Status Epilepticus

1. Definition

There is evidence that seizures of 30 minutes or longer duration cause neuronal damage, and this is the basis for the definition. However, do not wait for brain damage to occur--treat for status epilepticus if the seizure has lasted more than 5 to 10 minutes.
 

2. Classification of status

• Generalized
• • Convulsive
  • Nonconvulsive
  • • Absence
    • Late stage of convulsive
• Partial
• • Simple
  • Complex

3. Stages of status epilepticus

1. Discrete seizures
2. Merging seizures
3. Continuous ictal activity
4. Continuous ictal activity, punctuated by low voltage flat activity
5. Periodic epileptiform discharges on a quiet background

4. Systemic complications of status

• Lactic acidosis
• Hypo- or hyperglycemia
• Hyperpyrexia
• Dehydration
• Shock
• Rhabdomyolysis
• Death

5. Mortality of status epilepticus

• Dead of status 1.8%
• Dead of underlying cause 28.8%
• Dead other causes 6.5%
• Alive 63.1%

6. Mortality of status epilepticus

A comparison of survival by duration in status epilepticus shows a marked increase in mortiality for patients in prolonged status epilepticus.  (Towne et al. 1994)

7. Neuronal death

• Cerebral cortex (laminar necrosis)
• Hippocampus
• Amygdala
• Thalamus
• Cerebellum

8. Epilepsy

• Status epilepticus can produce epilepsy.
• 20 to 40% of persons develop epilepsy after an episode of status epilepticus. (Hesdorffer et al. 1998)
• The mechanism of this could be damage to hippocampus.

9.  Important!!

    Eliminate the electrical seizure to prevent neuronal injury in status epilepticus

10. Steps in treatment

1. ABC's
2. Quick assessment
3. Stop the seizure
4. Find the cause

11. Quick assessment

12. Causes of status

Some patients have more than one etiology.
(Towne et al. 1994)

13. Laboratory studies often useful

• Blood glucose, sodium, calcium, magnesium, creatinine, BUN, ABG, anticonvulsant levels
• CBC, CPK, toxicology screen
• CT scan w/o contrast
• Lumbar puncture
• EEG

14. Simple procedures always recommended

• Pulse oximetry
• Continuous ECG
• IV

15. Initial Rx for seizures

1. IV glucose (50 cc D50)
2. Thiamine (10 mg IV + 90 mg IM)

16. Anticonvulsants

• Standard:

• Lorazepam
  Diazepam
  Fosphenytoin
  Phenytoin
  Phenobarbital

• Useful:

• Valproate
  Midazolam

17. Benzodiazepines

• Use a benzodiazepine first. They work quickly, and status epilepticus is more difficult to control if treatment is delayed.
• Lorazepam 4 - 8 mg (0.1 mg/kg) IV
• • Slower onset, longer duration
• Diazepam 5 - 20 mg (0.15 - 0.25 mg/kg) IV
• • Rapid onset, short duration
• Give IV push
• Be prepared to intubate
• IV diazepam is not useful for serial seizures

18. Diazepam has a short duration of action

Diazepam has only a short duration of action. This is primarily because it quickly redistributes from brain to fat. Note that plasma diazepam concentration is less than half its peak ten minutes after an IV infusion.  (Ramsay et al. 1979)

19. Phenytoin

• Loading dose 18 - 20 mg/kg IV (1000 - 2000 mg)
• Rate < 50 mg/min. to avoid hypotension, arrhythmias
• Never give IM
• Never in dextrose
• Loading dose works up to 18 hours
• Stops 80% of generalized motor status epilepticus

20. Fosphenytoin

Prodrug of phenytoin for parenteral administration Rapidly and completely converted to phenytoin by nonspecific tissue phosphatases Water soluble, pH 8.6 - 9 Can be given IM No sterile necrosis or tissue abscesses Molecular weight 1.5 times that of phenytoin

21. IV loading of fosphenytoin

Fosphenytoin is rapidly converted to phenytoin. Plasma concentrations of phenytoin are essentially identical whether phenytoin or fosphenytoin is infused.

22. Phenobarbital

• Loading dose 20 mg/kg IV
• Not > 100 mg/min
• Patient should be intubated

23. Intravenous valproic acid

• Depacon^®
• Give an IV loading dose followed by a three times daily dose of valproic acid by mouth or IV.
• Package insert says not faster than 50 mg/min (but I have given it up to 200 mg/min, and this is probably safe).

24. Serial seizures

• Fosphenytoin IV or IM
• Phenytoin PO
• Lorazepam IV or PO
• Oral antiepileptic drugs
• Diazepam rectal gel
• Not IV diazepam

25. Refractory status: midazolam

• Give midazolam as a continuous infusion
• Use EEG monitoring if possible, titrate infusion to eliminate electrographic seizures.
• 200 micrograms/kg as a slow IV bolus, followed by 0.75 to 10 micrograms/kg/min.
• In the most refractory cases more than 10 micrograms/kg/min may be needed.'
• Hypotension is uncommon but may occur.

26. Refractory status: pentobarbital

• Administer pentobarbital as a continuous infusion.
• 5 mg/kg load, then 1-3 mg/kg/hour
• Must use EEG monitoring; goal is to titrate drug infusion to EEG burst suppression.
• Hypotension is common; fluids and pressors may be needed.

27. EEG burst suppression

A quiet EEG background is frequently interrupted by bursts of high voltage activity. The high voltage activity often contains epileptiform spikes or spike-wave discharges.

28. Other types of status epilepticus

• Generalized nonconvulsive status epilepticus
• • May be a late stage of convulsive status epilepticus
  • Signs may be subtle: subtle facial twitching, nystagmus, ocular deviation
• Myoclonic status epilepticus
• • May follow anoxic encephalopathy
  • May be stimulus-sensitive

29. Controversies in status epilepticus

• Significance of certain EEG patterns:
• • Periodic epileptiform discharges (PLEDs)
  • Bi-PLEDs
  • Periodic discharges
  • Frequent triphasic waves
• Titrate IV antiepileptic with EEG to:
• • Burst suppression
  • • Easy to see, but may go flat before burst suppression
  • Elimination of seizure
  • • Sometimes hard to recognize

30. Periodic discharges

This patient had right frontal periodic discharges and encephalopathy. Treatment with fosphenytoin and valproate improved the discharges, but the patient was clinically unimproved.

31. Time table for treatment of status

a. 0-10 min, do ABC's:

• O₂ by nasal cannula. Intubate if necessary.
• Establish IV access.
• Draw glucose, serum chemistries, CBC, toxicology screen.
• Draw antiepileptic drug levels if patient known to be treated.
• Thiamine (100 mg) then glucose (50 ml of 50%) if hypoglycemia demonstrated or suspected.

b. 10-20 min, administer a benzodiazepine drug:

c. 20-60 min, administer fosphenytoin or phenytoin

Phenytoin  In adults give 18 mg/kg no faster than 50 mg/min IV. Monitor ECG and BP during infusion. Do not use glucose-containing IV solution. Purge IV line with normal saline before infusion. Do not give phenytoin IM because it may cause sterile abscesses. Ensure adequate IV access because local infiltration of phenytoin can cause skin necrosis.

d. >60 min

• Administer additional doses of fosphenytoin or phenytoin up to a maximum of 30 mg/kg.
• Administer phenobarbital (20 mg/kg at 100 mg/min IV). Assisted ventilation will usually be required.

e. If seizures persist:

• Pentobarbital infusion. 5 mg/kg load, then 1-3 mg/kg/hr. Must use EEG monitoring, goal is to titrate to EEG burst-suppression. Avoid hypotension if possible, but fluids and pressors may be needed.
• Midazolam drip. Use with EEG monitoring if possible, titrate infusion to eliminate electrographic seizures. 200 micrograms/kg as a slow IV bolus, followed by 0.75 to 10 micrograms/kg/min continuous infusion. In the most refractory cases more than 10 micrograms/kg/min may be needed. Hypotension is uncommon but may occur.
• Propofol drip. Few advantages over pentobarbital.
• General anesthesia (isoflurane, ketamine).
• Paraldehye: no longer available.
• Diazepam drip. Used infrequently.
• Lidocaine drip. Used infrequently. May exacerbate seizures.
• Do not merely paralyze the patient.

References

1. Barry E, Hauser WA (1992) Status epilepticus: the interaction of epilepsy and acute brain disease. Neurology 43: 1473-1478. PubMed
2. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA (1998) Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus. Ann Neurol. 44: 908-12.
3. Parent JM, Lowenstein DH (1994) Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology 44: 1837-1840. PubMed
4. Ramsay RE, Hammond EJ, Perchalski RJ, Wilder BJ (1979) Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol. 36: 535-9. PubMed
5. Towne AR, Pellock JM, Ko D, DeLorenzo RJ (1994) Determinants of mortality in status epilepticus. Epilepsia 35: 27-34. PubMed
6. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB (1998) A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 339: 792-8.
7. Treiman DM, Walton NY, Kendrick C (1990) A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res. 5: 49-60. PubMed
8. Wilder BJ (ed.) (1993) The use of parenteral antiepileptic drugs & the role for fosphenytoin. Neurology 46 suppl. 1. PubMed
9. Working Group on Status Epilepticus (1993) Treatment of status epilepticus: recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA 270: 854-859.  PubMed