STATUS EPILEPTICUS UPDATE

Jo WilmshurstDepartment of Paediatric Neurology

Red Cross Children’s Hospital

What are the protocols? How should we monitor these children?

Definitions

Status epilepticus: Generalised convulsions > 30 minutes = brain damage / neuronal cell death

Refractory status: Generalised convulsions > 1hour, resistant to level 1-2/3 intervention – i.e. need PICU intervention

The longer it takes to gain control the worse the outcome and the harder it will be to terminate Sz

Outcome influenced by underlying aetiology – encephalitis worst result

Scott et al, ARCH 1998Holtkamp et al; JNNP 2005

Causes

Fever 36% Medication change 20% Unknown 9% Metabolic 8% Congenital 7% Anoxic 5% Other (trauma, vascular, infection, tumour, drugs) 15%

Haafiz et al; Ped Emerg Care 1999

Mortality

Adults 15-22% Children 3-32%

No figures for SA

Fountain et al; Epilepsia 2000

Lacroix et al; CCM 1994

Sahin et al; Epilepsia 2001

Optimal intervention times

Children > 5 years : typical GTCS seizure duration < 5 minutes

Younger children and infants: paucity of data. Suggested time frame for a typical GTCS is less than 10-15 minutes.

Mean age for status in children 3.4 years

Lowenstein DH, Bleck T, , Macdonald RL. Epilepsia 1999;40(1):120-2

Singh et al 2010 Neurology

Diagnostic assessment of the child with status epilepticus Blood glucose Anti-epileptic drug (AED) levels. Toxicology testing Blood cultures

Lumbar puncture (as clinically indicated & all children < 18 months)

Neuroimaging: Insufficient evidence for routine neuroimaging (8% yield)

Indications: When convulsive status is unexplained the patient remains unconscious, or new focal neurological signs become apparent.

Evidence- based quideline American Academy of Neurology (ANN) and Child Neurology Society (CNS)

Brain Monitoring

Continuous Non-invasive Highly sensitive to a variety of brain insults Reasonably specific User friendly Not too expensive!

Kurtz et al Curr Opin Crit Care 2009

Monitoring

cEEG (continuous EEG – full head montage) The Gold standard – not viable in most SA settings Non-convulsive seizures IschaemiaaEEG (Amplitude-integrated EEG) Assessing if burst suppression attained Non-convulsive seizures Potential artefact

Need to remember overall underlying cause usually the defining feature for the outcome of the child.

The future?

Basic external monitoring (BP, sats, HR) often underestimates true cerebral function

Cerebral Near-infrared spectroscopy (cNIRS) Non-invasive Used as a tool to assess regional brain

saturations (RSO2) Available in SA!

Comparison studies with serological markers (S100beta and NSE) – performed well (better infact)

Subbaswamy et al Neurocrit Care 2009

Treatment of Status Epilepticus Pre hospital treatment A&E treatment In-hospital treatment (Ward/High care) Anaesthesia (ICU)

What recommendations exist for managing Status

Epilepticus in Children?

Mayo Clinic

Boston Children’s hospital

European expert opinion 2007

European expert opinion 2007

Children’s Hospital of Philadelphia

Red Cross Guidelines

APLS guidelines (2005; The convulsing child)

ABCD↓

(Level 1) Lorazepam IV/IO or diazepam pr / midazolam buccal

↓Lorazepam IV / IO

↓Paraldehyde pr

(Level 2) ↓Phenytoin IV / IO / Phenobarbitone IV / IO

↓(Level 3) RSI with Thiopental

Level one

Arrival – First Hosp intervention Benzodiazepine

Diazepam PR/IV/IO Midazolam IN/SL/IV/IO Lorazepam IV/PR/IO

Repeat if necessary

Good specialist consistency, good study data

Scott et al;Lancet 1999Jeannet et al;Europ J Paed Neurol 1999

DeNegri et al; Pediatr Drugs 2001

Diazepam versus Lorazepam Both are equally effective at aborting status epilepticus.

IV lorazepam vs IV diazepam Rectal lorazepam might be more effective than rectal

diazepam

Lorazepam: Substantial longer duration of anti-seizure activity (lipid-

soluble) Less seizure recurrence and fever repeat doses required.

Appleton R et al Cochrane Database Syst Rev 2008 Jul 16;(3)

Transmucosal pharmacological therapy

Intranasal midazolam as effective as intravenous diazepam

Buccal midazolam as effective as rectal diazepam. Intravenous formulations of midazolam (given buccal

or intranasal routes) are relatively inexpensive. Caregivers prefer intranasal midazolam to rectal

diazepam.

Appleton R et al Cochrane Database Syst Rev 2008 Jul 16;(3)

Paraldehyde

Treatment with IV phenytoin as a second-line therapy was associated with a 9-times greater likelihood of seizure termination than was treatment with paraldehyde

Chin R, Neville B et al Lancet Neurol 2008;7:696-703

Level 2 intervention

Phenytoin IV over 20 mins, cardiac monitor, large vein, not mixed with

glucose Phenobarbitone IV/IM

Push, flush through, monitor for resp depression and hypotension

Both agents fairly accepted BUT studies becoming more limited

small numbers less children

Shanner et al;Neurol 1988

Prasad et al;Ann Neurol 2002

Phenytoin

Takes 30 minutes to administer Requires a syringe driver Requires a large IV (NOT central) line Requires cardiac monitoring for potential cardiac

toxicity Can only be given by IV route Cannot be repeated It not as effective as phenobarbitone

DeToledo & Ramsay; Drug Saf 2000Trieman et al; NEJM 1998

Fosphenytoin More favourable vehicle that does not contain proylene glycol

and pH 8.6-9 Administer in dextrose containing IV solutions at a more

rapid rate.

Equally effective: Time for conversion of pro-drug to active drug (8-15minutes) = therapeutic phenytoin concentrations reached at the same time.

Cost: Fosphenytoin 3 times equivalent dose of IV Phenytoin. Benefit: More favorable side effect profile (purple glove

syndrome)

Experimental Rescue therapy

NG phenobarbitone 20mg/kg given during level 2 intervention Provided good airway protection and ability for gastric absorption

…

Study at Red Cross (Wilmshurst et al J Paed Child Health 2009) Any child / infant entering established status (Level 2) 1-4 hours to therapeutic levels SAFE No need for repeat dosage for therapeutic levels but for control

of seizures could safely repeat Good viable addition to the protocol – especially where

parenteral access or supply lacking

Syed et al;Dev Pharmacol Ther 1986Yska et al;Pharm World Sci 2000

Yukuwa et al;J Clin Pharm Ther 2005

Level 3 intervention

Basically heading into refractory status Disastrous situation Resistant seizures –

prob exacerbated by underlying cause ( eg encephalitis),

secondary complications from drugs hypotension, respiratory depression

all affecting brain perfusion Sahin et al;Neurol 2003

Scott et al, ARCH 1998

Holtkamp et al; JNNP 2005

Level 3 intervention: Treatment of refractory SE

No prospective randomised trials comparing the effects of anesthetics in the treatment of RSE. Safety data lacking.

Options: Barbiturate anesthetics: Pentobarbital (US)

Thiopental (Europe Aus) Propofol Midazolam.

Evidence based medicine: No recommendations on data available.

Even in a large survey of neurologists in USA – little consensus for 3rd / 4th line intervention (J Neurol Sci 2003)

Rosenow et al;Epileptic Disord 2002

Midazolam infusion

Requires a syringe driver Greater risk of airway suppression (especially following

previous Benzo boluses) Takes long time to gain control (range 15 mins – 4.5

hours) Potential for children left with prolonged seizures and

irreversible neuronal cell death in centres without high care facilities

NOTE: Excluded from APLS guidelines

Rivera et al; CCM 1993Lal Koul et al; ARCH 1997

Ozdemir et al; Seizure 2005

CLONAZEPAM INFUSION

NO EVIDENCE

Thiopentone

Poor anticonvulsant Marked haemodynamic effects Prolonged drug effects if infusion used Local ICU capacity limited

Staffing Monitoring Anaesthetic experience

Very-high-dose Phenobarbitone Both barbiturates and benzodiazepines exert a primary effect on

the GABA receptor complex.

No antiepileptic ceiling effect ! No maximum dose beyond which further doses are likely to be ineffective >200mgkg!

Complications: Sedative and respiratory-depressant properties more likely in

combination with benzodiazepines. Hypotension unusual and related to the highest Phenobarbitone

levels and easily controllable. Complications usually related to underlying aetiology

Crawford et al; Neurol 1988

Intravenous Sodium Valproate FDA approved 1996. Not in APLS guidelines

No reports of respiratory depression or hypotension. Caution in children with underlying liver disease or suspected mitochondrial

disorder. Potential hepatic encephalopathy

Comparative studies: Intravenous Sodium Valproate vs Diazepam infusion Intravenous Sodium Valproate vs Phenytoin.

No large studies measuring efficacy Larger paediatric focused studies are needed

Still need syringe driver Very expensive

Drug of choice: Absence status

Limdi et al; Neurology 2005Rossetti & Bromfield; Neurology 2005

Limbdi N et al Epilepsia 2007 48(3):478-483 Morton L et al Pediatr Neurol 2007;36:81-83

Metha V et al J Child Neuro 2007; 22:1191

IV Levetiracetam

FDA approved adults over 16 yrs since 2006 Limited data in children (most retrospective

case reviews – n=10 and n=32) Loaded with 25-50mg/kg at level 3 Effective Safe Larger comparison studies needed

Kirmani et al Ped Neurol 2009Abend et al Pediatr Crit Care Med 2009

Gamez-Leyva et al CND Drugs 2009

Mx of status epilepticus in SA Most centres policy of repeated IV PB boluses

Resulted (anecdotally) dramatic reduction in admissions to PICU and complications of status epilepticus

IV Pb: WHO / IMCI guidelines first line for neonates; 2nd line for infants / children in Mx status

Why is IV phenobarbitone so good for resource poor countries? Highly effective at controlling status Safe Cheap It can be given by rapid IV bolus It can be repeated It can be given by IM route No need for syringe driver

If control not attained at 1 hour time to arrange transfer to tertiary unit – exceptional situation

Crawford et al; Neurol 1988; Wilmshurst & Newton; DMCN 2005

Lee et al;Pediatr Neurol 2005

Overall

Still do not have the ideal solution Still do not know what this is Need effective, rapidly acting, easy to

administer, cheap agent ..

Watch this space! Prospective comparison study underway

relevant for RLC

Final recommendations

2 targets Rapid identification of the underlying aetiology

Affects treatment Affects prognosis

Early initiation towards terminating SE Decreases morbidity and mortality

Recommend Level 1 – benzodiazepines Level 2 – phenytoin, phenobarbitone, sodium

valproate Level 3 – “other medications” e.g. levetiracetam and

pharmacologic coma induction Abend and Marsh. Curr Treat Options Neurol 2009