MANAGEMENT OFSTATUS EPILEPTICUS

WITH RECENT GUIDELINES

DR. PIYUSH OJHADM RESIDENT

DEPARTMENT OF NEUROLOGYGOVT MEDICAL COLLEGE, KOTA

• Worldwide incidence of Convulsive Status Epilepticus

- 3.8 to 38 per lakh per year in children.

- 6 to 27 per lakh per year in adults.

• Bimodal peak distribution, with peaks in children and elderly.

• Frequency of refractory status epilepticus in status epilepticus patients = 31-44%

• No community based incidence studies in India but is expected to be high because of high prevalence of epilepsy, CNS infections and treatment gap.

J K Murthy Convulsive status epilepticus API India 2013

• In approximately 50% cases, there is no prior history of epilepsy.

• Males are affected more compared to females partly attributed to lower seizure threshold in males.

• Mortality rates range between 10.5-28%.

• Neurological or cognitive sequelae in convulsive SE occur in 11- 16 % patients.

• Factors associated with poor outcome after generalised SE :

– Underlying etiology

– De novo development in hospitalised patients

– Older age

– Associated medical complication

– Duration of seizures

– Focal neurological signs at onset

Status epilepticus –common etiology

1. Low AED levels - 35%

2. Stroke, including haemorrhagic - 20%

3. Alcohol withdrawal - 15%

4. Anoxic brain injury - 15%

5. Metabolic disturbances - 15%

6. Remote brain injury/ cong. malformations - 20%

7. Infections - 5%

8. Brain neoplasms - 5%

9. Idiopathic - 5%

• According to an Indian study, the etiology of Status Epilepticuswas Infection in 53.8%, drug default in 7.9%, metabolic in 14.5%, Stroke in 12.8% and miscellaneous in 11% of patients.

• Infection as an etiology was more common in children, drug default and metabolic causes in adult and stroke in elderly.

• Mortality = 29% (elderly >> children)

(A clinical, radiological and outcome study of status

epilepticus, India J Neurology (2010) 257:224-229)

Definition

• The first definition of Status Epilepticus came from Clark and Prout as “ maximal development of epilepsy in which seizures are so frequent that coma and exhaustion are continuous between seizures.”

• The first official definition of SE was the product of 10th Marseilles Colloquium (1962) which was accepted by International League Against Epilepsy (ILAE) in 1964 and modified in 1971 as “a seizure that persists for sufficient length of time or repeated frequently enough that recovery between attacks does not occur.”

Operational Definition

• Status Epilepticus is defined as 5 minutes or more of :

1.continuous clinical and/or electrographic

seizure activity or

2. recurrent seizure activity without

recovery (returning to baseline) between

seizures

Clinical features

• Genaralized convulsive status epileptics-

• Self-perpetuating generalized tonic-clonic seizure or of a series of generalized tonic-clonic seizures without return to consciousness in between seizures.

• Initial compensatory phase-sympathetic overdrive

a. increased C.O.

b. increased BP

c. increased BS

d. increased blood lactate levels

• Decompensation –homeostatic faliure

1. Cardiorespiratory collapse

2. Electrolyte imbalance

3. Rhabdomyolysis & delayed tubular necrosis

4. Hyperthermia

5. Multi organ Failure

6. Raised ICP & cerebral oedema

• Nonconvulsive status epilepticus

• Diverse - severe impairment of consciousness to subtle phenomena.

• Motor manifestations if any –needs careful CNS exam.

• Often mistaken for psychiatric disorders.

• Refractory status epilepticus

• Do not repond to standard treatment regimen for status epilepticus (adequate doses of intialBZD followed by a second acceptable antiepileptic drug )

• Nearly 40% of status epilepticus are refractory.

• Predictors- encephalitis / nonstructural causes(HIE) / delayed diagnosis & treatment .

• Malignant / Super- refractory status epilepticus

• Status epilepticus that does not respond to a course of anesthetic drug.

• 20% of refractory status epilepticus patients.

• Needs combination therapy (AED & Anesthetic drugs) .

MANAGEMENT OF STATUS EPILEPTICUS

Aims of management of Status Epilepticus are as follows :-

1. Termination of Status Epilepticus

2. Prevention of Seizure Recurrence

3. Management of Precipitating cause

4. Management of complications

Approach: Diagnostic workup

All patients

• Obtain IV access

• Monitor vital signs (ABC).

• Head CT (appropriate for most cases)

• Labs: blood glucose, CBC, renal function tests, Calcium,Magnesium, electrolytes, AED levels.

• cEEG monitoring (preferably)

Consider based on clinical presentation

• Brain MRI

• Lumbar puncture

• Toxicology panel (i.e. isoniazid, TCAs, theophylline, cocaine,sympathomimetics, organophosphates, cyclosporine)

• Other relevant investigations as per the need

Brophy, et al NCC 2012

Continuous EEG Monitoring

Brophy, et al NCC 2012

•The use of cEEG is usually required for the treatment of SE.

•Continuous EEG monitoring should be initiated within 1 h of SE onset if ongoing seizures are suspected.

•The duration of cEEG monitoring should be at least 48 h in comatose patients to evaluate for non-convulsive seizures.

Indications for cEEG in SE

Brophy, et al NCC 2012

• Recent clinical seizure or SE without return to

baseline >10 min

• Coma, including post-cardiac arrest

• Epileptiform activity or periodic discharges on initial

30 min EEG

• Suspected non-convulsive seizures in patients with

altered mental status

Continuous EEG treatment endpoints

Brophy, et al NeuroCritical Care 2012

• Cessation of non-convulsive seizures

• Diffuse beta activity

• Burst suppression 8–20 s intervals

• Complete suppression of EEG

INDIVIDUAL DRUGS

BENZODIAZEPINES

• Drug of choice for out of hospital as well as in-hospital treatment.

• Effective in terminating seizures in 59-78 % cases.

• Lorazepam is the DOC for IV administration.

• Midazolam is the DOC for IM administration.

• Rectal Diazepam is effective in children.

• Other routes are buccal Midazolam and intranasal Midazolam (not commonly used)

• Benzodiazepines

– Diazepam

- 10mg IV push over 30-60 seconds

- repeat after 10-15mins, upto 40mg (5mg/min) -Repeat after 2-4hrs. (max 100mg/day)

- bolus dose should be given in undiluted form

at rate not exceeding 2-5 mg/min.

– Lorazepam

0.1- 0.15 mg/kg i.v, upto 4-6 mg over 1-2 minutes

If SE persists, repeat every 5-10 minutes

• DiazepamOne of the drug of choice for first line management of SE

• Good results, easy to administer. (fast acting, short lasting)

• More lipid soluble, hence short distribution half-life.

• Anti-seizure effect 15-30min.

• Sufficient cerebral levels are achieved within 1 min of IV administration and about 20 mins after rectal administration.

• Elimination half life abt 24 hrs (may accumulate)• Side effects -- hypotension, bradycardia,

respiratory depression, cardiac arrest, tolerance, depresses mental status.

• In children and elderly : Rectal Diazepam 0.5 mg / kg in children and 10 mgin elderly are also good alternatives.

• Lorazepam• Has emerged as preferred BZD for treatment of SE• The veteran affairs (VA) co-operative study demonstrated

advantage of IV Lorazepam over Phenytoin.

• Less lipid distribution with distribution half life of 2-3 hours

• So Fast acting, longer lasting compared to Diazepam– Longer therapeutic half-life. Anti-seizure effect for

6-12hrs.– 2mg dose, upto a max dose of 8mg in total

• Main disadvantage is rapid devlopment of tolerance, hence repeated doses are less effective and has no role in long term therapy.

• - If Benzodiazepines are successful in stopping

• GCSE, the decision to add another agent

• depends on the underlying etiology.

• - If the etiology is reversible (e.g. metabolic or

• toxic factors), BZDs may be the only treatment

• necessary.

• - Another longer-acting AED is needed if the

• underlying etiology is not rapidly reversible.

Seizures continuing / Stage of Established Seizure

• In patients taking Sodium Valproate -25mg/kg iv sodium valproate can be tried who may be sub therapeutic.

• Phenytoin:- 20mg/kg Bolus dose IV at the rate of

50mg/min.

• Fosphenytoin:- 20mg PE/kg Bolus dose IV at the rate of 150mg/min

• Above drugs have advantage that they lack sedative effects.

Phenytoin Fosphenytoin

• 15-20 mg/kg i.v.

@50mg/min

• 100 mg phenytoin =

• 20 mg PE/kg i.v @

150mg/min

Fosphenytoin 150 mg

pH 12

Extravasation causes

severe tissue injury

pH 8.6

Extravasation well

tolerated

• Onset 10-30 min • Onset 5-10 min

•May cause hypotension,

dysrhythmia(may be because of rapid administration

and propylene glycol which is used as

diluent)

• less cardiac complications as it

is water soluble and propylene

glycol is not used as diluent.

• Cheap • Expensive

Fosphenytoin Vs. Phenytoin• SO Fosphenytoin injection has the following advantages over

phenytoin

100% bioavailability

better tolerated at site of injection.

can be given IV more rapidly .

can be given IM when cardiac monitoring is not necessary

• But has the following disadvantages

– conversion of fosphenytoin to phenytoin takes about 15 minutes. Hence inappropriate for the initial treatment of status epilepticus (SE).

– transient paraesthesia and pruritus occur more frequently than with phenytoin.

– the use of phenytoin equivalents may be confusing.

PHENOBARBITAL

• Used in SE when BZD and Phenytoin have failed.

• Loading dose – 15-20 mg/kg

• Causes sedation and hypotension, so airway protection should be done.

• Diluted in Polyethylene Glycol which results in complications like renal failure, myocardial depresion and seizures.

SODIUM VALPROATE• FDA approved use in SE in 1997

• Parenteral loading is done when oral therapy is not possible.

• Broadspectrum action and is also useful in absence and myoclonic SE.

• Patients not responding to 2 first line AEDs may be given parenteral sodium valproate, especially in setting where intubation and artificial ventilation are not feasible.

PARALDEHYDE• Is used as an alternative to Diazepam in early SE where IV

administration is difficult or conventional AED are contraindicated or preoved ineffective.

• Given rectally or I/M with fast and complete absorption with rapid onset of action.

• Seizure tend to recur after initial control.

• Inappropriately diluted or decomposd drug is highly toxic.

• Given at a dose of 10-20ml of 50% solution rectally or I/M.

• Diluted in NS or arachis oil for rectal or I/M route.

• For I/V route, given as a 5 % infusion in 5% dextrose, freshly prepared up every 3 hours.

Refractory Status Epilepticus

Brophy, et al NCC 2012

•Refractory SE therapy recommendations should consist of continuous infusion AEDs, but vary by the patient’s underlying condition

•Dosing of continuous infusion AEDs for RSE should be titrated to cessation of electrographic seizures or burst suppression

•During the transition from continuous infusion AEDs in RSE, it is suggested to use maintenance AEDs and monitor for recurrent seizures by cEEG during the titration period.

•A period of 24–48 h of electrographic control is recommended prior to slow withdrawal of continuous infusion AEDs for RSE

Seizures continuing / Stage of Refractory Status

-General anesthesia should be induced

Propofol:- 2mg/kg IV bolus,Repeat if necessary, followed by infusion (2 – 10 mg/kg/hr)

Thiopental:- 100-250mg IV bolus over 20 sec. with further 50mg bolus every 2-3 min.until seizure control followed by IV infusion(3-5mg/kg/hr)

Midazolam:- 0.3mg/kg IV bolus dose at the rate of 4mg/min, rpt every 5 min 3 doses followed by infusion(2 ug/kg/hr)

Neuromuscular Blocking Agents :

If seizures have been controlled for 12hrs., reduce the dose over further 12hrs.

If seizure recurs again GA agent should be given

Lowenstein DH, Status Epilepticus, NEJM (1998)

• No difference has been found in mortality in groups treated with either of these agents.

• Pentobarbital was associated with lower frequency of acute treatment failures and breakthrough seizures.

• Superior pharmacokinetics and adverse effects profile makes Propofol preferred drug in Refractory status epilepticus in children as well as adults

THIOPENTONE

• Barbiturate anaesthetic given in ICU setting as patient requires intubation and mechanical ventialtion.

• Most troublesome S/E- hypotension (may require pressortherapy)

• Tendency to accumulate

• Caution advised in elderly or in cardiac, hepatic or renal diseases.

• 100-250mg bolus over 20 secs, with further 50mg boluses every 2-3 mins till seizures are controlled with maintainence dose as 3-5mg/kg/hr.

• Aqueous solution is unstable if exposed to air.

PROPOFOL

• Nonbarbiturate anesthetic

• Highly lipid soluble with high volume of distribution resulting in rapid and short lived action.

• Causes profound respiratory and cerebral depression requiring assisted ventilation.

• May cause involuntary movements which are not to be confused with seizures

• 2 mg/kg bolus dose followed by 5-10 mg/kg/hr infusion.

LEVITIRACETAM• S-enantiomer of Piracetam

• Was introduced for treatment of SE in 2006

• Insufficient data on safety and efficacy of this drug in status epilepticus.

• Several case reports its use in SE.

• European federation of neurological societies proposes its usefulness in refractory complex partial SE. (Meiekord H et al, EFNS guideline on the management of

status epilepticus in adults, Eur Journal 2010)

Levetiracetam

• Levetiracetam has been used to control SE, typically as second line drug.

• Levels peak within 2 hrs. Steady state in 2 days. No significant interactions.

• Mishra et al (2012) used LEV 20 mg./kg over 15 min. and compared with Lorezepam 0.1 mg./kg over 2 to 4 min. in 79 patients. Control was comparable (76.3% and 75.6%). 24 Hour seizure control was also similar. But hypotension and requirement of mechanical ventilation was significantly higher in Lorezepamgroup.

LACOSAMIDE

• In addition to anticonvulsant property, it has shown potential to retard kindling induced epileptogensis.

• One report shows efficacy in NonconvulsiveSE.(Kellinghaus C et al, Epilepsy Behav 2009)

• One report showed efficacy of oral Lacosamide in refractory convulsive SE.(Tilz C et al, Epilepsia 2010)

Lacosamide

• Christian et al (2010) reported successful termination of refractory SE given 22.5 mg. diazepam, 12.5 mg. etomidate & 5 mg. midazolam, 4 mg. lorazepam & 1500 mg. levetiracetam. Lacosamide 300 mg via per cutaneous gastric fistula resulted in cessation of SE in 30 min.

• Kellinghaus (2009) reported successful termination of SE with IV Lacosamide.

• However furthere large RCT are required to prove the efficacy and safety of this drug in SE.

IMPORTANT POINT

• Along with emergency control of SE, maintenance therapy should be started to prevent recurrence of seizures.

• In patients known to have epilepsy, their usual AED can be continued depending on serum AED levels.

• In patients presenting for the first time as SE, drugs like Phenytoin or Sodium Vaproate used to control the status can be continued as maintenance therapy.

EMERGING THERAPIES

• Inhalational Anaesthetic agents

(isoflurane and desflurane )

• Attractive features include efficacy, rapid onset of action, ability to titrate according to EEG.

• Both drugs in endtidal concentrations of 1.2-5%achieved an EEG burst suppression and termination of seizure activity within minutes.

• However further studies are needed in this field.

Mirasattari et al, treatment of refractory status epilepticus with inhalational anaesthetic agents : Isoflurane & Desflurane , Arch Neurology 2004

Shorovan M et al,The treatment of refractory status epilepticus Brain 2011

KETAMINE

• an NMDA receptor antagonist

• Experimental studies have demonstrated synergistic action of diazepam and ketamine in termination SE.

• Efficacy in extremely refractory SE has been documented in both children and adults.

• No cardiac depressant properties, hence doesnot cause hypotension.

KETOGENIC DIET

• Diet high in fat and low in carbohydrates

• Induces ketosis in body and thought to suppress seizures by release of Leptin.

• Exact mechanism remains unknown.

Steroids and Immunotherapy

• Rationale that refractory SE may be due to antibodies directed against neural elements.

• Increasing recognition the role of inflammation in epileptogenesis.

• SE may be the initial presenting feature of some immune mediated encephalopathies.

Shorovan M et al,The treatment of refractory status epilepticusBrain 2011

NONPHARMACOLOGICAL TREATMENTS

• Resective surgery

• Vagal nerve stimulation

• Hypothermia- decrease brain metabolism which is neuroprotective.

• Electroconvulsive therapy - ECT-dose-1 session daily for 3-8 days. Mechanism-not known

STATUS EPILEPTICUS

Rapid IV access available

NO

IM Midazolam 0.2mg/kg (max10mg)OR

Buccal or Intranasal Midazolam0.5mg/kg (max10mg)

YES

IV LORAZEPAM 0.1mg/kg slow push (max 4mg)

Repeat IV LORAZEPAM 0.1mg/kg slow push

If Seizure donotstop in 5 minutes

If Seizure donotstop in 5 minutes,Achieve IV access

Shift to 2nd line drugs

If Seizure donotstop in 5 minutes

IV Phenytoin 20mg/kg @ 50mg/minOR

IV Fosphenytoin 20mg/kg @ 150 mg/min

If Seizure donot stop in 20 minutes

If possibility of subttherapeutic levels, Valproate 40-60 mg/kg @ 6 mg/kg/min can be tried

If Seizure donot stop in 10 minutes

Repeat IV Phenytoin 5mg/kg ORIV Fosphenytoin 5mg/kg

IV Phenobarbitone 20mg/kg @ 100mg/min f/by 3-5 mg/kg.hr cont infusion

ORIV Midazolam 0.2 mg/kg loading dose f/by 0.1-0.4 mg/kg/hr cont infusion

ORIV Propofol 2mg/kg bolus f/by 2-10 mg/kg/hr cont infusion

ORIV Pentobarbital 5 mg/kg loading dose f/by1-3 mg/kg/hr cont infusion

If seizure persists after 24 hrs, try emerging novel therapies: Ketamine bolus 0.5-4.5 mg/kg infusion (upto 5 mg/kg/hr ) ; Immunomodulation IV Methylprednisolone or IVIg; Resective surgery ; Ketogenic diet ; hypothermia

Alternative drugValproate 40-60 mg/kg @ 6 mg/kg/min

Alternative DrugLevitiracetam20-30mg/kg @ 5 mg/kg/min

Seizure not controlled

Seizure not controlled

THANK YOU

References.

• Review article-Status Epilepticus-Lawrence J .Hirsch,MD,FAAN: Nicolas Gaspard,MD,Phd-2013

• Guidelines for evaluation and management of status epilepticus Neurocritical Care Society 2012

• article-Status Epilepticus-Lawrence J .Hirsch,MD,FAAN: Nicolas Gaspard,MD,Phd-2013

Levetiracetam IV- Efficacy and Safety

Thongplew and collegues reviewed the clinical use, efficacy, andoutcomes of intravenous levetiracetam in adults with statusepilepticus.

Results:

• 34 prescriptions for intravenous levetiracetam in patients withstatus epilepticus were noted.

• All patients had at least one co-morbidity condition

• The seizure control rate was 61.8%

• 41.2% survived and had an improved status at discharge.

Neurology Asia 2013; 18(2) : 167 – 175

Intravenous levetiracetam has good efficacy and may be a good option for status epilepticus.

Levetiracetam IV- Alternative to Lorazepam

Randomized, open labeled pilot study compared the efficacy and safety oflevetiracetam and lorazepam in status epilepticus.

–Patients with convulsive or subtle convulsive SE were randomized toLevitiracetam 20 mg/kg IV over 15 min or Lorazepam 0.1 mg/kg over 2-4min.

J Neurol. 2012 Apr;259(4):645-8

Levetiracetam Lorazepam

In first instant, SE controlled

76.3 75.6

In those resistant, SE controlled

70.0 88.9

24-h freedom from seizure

79.3 67.7

Lorazepam • Significantly higher need

of artificial ventilation• Insignificantly higher

frequency of hypotension

For the treatment of SE, levetiracetam is an alternative to lorazepam and may be preferred in patients with respiratory compromise and hypotension.