new guidelines for status epilepticus

MANAGEMENT OFSTATUS EPILEPTICUS WITH RECENT GUIDELINES

DR. SAMRAT A SHAH DEPARTMENT OF NEUROLOGY

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%

J K Murthy Convulsive status epilepticus API 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.

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 Epilepticus was 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

Genaralized convulsive status epileptics

Series of generalized tonic-clonic seizures without return to consciousness in between seizures or a single prolonged seizure without charecterstic evolution of single discrete seizure.

SUBTLE SEIZURE: Profound coma,convulsive activity has only subtle twitches of extremities or trunk or nystagmoid movements of eyes and bilateral ictal discharges on EEG.

Initial compensatory phase-sympathetic overdrivea. increased CO.b. increased BPc. increased BSd. increased blood lactate levels

Decompensation –homeostatic failure

1. Cardiorespiratory collapse2. Electrolyte imbalance 3. Rhabdomyolysis & delayed tubular necrosis4. Hyperthermia5. Multi organ Failure6. Raised ICP & cerebral edema

Nonconvulsive status epilepticus(NCSE)

Two types: COMPLEX PARTIAL SE. ABSENCE SE.

Duration of seizures doesn’t affect prognosis in NCSE.

COMPLEX PARTIAL SE

Post ictal confusion following a CPSE is not said to be SE.it is nonepileptiform cortical disturbances.

Prolonged Postictal confusion can sometimes be due to continued seizure activity either localized or diffuse following a discrete seizure.

Etiology: Most commmon cause: AED changeOther causes: Stroke Encephalitis. Old glioma, scar, tumour, hemartoma Precipitating factors include alcohol, drug

withdrawal, stress, sleep deprivation.

Clinical features:

Wide variety of presentation which may be indistinguishable from ASE.

Can have 2 types of presentation: Continues activity or recurrent cyclic activity. CPSE usually has cyclic seizure activity with with

incomplete clearing between episodes. Impairement of conciouness is must, in form of

continues or fluctuating confused state to agitated unresponsiveness with psychotic activity.

Absence SE

Defined as a prolonged or serial typical absence attacks that were sufficiently close together to give rise to prolonged disturbances in consciousness and EEG pattern of classic ictal 3hz spike wave pattern.

Alteration of consciousness is less profound in Absence SE then in typical absence attacks.

Types:

1. TYPICAL ASE: Simple confused state at times with subtle jerks of

eyelids,with rhythmic 3hz swd. Prognosis is excellent.

2. ATYPICAL ASE: Seen in patients with generalized seizures characterized

by fluctuating confusional states with predominant tonic,clonic,atonic ,myoclonic and lateral ictal manifestations.

Immediate prognosis is guarded.

3.ASE WITH FOCAL FEATURES: Seen in cases of preexisting or newly developing

lateralized seizures most often extra temporal in origin. EEG shows bilateral asymmetrical ictal discharges.

4.ASE OF LATE ONSET: Middle aged or elderly adults. Extreme end of continum of childhood epilepsy. Usually in 6 decade. Most common cause being withdrawal of pyschotropical

drugs.

Clinical features:

Couding of conciousnes is divdied into 4 grades:1. Slight : complains of bad days2. Marked: most typical, frank confusion seen.3. Profound: limited motor and verbal response.4. Lethargic stupor: catatonia,motionless with

incontinence. Myoclonus: bilateral jerky movements of face,

eyelids and arms with little impairment of consciousness with eyes closed.

SIMPLE PARTIAL SE AND EPILEPSIA PARTIALIS CONTINUA:

Defined as: Clinical or EEG signs and symptoms of at least 30 min duration with spectrum of large ictal manifestations as well as subtle clinical signs with some behaviour disturbances and psychosis like state in particular hallucinations without loss of consciousness or severe alteration in consciousness.

EPILEPSIA PARTIALIS CONTINUA: Partial somatomotor SE for minimum of 1 hour and recurring at regular intervals of no more then 10 seconds and as spontaneous regular or irregular clonic twitching of cerebral cortical origins sometimes aggravated by action or sensory stimulus confined to one part of body and continuing for hours,days,weeks.

Refractory status epilepticus Do not repond to standard treatment regimen

for status epilepticus (adequate doses of intial BZD 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 workupAll 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

•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


• 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

0-5 minutes….

Give glucose (100 ml D25%), unless normo- or hyperglycemic

Hyperglycemia has no negative effect in SE (as long as significant hyperosmolality is

being avoided)

Thiamine 100 mg IV - if given D25 or if malnourished/alcoholic

Treatment (Pharmacotherapy)5-15 minutes..

The longer we wait with anticonvulsant, the more anticonvulsant we will need to stop SE

Most common mistake is ineffective dose. Benzodiazepines

Lorazepam 0.1- 0.15 mg/kg i.v upto 4-6 mg over 1-2 minutesIf SE persists, repeat every 5-10 minutes

If lorazepam is successful in stopping GCSE, the decision to add another agent depends on the underlying etiology.

Lorazepam’s duration of action is approximately 12 to 24 hours.

If the etiology is reversible (e.g., status epilepticus due to metabolic or toxic factors), lorazepam 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 15 – 35 min

Phenytoin:- 20mg/kg Bolus dose IV at the rate of 50mg/min. Fosphenytoin:- 20mg /kg Bolus dose IV at the rate of 150mg/min(Repeat dose of 10mg/kg can be given)

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)

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

If seizure recurs again GA agent should be given

STATUS EPILEPTICUS

Rapid IV access available

NO

IM Midazolam 0.2mg/kg (max10mg) ORBuccal 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 donot stop in 5 minutes

If Seizure donot stop in 5 minutes,Achieve IV access

Shift to 2nd line drugs


IV Phenytoin 20mg/kg @ 50mg/min OR IV Fosphenytoin 20mg/kg @ 150 mg/min


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


Repeat IV Phenytoin 5mg/kg OR IV 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 DrugLevitiracetam 20-30mg/kg @ 5 mg/kg/min

Seizure not controlled

Seizure not controlled

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

Diazepam One 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 mg in 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 development 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 12Extravasation causessevere tissue injury

pH 8.6Extravasation welltolerated

• 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 depression 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.

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

administration is difficult or conventional AED are contraindicated or proved 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 decomposed drug is highly toxic. Given at a dose of 10-20ml of 50% solution rectally or I/M. Diluted in NS 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


•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 anesthetic given in ICU setting as patient

requires intubation and mechanical ventilation. Most troublesome S/E- hypotension (may require

pressor therapy) 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 maintenance 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 Lorezepam group.

Levetiracetam IV- Efficacy and Safety

Thongplew and collegues reviewed the clinical use, efficacy, and outcomes of intravenous levetiracetam in adults with status epilepticus.

Results:• 34 prescriptions for intravenous levetiracetam in patients with

status 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 of levetiracetam and lorazepam in status epilepticus.

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

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.

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.

LACOSAMIDE

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

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

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

IMPORTANT POINTS

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 end tidal 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.

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

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.

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

THANKYOU

References.

Textbook of epilepsy by JEROME ENGEL,PEDLEY

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

new guidelines for status epilepticus

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