CURRICULUM VITAE

dr. Imam Rusdi,Sp S (K)

Lahir Pekerjaan Alamat : Yogyakarta, 16 September 1952 : Dosen /dokter : Jl Sisingamangaraja 76 Jogja

Riwayat Pendidikan Spesialis Saraf UGM (1997) Riwayat Jabatan / pekerjaan - KepalaSMF Saraf/BagianSarafRS Sardjito/FK UGM - Anggota PERDOSSI - AnggotaPokdiNyeri&NyeriKepala - AnggotaPokdiEpilepsi

Neuro-Emergency Update
Status Epilepticus in
Children Adult Pregnancy Childbearing

Imam rusdi, Neuro-Emergency Update,FK UGM/RS Dr Sardjito, 26-27 Maret 2011

Status Epilepticus (SE)

The term status epilepticus may be used to describe any continuing type of seizure. Status epilepticus is a common, life-threatening neurologic disorder. It is essentially an acute, prolonged epileptic crisis. In early studies, SE was defined by its duration, that is, as continuous seizures occurring for longer than 1 hour. Clinical and animal experiences later showed that pathologic changes and prognostic implications occurred when SE persisted for 30 minutes. Therefore, the time for the definition was shortened.
EFNS guideline on the management of status epilepticus in adults European Journal of Neurology 2010, 17: 348355
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Status Epilepticus (SE)-cont

More than 30 minutes of continuous seizure activity or two or more sequential seizures without full recovery of consciousness between seizures. More recently, SE be defined as any seizure lasting longer than 5 minutes based on natural history data that show typical generalized convulsive seizures that resolve spontaneously after 3-5 minutes.

Causes of SE
Diagnosis
Stroke

Children (%)
3

Adults (%)
25

Drug change/noncompliance
Alcohol/other drugs CNS infection Hypoxia Metabolic Tumor Trauma Fever/infection Congenital

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2 5 5 10 <1 3.5 35 10

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15 10 10 10 5 5 2 <1
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Causes of SE
o o o o o o Low blood concentrations of AED Remote symptomatic causes Cerebrovascular accidents Anoxia or hypoxia Metabolic causes Alcohol and drug withdrawal (34%) (24%) (22%) (10%) (10%) (10%)

SE Classification
Generalized convulsive SE (GCSE) Subtle SE Non-Convulsive SE (NCSE)
Absence SE Complex partial SE

Simple Partial SE

Non Colvulsive Status Epilepticus

NCSE refers to continuous seizure activity without predominant motor activity. This should not be confused with subtle status epileptics which refers to GCSE in which the motor findings have diminished either through high doses of administered medications or from muscular fatigue due to prolonged seizure activity
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Patomekanisme Status Epilepticus

Proses dasar dari munculnya SE adalah gagalnya mekanisme normal untuk mengakhiri serangan. Inhibisi yang menurun dan excitasi yang persisten menimbulkan aktifitas serangan yang berlangsung terus menerus. Selama aktifitas serangan yang berkepanjangan, terjadi perubahan dinamika pada fungsi reseptor GABAA dan fungsi reseptor NMDA yang dikenal dengan receptor traficking.
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Patomekanisme Status Epilepticus

cont. Aktifitas serangan yang berlangsung terus akan mengurangi secara bertahap reseptor2 GABAA pada synaptic membrane diikuti dengan internalisasi reseptor ke dalam vesikel2 endositotik dan degradasi berikutnya. Proses ini berakibat pada erosi endogen GABA ergic inhibisi yang akan meningkatkann aktifitas epileptic berkepanjangan.

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Patomekanisme Status Epilepticus

cont.
Hilangnya reseptor GABAA post sinaptik merupakan factor patofisiologik yg relevan sehingga terjadi farmakoresisten terhadap obat2 seperti benzodiazepine, barbiturate dan propofol. Sebaliknya, selama aktifitas epileptic berlangsung, reseptor NMDA secara progresif berpindah ke synaptic membrane, sehingga menambah reseptor NMDA exitatorik presynaps. Proses ini memudahkan exitabilitas neuron dan berikutnya memperpanjang SE.
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Patomekanisme Status Epilepticus

cont.

Namun sebaliknya, meningkatnya expressi reseptor Glutamat dapat merupakan target yang dipakai pada farmakological management dari SE advanced stage. Absance SE with 3-Hz spike wave discharge akan menginduksi dengan excessive inhibition. Bentuk SE spt ini tdk menyebabkan neuronal injury dengan excitasi yang excessive.

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Seizures produce a number of physiologic consequences.

During a generalized convulsion transient apnea and hypoxia. Initially, brain compensatory mechanisms may prevent neuronal injury from seizures hypertension with increased cerebral blood flow. Normal physiological response includes an increase in body temperature with up to 43% Temperature >100 F
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Seizures produce a number of physiologic consequences. Cont.

Glucose levels also increase, and lactic acidosis (occurs within 60 seconds of a convulsive event and normalizes within one hour after ictus).
A rise in the peripheral white blood cell count without an increase in bands is often seen. If the seizure persists, at approximately 30 minutes the homeostatic mechanisms begin to deteriorate.
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Seizures produce a number of physiologic consequences. Cont.

Animal models suggest that, even if systemic factors, such as acidosis and hypoxia are controlled, prolonged status epilepticus results in direct neuronal damage from neurotoxic amino acids and calcium influx.

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Differential Diagnosis of Status Epilepticus

A number of conditions mimic seizures. These include convulsive syncope (with or without cardiac dysrhythmias), decerebrate posturing, psychogenic events, dystonia, and migraine headaches. Patients with strychnine poisoning may develop seizure-like activity yet demonstrate normal mental status.

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Management of Status Epilepticus

oPrehospital Concerns oEmergency Departement oICU

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Prehospital Concerns
Managing the airway Maintaining oxygenation Obtaining Intra Venous access Protecting the patient from injury. (The use of a padded tongue blade is contraindicated since it may induce emesis or break a tooth )

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Prehospital Concerns cont..

In most cases, pre-hospital personnel will arrive at least 5 minutes after the onset of seizure activity, such that patients who are still seizing should be managed as presumed status epilepticus. If a patient is found convulsing or remains confused or unresponsive, paramedics should immediately measure the patients blood sugar or, if this test is not available, they can empirically administer dextrose (D50).
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Prehospital Concerns cont..

When IV access is not immediately available, rectal diazepam is an option. One prospective study reported that there were no significant differences between rectal and intravenous diazepam therapy with regard to SE duration, intubation, or recurrent seizures in the emergency department (ED). These data suggest that prehospital administration of diazepam may shorten the duration of SE in children and simplify the subsequent management.
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Prehospital Concerns cont..

In a retrospective study on prehospital seizure management in children, rectal diazepam (5 mg/kg), was compared to IM midazolam(15 mg /kg). Over the 4 year study period, 2566 children presented with seizures and 107 children were eligible for entry into the study. Of these 107 patients received diazepam and 45 received midazolam.

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Prehospital Concerns cont..

Both drugs were effective in stopping seizures within 5 minutes of drug administration; however, fewer patients in the midazolam group suffered apnea. In a study comparing IV diazepam to IM midazolam, Chamberlain et al concluded that IM midazolam is an effective anticonvulsant for children with motor seizures and an important alternative when IV access is not easily available.

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Prehospital Concerns cont..

Vilke et al compared IM to IV midazolam and reported that IV delivery was more effective: 47/49 in the IV group vs 20/25 with IM administration (p less than 0.05). Four patients (three treated IM and one IV) had respiratory compromise necessitating field airway management. In light of the Chamberlain and Vilke studies, some experts recommend IV midazolam as the agent of choice in the prehospital management of seizures.
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Diagnostic Testing Laboratory

Tests include a determination of : serum glucose electrolytes urea nitrogen, creatinine magnesium, phosphate, calcium complete blood count pregnancy tests anti-epileptic drug levels liver function tests drugs of abuse screening.
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Status Epilepticus Clinical manifestations

Convulsive SE
Related to acutely elevated serum catecholamine levels Respiratory interference Cardiovascular system adversely affected Acidosis and rhabdomyolysis
Hyperkalemia Myoglobinuria

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Status Epilepticus Clinical manifestations

Nonconvulsive SE (10-15%)
Obtundation
underlying systemic or neurological disorder sedating or paralyzing medication

Alterations in behavior
Slow mentation Confusion Stupor coma

Unexplained, prolonged coma

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Subtle clinical and physiological changes in Nonconvulsive Seizures

Clinical changes
Early
Tachycardia Hypertension Eye deviation Facial twitch Rapid and deep respiration Salivation Pupillary dilation Desaturation Hypotension Hypo- or hyperthermia

Physiological changes

Hyperglycemia Acidosis respiratory and metabolic Increased prolactin

Late

EEG should be considered if any of these symptoms detected in a patient with unexplained coma

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Protocol for Convulsive SE

Minutes 0-5 100% O2 by mask or canula Head position for airway patency Assist ventilation if necessary Cardiac monitoring Record vital signs: BP, temperature, etc. Check glucose Establish IV Draw blood for glucose, chemistry, CBC, toxicology, antiseizure medication level, etc.
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Protocol for Convulsive SE

Minutes 5-15
Thiamine 100 mg IV and 50 ml D50W if indicated Sedatives
Lorazepam (ativan) 0.1 mg/kg IV, 2 mg/min, OR Diazepam (valium) 0.2 mg/kg IV, 5 mg/min, OR Diazepam (valium) 0.5 mg/kg per rectum (if no IV)

Anticonvulsant
Fosphenytoin 15-20 mg/kg IV, 150 mg/min, OR Phenytoin (dilantin) 15-20 mg/kg IV, 50 mg/min, OR Valproic acid (depakin) 800 mg IV

Monitor BP and cardiac rhythm Do not infuse phenytoin through a line containing glucose
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Protocol for Convulsive SE

Minutes 15-30
Repeat lorazepam or diazepam if seizure continues Additional fosphenytoin or phenyoin in increments dose of 5 mg/kg to total 30 mg/kg

Minutes 30-60
Monitor respirations because patient may require assisted ventilation (intubation). Monitor EEG. If status persists, give phenobarbital 20 mg/kg, 100 mg/min Midazolam (dormicum) IV infusion (0.2 mg/kg slow bolus; 0.1-2.0 mg/kg/hr) Propofol 1-5 mg/kg bolus over 5 min, then 2-4 mg/kg/hr

Minutes 60 or more
If status remains refractory, consider pentobarbital 5 mg/kg load, then 1-4 mg/kg/h infusion
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Treatment of Nonconvulsive SE
Treatment
IV diazepam (5-10 mg), or IV lorazepam (1-2 mg) Disappearance of epileptiform EEG abnormality and improvement of mental state

Long-term seizure control

IV phenytoin, phenobarbital, valproic acid Oral gabapentin (Neurontin) or levetiracetam (Keppra)
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Seizures continuing stage of Refractory Status Epilepticus

General anesthesia should be induced Propofol : 2mg/kg IV bolus, Repeat if necessary, followed by infusion (5mg/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 : 0.1-0.3mg/kg IV bolus dose at the rate of 4mg/min followed by infusion(0.05-0.4mg/kg/hr) If seizures have been controlled for 12hrs., reduce the dose over further 12hrs. If seizure recurs again GA agent should be given

Lancet Neurol 2006; 5: 252

Differential Diagnosis Of Altered Mental Status In The Patient Who Has Seized

Post-ictal state NCSE or subtle convulsive status Hypoglycemia CNS infection CNS vascular event Drug toxicity Psychiatric disorder
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Nonconvulsive Status Epilepticus (NCSE)

NCSE, like convulsive status epilepticus, is a state of continuous or intermittent seizure activity lasting more than thirty minutes without a return to baseline function.

NCSE can be either a primary generalized process (absence status) or secondary generalized (complex partial status).

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NCSE
Though the distinction is not clear in the literature, NCSE in general should be distinguished from subtle GCSE, which is the end stage of GCSE, associated with anoxic brain injury, and has a very poor prognosis.

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Treatment of NCSE
When presented with a patient thought to be in NCSE, EEG confirmation is indicated. Benzodiazepines are generally effective in terminating the seizure, though they do not provide long term control. The literature is unclear as to the urgency of controlling NCSE, although there is evidence that ongoing neuronal firing does result in neuronal injury. A neurology consultation should be obtained to determine long-term therapy.
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Special Situations
Alcohol Withdrawal Seizures (AWS)
Of special concern to any emergency physician is the relation of alcohol to seizures. Twenty to 40% of seizure patients presenting to an ED will have their seizures related to alcohol abuse, and alcohol is reported as a causative factor in 15 to 24% of patients with status epilepticus. Diagnostic yield for CT after first alcohol related seizure is high, mainly because patients who overuse alcohol have a high incidence of structural intracranial lesions, such as subdural hematomas or other intracranial hemorrhages.

Eclampsia
Eclampsia is the major consideration in pregnant patients of more than 20-week gestation and up to 23 days postpartum who present with new onset seizures. Magnesium has been demonstrated to be the therapy of choice in the treatment of acute eclamptic seizures and for prevention of recurrent eclamptic seizures. A systematic review of four good quality trials involving 823 women found magnesium sulfate to be substantially more effective than phenytoin with regards to recurrence of convulsions and maternal death.
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Eclampsia
Complications, such as respiratory depression and pneumonia, were also less for magnesium than for phenytoin. Magnesium showed a trend towards increased incidence of renal failure when compared to phenytoin; however, this was not statistically significant. Magnesium sulfate was also associated with benefits for the baby, including fewer admissions to the NICU.

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Eclampsia
In the eclamptic patient, give 4 grams of intravenous magnesium sulfate followed by a 2 gm/h drip (some centers use intramuscular regimens). Control the patients blood pressure if very high (SBP greater than 160 and/or DBP greater than 110)

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Febrile Seizures
The major challenge of an emergency physician when presented with a febrile seizure idifferentiating simple from complex febrile seizure. By definition, a simple febrile seizure lasts less than 15 minutes, is non-focal, does not have a prolonged postictal period and occurs in a child between six months and five years of age.

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Febrile Seizures
Ten to 50% of cases of status epilepticus in children are associated with febrile seizures; status in this group is a consistent predictor of increased risk for subsequent seizures. Simple febrile seizures are a benign process. When they occur in children older than 18 months who have not been on antibiotics, they do not require any particular diagnostic work-up, even for a first time event. Management focuses on a careful history and physical, and on parental education.
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Febrile Seizures
Two to four percent of all children will have a simple febrile seizure. Children who have had a febrile seizure have a 25 to 50% chance of having a second event, usually within a year. Children at highest risk for recurrence are those with a first degree relative who has had a febrile seizure, complex first febrile seizure, or age younger that one year when the first event occurred. There is an increased incidence of developing epilepsy in children who have had a simple febrile seizure (2.4% versus a .4% incidence in the general population).

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Febrile Seizures
Patients with simple febrile seizures require no special workup or treatment. Reassuring the parents is often the most Herculean task. Nearly half of parents think that their child is dying during the seizure. Such concerns need to be addressed; simply suggesting the child be discharged on acetaminophen is not appropriate.

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Non-Febrile Seizures
The evaluation of non-febrile seizures, complex seizures, and febrile seizure outside of the usual age group, in essence, parallels the discussion presented on adults in the preceding sections. If the seizure was exertional, consider the possibility of convulsive syncope secondary to a cardiac arrhythmia. In children, this could be due to a prolonged QT syndrome or hypertrophic cardiomyopathy. During the evaluation, be attentive to the stigmata of the phakomatoses (hereditary disease characterized by tumors in multiple tissues) such caf au lait spots (tuberous sclerosis) or fleshy bumps (neurofibromatosis). Both of these may result in seizures secondary to CNS tumors.
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Status Epilepticus In Children

The treatment of status seizures in children is similar to that of adults. Interosseous access is an alternative when intravenous access is not secured. While rectal diazepam has long been used as an alternative to parenteral administration in children, buccal midazolam may be equally effective (and more palatable). Intranasal midazolam (0.2 mg/kg) has been reported to have equal efficacy with IV diazepam (0.3 mg/kg) for prolonged febrile seizures. .
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Status Epilepticus in Children

Both phenytoin and phenobarbital are often effective in pediatric status if a bolus administration of a benzodiazepine fails. However, as in adults, continuous infusion of benzodiazepines have been reported as successful. Infection has been reported as a more common cause of status in children than in adults. Therefore, many physicians will empirically cover such children with broad-spectrum antibiotics, usually ceftriaxone (or the combination of ceftriaxone and amoxicillin in neonates). The routine use of empiric acyclovir to treat presumed herpes encephalitis in the neonate remains unstudied.

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Status Epilepticus in Children

Status epilepticus (SE) presents in a multitude of forms, dependent on etiology and patient age (myoclonic, tonic, subtle, tonic-clonic, absence, complex partial etc.) Generalized, tonic-clonic SE is the most common form of SE

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

tumor, drugs)...
DeLorenzo RJ. Epilepsia 1992;33 Suppl 4:S15-25

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Drugs which can cause seizures

Antibiotics
Penicillins Isoniazid Metronidazole

Psychopharmaceuticals
Antihistamines Antidepressants Antipsychotics Phencyclidine Tricyclic antidepressants

Anesthetics, narcotics
Halothane, enflurane Cocaine, fentanyl Ketamine

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Mortality
Adults Children 15 to 22% 3 to 15%

Reviewed in: Fountain NB, Epilepsia 2000; 41 Suppl 2:S 23-30

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Prolonged seizures

Temporary Systemic changes

Life threatening systemic changes

Death

Duration of seizure

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Respiratory
Hypoxia and hypercarbia
ventilation (chest rigidity from muscle spasm) Hypermetabolism ( O2 consumption, CO2 production) Poor handling of secretions
- Neurogenic pulmonary edema?

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Hypoxia
Hypoxia/anoxia markedly increase the risk of mortality in SE Seizures (without hypoxia) are much less dangerous than seizures and hypoxia

Towne AR. Epilepsia 1994; 35(1): 27-34

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Neurogenic pulmonary edema

Rare complication Likely occurs as consequence of marked increase of pulmonary vascular pressure

Johnston SC. Postictal pulmonary edema requires pulmonary vascular pressure increases. Epilepsia 1996; 37(5):428-32
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Acidosis
Respiratory

Lactic
Impaired tissue oxygenation Increased energy expenditure

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Hemodynamics
Sympathetic overdrive
Massive catecholamine / autonomic discharge Hypertension Tachycardia High CVP

Exhaustion
Hypotension hypoperfusion

0 min

60 min

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Cerebral blood flow

Cerebral O2 requirement

O2 requirement

Hyperdynamic phase
CBF meets CMRO2

Exhaustion phase
CBF drops as Hypotension sets in Autoregulation exhausted Neuronal demage ensue

Blood flow Blood pressure

Seizure duration
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Glucose

Glucose

SE

30 min

SE + hypoxia

Seizure duration
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Hyperpyrexia
Hyperpyrexia may develop during protracted SE, and aggravate possible mismatch of cerebral metabolic requirement and substrate delivery
Treat hyperpyrexia aggressively
Antipyretics, external cooling Consider intubation, relaxation, ventilation

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Other alterations
Blood leukocytosis (50% of children) Spinal fluid leukocytosis (15% of children) K+ Creatine kinase Myoglobinuria

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A B C

Oxygen, oral airway. Avoid hypoxia! Consider bag-valve mask ventilation. Consider intubation IV/IO access. Treat hypotension, but NOT hypertension

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Treatment
Arterial blood gas?
All children in SE have acidosis. It often resolves rapidly with termination of SE

Intubate?
It may be difficult to intubate the actively seizing child Stop or slow seizures first, give O2, consider BVM ventilation If using paralytic agent to intubate, assume that SE continues
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Initial investigations
Labs
Na, Ca, Mg, PO4 , glucose CBC Liver function tests, ammonia Anticonvulsant level Toxicology

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Initial investigations
Lumbar puncture
Always defer LP in unstable patient, but never delay antibiotic/antiviral rx if indicated

CT scan
Indicated for focal seizures or deficit, history of trauma or bleeding d/o

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Treatment
give Glucose (2-4 ml/kg D25%, infants 5 ml/kg D10%), unless normo- or hyperglycemic

Hyperglycemia has no negative effect in SE

(as long as significant hyperosmolality is being avoided)

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Treatment
Hyponatremia:
Give 5 cc/kg of 3% (hypertonic saline)

Hypocalcemia:
Give 20-25 mg/kg of Calcium Chloride

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Treatment
The longer you wait with anticonvulsant, the more anticonvulsant you will need to stop SE
Most common mistake is ineffective dose

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Anticonvulsants
Rapid acting
plus

Long acting

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Anticonvulsants - Rapid acting

Benzodiazepines
Lorazepam 0.1 mg/kg i.v. over 1-2 minutes Diazepam 0.2 mg/kg i.v. over 1-2 minutes

If SE persists, repeat every 5-10 minutes

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Benzodiazepines
Lorazepam
Low lipid solubility Action delayed 2 minutes Anticonvulsant effect 6-12 hrs Less respiratory depression than diazepam

Diazepam
High lipid solubility Thus very rapid onset Redistributes rapidly Thus rapid loss of anticonvulsant effect Adverse effects are persistent:
Hypotension Respir depression
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Midazolam
May be given i.m.

Anticonvulsants - Long acting

Phenytoin
20 mg/kg i.v. over 20 min pH 12 Extravasation causes severe tissue injury Onset 10-30 min May cause hypotension, dysrhythmia Cheap

Fosphenytoin
20 mg PE/kg i.v. over 5-7 min PE = phenytoin equivalent pH 8.6 Extravasation well tolerated Onset 5-10 min May cause hypotension Expensive

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Anticonvulsants - Long acting

Phenobarbital
20 mg/k g i.v. over 10 - 15 min Onset 15-30 min May cause hypotension, respiratory depression

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Initial choice of long acting anticonvulsants in SE

Is patient an infant? Is patient already receiving phenytoin?

No

Yes

At high risk for extravasation ?

(small vein, difficult access etc.)?
No Yes

Phenobarbital

Phenytoin

Fosphenytoin
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If SE persists
Midazolam infusion 1 - 10 mcg/kg/min after bolus 0.15 mg/kg Pentobarbital infusion 1-3 mg/kg/hr after bolus 10 mg/kg

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NCSE?
Neurologic signs after termination of SE are common:
Pupillary changes Abnormal tone Babinski Posturing Clonus May be asymmetrical
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NCSE?

Up to 20% of children with SE have NCSE after GCSE

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NCSE?
If child does not begin to respond to painful stimuli within 20 - 30 minutes after tonic-clonic SE suspect non-convulsive SE
Urgent EEG

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Management of a pregnant patient in status epilepticus

Establish the ABCs, and check vital signs, including oxygenation. Assess the fetal heart rate or fetal status. Rule out eclampsia. Administer a bolus of lorazepam (0.1 mg/kg, ie, 5-10 mg) at no faster than 2 mg/min. Load phenytoin (20 mg/kg, ie, 1-2 g) at no faster than 50 mg/min, with cardiac monitoring. If this is not successful, load phenobarbital (20 mg/kg, ie, 1-2 g) at no faster than 100 mg/min. Check laboratory findings, including electrolytes, AED levels, glucose, and toxicology screen. If fetal testing results are nonreassuring, move to emergent delivery.
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Management of WWE upon labor and delivery

Check levels of antiepileptic drugs (AEDs). Inform all care providers, including nurses, anesthesiologists, and pediatricians, that the patient has epilepsy. Consider seizure prophylaxis with intravenous benzodiazepines or phenytoin. Manage seizures acutely with intravenous benzodiazepines (1-2 mg of diazepam), then load phenytoin (1 g loaded over 1 h). Labor management should be based on routine standards of care. Start administration of vitamin K for the infant, and send the cord blood for clotting studies.
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Alhamdulillahirobbil alamin Semoga bermanfaat

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