  has  fallen  from  27%  to  5%  of 
patients  with  early  aneurysm  repair,  and  40%  of  subarachnoid  hemorrhage  patients  with  seizures  had  them  at 
presentation.  Nevertheless, the majority of surgeons surveyed in the 1990s still used prophylactic AEDs, which were 
associated  with  poorer  neurologic  outcome  (OR,  1.56)  [15].  Anticonvulsants  that  suc-  cessfully  abort  SE  are 
beneficial in patients who are obtunded because of NCSE. 
Phenytoin and phenobarbital depress the sensorium and increase the risk of hypersensitivity and central fever [16, 
Class II]. Therefore, if no seizures occur in the first month, any AEDs used prophylactically should be dis- 
continued, as neurologic recovery may be impeded [17]. Clot evacuation is dictated by the need to reverse herniation 
or other life-threatening states, as there is no salutatory effect on seizure control. 
Traumatic brain injury Traumatic brain injury accounts for 5% of symptom- atic epilepsy, especially in people under 
age 34 [18•]. The relative risk of developing epilepsy can reach 17 after severe trauma [1] but is only 1.5 in mild 
injury. Risk of recurrence is high; once a remote seizure occurs, there is an 80% recurrence rate. Continuous EEG in 
the acute period following trauma uncovers many silent seizures [19]. Although anticonvulsants can suppress early 
seizures, trials of phenytoin and, more recently, valproate failed to prevent the development of post- traumatic 
epilepsy [20, Class II]. 
Surgery Postoperative seizures occur in 15% to 20% of patients undergoing supratentorial surgical procedures [21]. 
This rate can be suppressed to 1% with AEDs such as levetiracetam and phenytoin [22•], but epilepsy is not 
prevented. Tumors, responsible for 4% of epilepsy cases, often present with a seizure, obscuring the effectiveness of 
prophylactic AEDs [23, Class I]. Seizures are most common with glioma, followed by meningioma and metastases 
[1]. Treatment of the underlying mass may lower the incidence of epilepsy. 
Oncology  patients  receiving  chemotherapy  should  avoid  enzyme-inducing  AEDs,  which  may  lower  the  serum 
level (and efficacy) of the chemotherapeutic agent. 
Medications and dyes Seizures may arise from toxic levels of AED (phenytoin > 40 μg/mL, carbamazepine > 18 
μg/mL) [24], valpro- 
ate  in  patients  with  inborn  errors  of  metabolism  [25],  lamotrigine  overdose  [26],  drug  interactions  during 
polypharmacy,  choice  of  an  inappropriate  AED  for epi- lepsy type (eg, carbamazepine with myoclonic epilepsy), or 
a paradoxical reaction to a correct medication. With- drawal of the inciting AED is the treatment [24]. 
Prevention  of  seizures  related  to  toxic  doses  of  anti-  biotics  is  possible  if  dosage  adjustment  for  weight  and 
creatinine clearance is made a priori [27]. 
Radiographic  contrast  dye  has  provoked  seizures,  especially  when  delivered  directly  to  the  brain  during 
angiography [28]. 
Psychiatric  medications  cause  seizures  most  often  in  overdose  situations,  but  some,  such  as  clozapine, 
maprotiline, and short-acting bupropion, lower the seizure threshold in therapeutic doses [29–31]. 
Alcohol intoxication or withdrawal Alcoholics who experience seizures during withdrawal (usually 24–48 hours 
after lowering or stopping con- sumption) are at increased risk with each detoxification [32••]; seizures also can 
herald delirium tremens [33]. Intoxication, as well as withdrawal, is associated with increased risk of seizures [33]. 
Magnesium may need to be replaced and hyponatremia corrected. 
Acute  symptomatic  seizures  should  be  treated  with  phenobarbital  or  benzodiazepines,  which  may  also  help 
control delirium tremens. 
Alcoholics  also  sustain  epileptogenic  lesions  such  as  subdural  hematomas  and  contusions,  which  may  require 
maintenance  treatment  with  AEDs.  Fear  of  future  noncompliance  should  not  impede  their  use.  Although  many 
AEDs  are  labeled  “Not  to  be  taken  with  alcohol,”  patients  can  be  counseled  to  continue  their  use  even  while 
drinking,  as  the  damage  of  withdrawal  seizure  outweighs  that  of  depression  of  mental  state.  In  fact,  some  AEDs, 
such as topiramate, may benefit addiction. Patients with cerebellar dysfunction should avoid phenytoin. 
Stimulants and sedatives Many stimulants provoke seizures. Nasal insufflation of powdered cocaine is associated 
with partial sei- zures, especially in people with a history of epilepsy in the setting of prior brain insult (eg, stroke) 
[34]. Prevention requires treatment with appropriate AEDs in addition to abstinence from cocaine. The incidence of 
seizures in intravenous users or those who smoke “crack,” with rapid entry of cocaine to the brain, is 9% [33–36]. 
Phenytoin cannot protect from seizures in cases of severe cocaine overdose [35] and AEDs are ineffective in treating 
addiction [37]. 
Seizures  occur  with  the  use  of  some  oral  stimulants,  such  as  MDMA  (methylenedioxymethamphetamine)  or 
“Ecstasy,” but generally only when large doses are ingested or the drug is injected. Therapeutic stimulant medica- 
 
Treatment of Acute and Remote Symptomatic Seizures Koppel 235 
tions (eg, methylphenidate) are safe even in children with epilepsy and attention deficit hyperactivity disorder. 
Heroin  use  increases  the  OR  of  a  seizure to 4.70 for recent use [33]; opiates, including meperidine and fentanyl, 
also cause seizures. 
Sedative  drugs,  including  the  “club”  drug  γ-hydroxy-  butyric  acid  (GHB),  can  cause  withdrawal  seizures  in 
heavy  users  [38].  Common  anxiolytics are associated with seizures in regular users of high doses, such as more than 
4  mg  of  clonazepam,  8  mg  of  alprazolam,  20  mg  of daily diazepam, or, rarely, buspirone or the hypnotic zolpidem. 
Withdrawal  symptoms  occur  ear-  lier  with  shorter-acting  agents  and  are  managed  with  tapering  doses  of 
benzodiazepines in a calm, well- observed environment. 
Treatment of stimulant-induced seizures involves benzodiazepines. SE may require general anesthesia. 
Infections Acute symptomatic seizures have been reported in up to 31% of all patients with central nervous system 
infec- tions; they independently predict mortality, with an OR of 17.6 [39]. The pathophysiology of seizures may 
involve cortical irritation by inflamed meninges, venous thrombosis, abscess, or empyema. In one series, remote 
seizures after meningitis occurred in 7% of children, all of whom had had early seizures and most of whom had 
Treatment 
• First aid for a seizure involves protecting the patient from injury and suffocation. Seizures should be timed so that 
the risk of SE can be recog- nized. Gentle stimulation and reassurance when the seizure ends help to restore 
respiration and orientation. 
• Overall, benzodiazepines such as lorazepam have been most successful in aborting seizures, although phenytoin is 
good for short-term elimination of attacks following head trauma and craniotomy, unfortunately without preventing 
the development of epilepsy. In a meta-analysis of 47 trials, phenobarbital was useful in treating seizures related to 
malaria and fever [21]. 

Status epilepticus 
• While the cause of SE is being sought, basic first aid, oxygen, and sup- port of the airway and circulation should be 
instituted and any metabolic problems should be corrected. Dialysis may be required to eliminate toxins. Blood 
levels of AEDs should be checked; if they are low, reloading should be done and the patient’s AED levels should be 
maintained during man- agement of SE. High therapeutic blood levels—phenytoin, 20–30 μg/mL; phenobarbital, 
35–50 μg/mL; valproate, 80–120 μg/mL (corrected for albumin if needed)—may be necessary. Treatment of SE and 
NCSE requires intravenous medications, or even inhalation anesthesia, with EEG guidance to maintain a 
burst-suppression pattern or even total flattening of brain activity, interrupted by “drug holidays” to see when 
medication can be stopped. Table 3 summarizes a protocol for treatment of SE. 
neurologic  deficits  [39].  Viral  encephalitis,  especially  when  due  to  herpes  simplex,  causes  both  acute  seizures  and 
chronic  epilepsy  that  is difficult to control. Neuro- cysticercosis causes seizures both remotely (36% of patients with 
calcifications)  and  while  the  larval  form  of  Taenia  solium  is  dying.  MRI  performed  within  5  days  of  a  seizure can 
show edema surrounding the calcified lesion, establishing its role in epilepsy [40, Class I]. 
Metabolic derangement Hyponatremia, hypomagnesemia, hypocalcemia, and hypoglycemia all cause seizures [41], 
and epilepsia partialis continua is a feature of nonketotic hyper- glycemia. SE has also been reported during hepatic 
encephalopathy [42]. Hepatic or renal encephalopathy is often accompanied by seizures, myoclonus, tremor, and 
other signs of cortical irritability. Anoxia is the strongest cause of SE. 
Diet and lifestyle Many patients attribute symptomatic seizures to stress. Sleep deprivation and disruption (eg, by 
nocturnal sei- zures, AEDs, or binging on cocaine or amphetamines) are known seizure triggers [43•, Class I]. 
Hypertension and diet are less often provocative, although regular meal consumption is recommended, especially for 
patients who take their AED with food. 
 
236 Epilepsy 
Table 3. Treatment of status epilepticus 
If IV access, 1 ampule of D50 and 100 mg IV thiamine. Lorazepam (4 mg IV) over 2 min, repeat in 5 min if still seizing. If no IV 
access, give diazepam (20 mg PR) or midazolam (10 mg IM, intranasal, 
or buccal). If seizures persist at 10 min, give IV fosphenytoin (20 mg/kg) no faster than 150 mg/min or phenytoin (15–20 mg/kg 
or 1 g in normal saline) no faster than 50 mg/min; monitor blood pressure and ECG. If seizures persist at 20 min, give IV 
valproate (30–40 mg/kg) over 10 min, with 
additional 20 mg/kg over 5 min if needed.* Alternatively, at 20 min give IV phenobarbital (20 mg/kg) at 50–100 mg/min. If 
above measures fail, use general anesthesia with EEG guidance (to discover non- 
convulsive seizures or suspicious patterns such as periodic lateralized epileptiform discharges) with: —Midazolam: Load with 
0.2 mg/kg, repeated every 5 min until seizures stop, 
or give continuously IV at 0.1 mg/kg/h. —Propofol: Load with 1–2 mg/kg; repeat with boluses of same dose every 3–5 min 
until seizures stop or total loading dose of 10 mg/kg has been given; follow with continuous infusion at 2 mg/kg/h. Advantage is 
rapid reversal. Disadvantages are cost and need to follow acid-base status and monitor for propofol infusion syndrome (sudden 
cardiac depression, especially in children). —Pentobarbital: Load with 5–50 mg/kg/min and repeat in 5-mg/kg boluses until 
seizures stop; infuse at 1 mg/kg/h titrated up to 10 mg/kg/h until seizures stop or burst-suppression pattern is seen. Disadvantage 
is depression of blood pressure and unpredictable time required to reverse. In Europe, thiopental is available and used instead of 
pentobarbital. 
*An IV preparation of levetiracetam is available, but it has not been studied in SE. D50—50% dextrose; 
ECG—electrocardiogram; EEG—electroencephalogram; IM—intramuscular; IV—intravenous; PR—per rectum; SE—status 
epilepticus. 
• Cooling is needed only with prolonged seizures and extreme hyper- thermia. Hydration must be carefully balanced 
between circulatory support and avoidance of pulmonary edema and rhabdomyolysis- induced renal failure. 
• Medications used for SE are the same as those for the aborting of acute symptomatic seizures, but ketamine, 
lidocaine, and inhalation anesthet- ics are used only in SE. Ketamine is not yet in common use, but this 
N-methyl-D-aspartate (NMDA) receptor antagonist, used in general anaesthesia, can stop SE. It is given as loading 
dose of 0.5–2 mg/kg with infusion of 10–50 μg/kg per minute, or it can be given intramuscularly (IM) at 4–10 
mg/kg, which will produce a delayed onset of action. Problems include cardiac stimulation and cerebellar damage 
after prolonged use. Lidocaine, given as a bolus or brief intravenous infusion, is rarely used because of its brief 
action and inability to be used in patients with myocardial disease. Isoflurane (at doses of tidal concen- tration of 
0.8%–2%, adjusted to produce a burst-suppression pat- tern on EEG) and desflurane are inhalation anesthetics that 
have been reported to abort refractory SE [2••]. 
• Surgery is sometimes used to remove a lesion or focus. The limited success achieved may be due to the prolonged 
duration of SE that precedes resection. 
• Direct brain stimulation and transcranial magnetic stimulation or electroconvulsive shocks have not been 
systematically studied; theo- retically they should induce aftergoing depolarization and inhibition of repeated spikes. 
 
Treatment of Acute and Remote Symptomatic Seizures Koppel 237 
• NCSE may present with unexplained altered consciousness or coma, where it was detected in 76% of one series of 
continuously monitored ICU patients [44]. Compressed spectral array has demonstrated cyclic seizure patterns, 
thought to be partially controlled NCSE, after general- ized convulsions are no longer occurring [45•]. 
• Overtreatment of epileptiform patterns that may not represent true seizure activity is one area of controversy in the 
management of NCSE and SE. Larger prospective studies are needed, as the medications used are not benign. The 
prognosis is poor in these patients [46•]. 

Pharmacologic treatment 
• Unlike epilepsy, not all symptomatic seizures require pharmacologic treatment, although some AED use is driven 
by the hope that short-term seizure control with medication will truly be “antiepileptic” in the sense of preventing 
later development of epilepsy. SE, even when symptomatic, requires rapid control with AEDs. In some instances, in 
which observing the patient’s mental status is critical, AEDs can be detrimental, as they depress cerebral function. In 
extreme cases, such as SE, their use can depress respiration and circulation, even though they are effective in 
preventing repeated seizures. 
• Benzodiazepines, including diazepam, lorazepam, midazolam, and clonazepam, are often used for isolated 
symptomatic seizures before permanent treatment decisions are made. For SE, benzodiazepines have been the 
treatment of choice for many years, and a clinical trial in 384 patients confirmed lorazepam’s greater efficacy 
compared with phenytoin [47, Class I]. Lorazepam was successful in terminating seizures in 64.9% of patients with 
convulsive SE, phenobarbital in 58.2%, diazepam plus phenytoin in 55.8%, and phenytoin alone in 43.6%. 
Diazepam 
Standard dosage Diazepam has been used intravenously (IV) for many years, in doses of 1 to 5 mg/mL repeated at 
intervals of no less than 15 minutes. It is also available in a rectal gel delivery system (ie, a needleless syringe), in 
doses for children to adults (2.5, 5, 10, 15, and 20 mg), calculated at 0.2 mg/kg. This form can be given by family 
members at home to prevent escala- tion of seizure flurries to SE, with very good absorption from the mucus 
membranes, but it suffers from patient and family reluctance to use a rectal delivery form. Main side effects 
Respiratory depression (may require intubation), venous phlebitis at the 
IV entry site. Special points Advantages include ease of storage, rapid efficacy due to lipid 
solubility, 
and ability to cross the blood–brain barrier. The major disadvantage is its short therapeutic effect due to 
redistribution from brain to fat, where further effects are unpredictable. Cost The cost of the rectal gel is $18 for two 
applications. 
Lorazepam 
Standard dosage 0.1 mg/kg at 2 mg/min IV. Lorazepam is available as 2-mg/mL and 4-mg/mL 
injectable solutions. Main side effects Lorazepam is less irritating to the vein than diazepam and somewhat less 
likely to lead to intubation. Special points Despite its slower therapeutic onset (5 minutes), lorazepam is the most 
frequently used benzodiazepine because of its good duration of action 
 
238 Epilepsy 
(6–8 hours), IM delivery form for patients with no IV access, and famil- iarity to health care workers, who use it 
often to control agitation. Cost $1.28 per 1-mL vial. 
Midazolam 
Standard dosage Midazolam can be used intranasally or as a syrup for intrabuccal use, IM, 
or as IV boluses of 0.2 mg/kg loading and repeated every 5 minutes until seizures stop. In SE, it is given 
continuously IV at 0.1 mg/kg per hour, titrated to seizure cessation or burst-suppression pattern on EEG. 
Contraindications One disadvantage of midazolam is the unpredictable time required for 
reversal of action, but in most patients (with normal hepatic function) no more than several minutes are needed. 
Special points In delirious patients, especially those who have consumed stimulants such 
as methamphetamine, midazolam is also effective as a form of general anesthesia for control of psychosis along with 
SE. Cost $44.59 per bottle of syrup. Injectable forms (1, 2, and 5 mg/mL) cost 
only $0.39 for a 2-mL vial or $5.83 for a 10-mL vial, but the overall cost of prolonged infusions in ICU settings with 
nursing care is much more. 
Clonazepam 
Clonazepam can be delivered IV or IM. It has unpredictable and slow absorption and is rarely used in SE. 
Phenytoin 
Phenytoin has been used for more than 50 years. Its mechanism of action is the blockage of actively repetitively 
firing sodium channels, or “use- dependent” voltage-gated sodium channels. Standard dosage 300–600 mg/d. Oral 
forms of phenytoin are capsules of 30 and 100 mg, 
tablets of 50 mg, and a suspension of 125 mg/5 mL. (The suspension must be shaken vigorously before each use to 
avoid variable dosing.) Main side effects The IV preparation may induce hypotension and must be slowly delivered, 
delaying its therapeutic effect. It also is irritating to the vein and, if extrava- sated, causes severe tissue damage 
(“purple hand syndrome”). Special points Drug levels must be measured to guide dosing, as oral absorption can be 
unpredictable and metabolism varies with other medications and genetics (rapid acetylation). The therapeutic range 
is 10 to 20 μg/mL in most patients. Free levels are optimal, as phenytoin is highly protein bound. A formula to 
correct for low albumin is C corrected = C measured/(0.2 × albumin) + 0.1; in patients with renal failure (creatinine 
clearance < 10 mL/min), the correc- tion factor is 0.1 × albumin. The half-life of phenytoin is 12 hours. Cost $2.61 
per 5-mL vial (50 mg/mL) for the IV preparation. 
Fosphenytoin 
Fosphenytoin is a purely parenteral preparation of the prodrug of pheny- toin that is used for management of SE or 
patients without IV access, who must receive it IM. Standard dosage Fosphenytoin is dose-equivalent to the IV 
preparation of phenytoin and 
can be given more rapidly, up to 150 mg/min. Main side effects Fosphenytoin can cause cardiovascular depression, 
requiring monitoring 
of blood pressure. Special points The neutral pH of fosphenytoin causes less irritation of veins than 
phenytoin and also allows IM use. Cost $20.72 for the 2-mL, 100-mg vial; $69.61 for the 10-mL, 500-mg 
vial. 
 
Treatment of Acute and Remote Symptomatic Seizures Koppel 239 
Phenobarbital 
Phenobarbital is considered a third-line treatment for SE because of the limitations of respiratory and cardiac 
depression and need for relatively slow (10-minute) delivery of each dose. Its long half-life of 3 to 7 days causes 
prolonged sedation, but also makes it an ideal medication for the management of seizures due to withdrawal of 
alcohol or sedative drugs. (It is active at the same GABA 
A 
receptor). Standard dosage 60–120 mg/d. Doses of injectable 
phenobarbital up to 1000 mg can be given if seizures persist. Oral forms include a suspension (20 mg/5 mL, used in 
children and patients with feeding tubes) and tablets of 15 (or 16.2) mg, 30 (or 32.4) mg, and 100 (or 97.2) mg. 
Therapeutic levels are 15 to 45 μg/mL. Main side effects Respiratory and cardiac depression. 
Special points Phenobarbital has no role in one of its earlier uses, the prevention of 
febrile seizures in children, as it interferes with normal learning. Cost All tablets cost about 1 to 5 cents per pill. A 
130 mg/mL syringe system 
(Carbuject; Hospira, Inc., Lake Forest, IL) costs $3.37. 
Sodium valproate 
An IV preparation (100 mg/mL) became available in 2000, allowing val- proate to be considered in treating SE, as 
well as in patients who cannot take oral medications. The mechanism of action is GABAergic. Standard dosage IV 
valproate can be given at 20–30 mg/kg loading, followed by repeated 
doses. Therapeutic levels are 50–100 μg/mL, although some people tolerate higher levels. Oral forms include 
125-mg capsules that can be sprinkled, enteric-coated tablets of 250 and 500 mg, and extended-release tablets of the 
same doses, as well as a suspension. Cost The cost of a 100-mg vial of the IV preparation is $3.20. Extended- 
release tablets cost $2.87 and a suspension costs $0.30 to $1.48 per dose. Only the enteric-coated pills are available 
as a generic. 
Levetiracetam 
The IV form of levetiracetam (500-mg IV bags) was introduced in 2006 and has been effective in stopping SE, 
probably by desynchronizing neuronal networks and preventing burst firings, but it has not yet been approved for 
this use by the US Food and Drug Administration [48, Class III]. Standard dosage Tablets were introduced in 1999 
at strengths of 250, 500, 750, and 
1000 mg. A suspension (500 mg/5 mL) is also available. After becoming generic, a 500-mg extended-release form 
was introduced in 2008. The usual daily dose is up to 3000 mg. Special points Levetiracetam is often chosen for its 
renal clearance, lack of drug interac- 
tions, and minimal adverse effects. Cost The IV preparation costs $14.51 for 5 mL (500 mg). Tablets cost 
$1.02 
to $1.79 per pill. 
Lamotrigine 
Standard dosage 100–500 mg/d. Rash (Stevens-Johnson syndrome) may occur if therapeutic 
doses are given immediately; an 8-week titration period is needed [49]. Cost Available in 5-mg and 25-mg 
dispersible tablets and tablets of 25, 100, 
150, and 200 mg, the branded medication costs $1.18 to $1.30 per dose, but a generic version recently became 
available. 
Carbamazepine 
Standard dosage 800–1600 mg/d. Main side effects Toxicity includes hyponatremia, neurocognitive effects, and 
dizziness. 
 
240 Epilepsy 
Cost Tablets (100 or 200 mg), extended-release tablets (200 or 400 mg), and 
sprinkle capsules (200 or 300 mg) cost from $0.02 to $0.57 per dose (for extended-release forms and capsules). 
Other agents 
Oxcarbazepine, gabapentin, pregabalin, tiagabine, topiramate, and zonisamide are all useful in treating remote 
symptomatic seizures. More information can be found in the article by Liu and Henry [50]. 

Disclosure 
No potential conflict of interest relevant to this article was reported. 

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