Status Epilepticus

status epilepticus in pediatric emergency

1. STATUS EPILEPTICUS Dr . Kumar keshav chandra JR 3, Dept of Pediatrics

2. Status epilepticus (SE) is a medical emergency that should be anticipated in any patient who presents with an acute seizure. The ILAE has refined the definition of SE to reflect the time at which treatment should be initiated (t1 ) and time at which continuous seizure activity leads to long-term sequelae (t2 ) such as neuronal injury.

3. Classic old definition was seizure lasting more than 30min or 2 or more seizure in this duration without regaining consciousness in between. This definition was based based on animal studies that showed evidence of neuronal damage after this time point, but this has been reduced to emphasize the risks involved with the longer durations and the need for early and aggressive pharmacologic intervention

4. For generalized tonic- clonic seizures, SE is defined as continuous convulsive activity or recurrent generalized convulsive seizure activity without regaining of consciousness (t1=5min, t2 ≥ 30 min). The definition differs for SE consisting of focal seizures with impaired awareness (t1 = 10 min, t2 = 30 min) and absence SE (t1 = 10-15 min, t2 = unknown ).

5. Time after which if seizure don’t terminate , pt considered in SE (t1) Time after which ongoing seizure have long term consequences (t2) Convulsive SE 5 min 30 min Focal SE with impaired consciousness 10 min >60 min Absence SE 10-15 min unknown

6. Operational definition of SE limited to 5min because most seizures will terminate within 2min and if it persists beyond 5min its unlikely terminate and more damage to the brain. more practically any patient who presents to health care facility in convulsing state should be assumed to be in SE.

7. Convulsive SE :- MC type of SE. -manifests as generalized tonic, clonic , or tonic- clonic Non convulsive SE :- focal SE with impaired consciousness Absence SE Manifests as - confusional state, dementia, - hyperactivity with behavioral problems, - fluctuating impairment of consciousness, -with at times unsteady sitting or walking, -fluctuating mental status, hallucinations, paranoia, aggressiveness catatonia, and or psychotic symptoms. It should be considered in any of these situations, especially in an unresponsive or encephalopathic child.

8. Refractory SE :- is SE that has failed to respond to therapy, usually with at least two medications (such as a benzodiazepine and another 2 nd line medications such as phenytoin , levetiracetam , valproic acid). Superrefractory SE ;- is SE that has failed to resolve, or recurs, within 24 hr or more despite therapy that includes a continuous infusion such as midazolam and/or pentobarbital.

9. New-onset refractory status epilepticus (NORSE) has been identified as a distinct entity that can be caused by almost any of the causes of SE in a patientwithout prior epilepsy. It also is often of unknown etiology, presumed to be encephalitic or postencephalitic , can last several weeks or longer, and often, has a poor prognosis.

10. Devastating epileptic encephalopathy in school-age children (DESC ), also called fever-induced refractory epilepticencephalopathy in school age children ( FIRES ), :- is a syndrome of refractory SE that is associated with acute febrile infections, appears to be parainfectious in nature appears to be highly drug resistant often responsive to the ketogenic diet.

11. The incidence of SE ranges between 10 and 60 per 100,000 population. SE is most common in children younger than 5 yr of age, with an incidence in this age-group of > 100 per 100,000 children. Approximately 30% of patients presenting with SE are having their first seizure, and approximately 40% of these later develop epilepsy. Febrile status epilepticus is the most common type of SE in children In the 1950s and 1960s, mortality rates of 6–18% were reported after SE. Currently, with the recognition of SE as a medical emergency, a lower mortality rate of 4–5% is observed, most of it secondary to the underlying etiology rather than to the seizures. SE carries an approximately 14% risk of new neurologic deficits, most of them (12.5%) secondary to the underlying pathology

12. Etiology New-onset epilepsy of any type Febrile SE Drug intoxication (TCA) in children and drug and alcohol abuse in adolescents; drug withdrawal or overdose in patients taking AEDs Hypoglycemia; Hypocalcemia ; Hyponatremia ; Hypomagnesemia ; Acute head trauma; encephalitis; meningitis; autoimmune encephalitis Ischemic (arterial or venous) stroke Intracranial hemorrhage Folinic acid and pyridoxine and pyridoxal -phosphate dependency (these usually present in infancy, but childhood onset is also possible.

13. Inborn errors of metabolism such as nonketotic hyperglycinemia in neonates and mitochondrial encephalopathy with lactic acidosis (MELAS) in infants, children and adolescents; ion channel–related epilepsies (e.g., sodium and potassium channel mutations) Hypoxic-ischemic injury (e.g., after cardiac arrest), Systemic conditions (such as hypertensive encephalopathy, posterior reversible encephalopathy, renal or hepatic encephalopathy); brain tumors; brain malformations, neurodegenerative disorders. Infections that are more likely to cause encephalitis with SE, such as - herpes simplex (complex partial and convulsive status), - Bartonella (particularly nonconvulsive status), -Epstein-Barr virus , and - mycoplasma ( postinfectious encephalomyelitis with any type of status epilepticus ). Postinfectious encephalitis and acute disseminated encephalomyelitis are common causes of SE, including refractory SE.

14. PATHOPHYSIOLOGY failure of desensitization of AMPA glutamate receptors, thus causing the persistence of increased excitability, Reduction of GABA-mediated inhibition as a result of intracellular internalization of GABAA receptors. This explains the clinical observation that SE is often less likely to stop in the next specific period of time the longer the seizure has lasted and why benzodiazepines appear to be decreasingly effective the longer seizure activity lasts. During SE, there is an increased cerebral metabolic rate and a compensatory increase in cerebral blood flow that, after approximately 30 min, is not able to keep up with the increases in cerebral metabolic rate. This leads to a transition from adequate to inadequate cerebral oxygen tensions and, together with other factors, contributes to neuronal injury resulting from SE. AMPA( alpha amino 3-hydroxy 5-methyl lisoxazole 4-proproinate )

15. CNS damage -----mechanism:- uncontrolled neuronal firing -> excess glutamate -> this sustained high influx of calcium ions into neurons leads to cell death (“ excitotoxicity ”) GABA released to counteract this, but GABA receptors eventually desensitize these effects worsened if hyperthermia, hypoxia, or hypotension

16. Clinical presentation MC is convusing SE. During initial compensatory phase-sympathetic overdrive leading to- - increased C.O -increased BP -increased RBS -increased blood lactate levels

17. Decompensation –homeostatic failure Reduced  C.O/ BS/SPO2 levels leading to 1. Cardiorespiratory collapse 2. Electrolyte imbalance 3. Rhabdomyolysis - Renal tubular necrosis 4.Hyperthermia 5 . Raised ICP & cerebral edema

18. Important to obtain a brief history It is important to obtain a brief history including any history of seizure disorder, other symptoms (fever ), medication usage and allergies to medications. This can be completed by a designated person not immediately involved in the acute resuscitation. This history will allow a simultaneous search for cause and focused physical examination to be completed while termination of the seizure is undertaken.

19. MANAGEMENT Broadly divided into :- 1)Initial stabilization 2)Seizure termination 3)Evaluation and Treatment of underlying cause Both diagnostic evaluation and seizure control should be achieved simultaneously to improve the outcome.

20. Initial Stabilization: Airway: airway patency is maintained, 100 % O 2 should be provided to prevent hypoxia Breathing: in case of respiratory failure if GCS score is less than 8, rapid sequence intubation must be done. Circulation: IV access should be secured promptly. In case IV access is not easily accessible buccal, rectal or intraosseus route can be considered Vital parameters like Heart rate ,Respiratory rate,ECG and Oxygenation saturation should be monitored

21. Seizure termination Pharmacotherapy:- Mechanisms of action of AEDs, which are diverse, mainly involving modulation of voltage-activated ion channels, potentiation of GABA, and inhibition of glutamate. 1. Benzodiazepines:- these are 1 st line drug for SE using either i /v lorazepam , i /v diazepam, or i /m midazolam . BZD act at the GABA receptor and inhibit neuronal transmission. However, as seizures progress, these receptors are internalized resulting in lesser efficacy of these drugs in prolonged seizures. The potency of benzodiazepines may decrease 20-fold in 30 min of SE. If intravenous access is not available, other options besides i /m midazolam include buccal or intranasal midazolam, intranasal lorazepam, or rectal diazepam. With all options, respiratory depression is a potential side effect for which the patient should be monitored and managed as needed. If seizures persist 5 min after the initial benzodiazepine dose, a second dose of the drug should be given.

22. 2. PHENYTOIN:- Phenytoin , as a second line agent, is usually indicated when seizure is not controlled after one or more doses of benzodiazepines. Phenytoin acts by slowing the rate of recovery of voltage-activated sodium channel. Infused at a L.D of 20mg/kg(not compatible with dextrose solution) and infused @ 1mg/kg/min. phosphenytion – water soluble phosphate ester of phenytoin and a prodrug of phenytoin . Lesser side effect as compared to phenytoin . 75 mg of phosphenytoin is equivalent to 50 mg of phenytoin .

23. 3 . Phenobarb :- acts by enhancing GABAa activity. Used at a L.D of 20 mg/kg and infused @2mg/kg/min has high incidence of resp depression , especiallu when used in addition to BZDs. 4. Valproate :- acts It acts through several mechanisms of action including modulation of sodium and calcium currents, and increasing inhibitory GABA transmission. It has especially low risk of hemodynamic adverse effects even at very high infusion rates. Variable doses ranging from 20 to 40 mg/kg over 5-10 min have been used with success. 5. Levetiracetam :- It is a new broad spectrum anticonvulsant. It is minimally protein bound and excreted via renal route, hence requiring dosage modification in renal dysfunction. It is free of any significant drug interactions. It has multiple sites of action including calcium channels glutamate receptors and GABA modulation. Also having Neuroprotective effects. L.D @20-60 mg/kg at 5 mg/kg/min..

24. 6.Pyridoxine:- Pyridoxine-dependent seizures occur due to a rare AR mutation in the ALDHTA1 gene which encodes antiquitin . This condition usually presents in the early infantile period with seizures that are refractory to standard anticonvulsants. Intravenous pyridoxine 100mg trial should be considered in children< 2 age with refractory SE.

25. 7.Midazolam Infusion:- Midazolam is effective not only as a bolus dose in the ínitial management of SE but also later in SE or refractory SE when second line drugs have failed. - Midazolam is a water soluble benzodiazepine that is rapidly acting, and has a short half life. It is metabolized in the liver and excreted by the kidneys. - Midazolam has been used upto (32 ug /kg/min with no serious side effects. - While rapid escalation of infusion rate after a bolus dose may be associated with rapid seizure control, there would be a concern about early need for intubation and mechanical ventilation.

26. Management of refractory SE I V Mdazolam 0.2 mg/kg bolus followed by infusion @ 1 mcg/kg/min increasing to 1 mcg/kg/min every 5-10 min till seizure stop, upto a maximum of 30 mcg/kg/min. Starts tapering 24 hr after seizure stops@ 1 mcg/kg/min. Because most of these patients need to be intubated and paralyzed, the EEG becomes the method of choice by which to follow them. If seizure persists on midazolam infusion Barbiturate coma( Thiopentol and Pentobarbitol );- these are barbiturate anaesthetic , and have good efficacy in RSE but having serious side effect. Pentobarbitol is not available in India.

27. Thiopental has been used in a loading dose of 3-5 mg/kg followed by further boluses of 1-2 mg/kg within 3-5 min till seizure stop( max dose of 10mg/kg) followed by a continuous infusion of 3-5 mg/kg/hr. Starts tapering after 24 hr of seizure free period. Barbiturate coma is associated with serious side-effects including hypotension, respiratory depression and decreased cardiac contractility. These drugs may also cause suppression of lymphocyte activation which is a cause of concern in critically ill patients.

28. Propofol :- t is an intravenous general anesthetic, and acts through GABA receptors. Propofol can cause "propofol infusion syndrome in children with higher infusion rates (>67 μg /kg/min), characterized by cardiac failure, rhabdomyolysis , metabolic acidosis, renal failure, and sometimes death. This limits the use of propofol in the pediatric population Propofol is used as an initial bolus of 1-2 mg/kg, followed by a continuous infusion of 1-2 mg/kg/h and titrated to amaximum of 5 mg/kg/h. Limit use to <48 hr.

29. Ketamine ;- It is a non-competitive NMDA receptor antagonist, and may also have additional neuroprotective effects. It is administered iv with initial bolus of 1.5 mg/kg followed by an infusion @ of 0.01-0.05 mg/kg/h. However, ketamine may increase ICP and hence, should be used only after neuroimaging has ruled out Space occupying lesion. Starts tapering after 24 hr of seizure free period.

30. superrefractory SE Patients with superrefractory SE have persistent seizure activity or seizure recurrence despite 24 hr of general anesthesia with medications such as midazolam , pentobarbital, and/or propofol . In addition to these continuous infusions, polytherapy with other AEDs is usually initiated, most commonly used drugs are fosphenytoin , valproate , phenobarbital , levetiracetam , topiramate , and lacosamide . It differentiates from refractory status epilepticus (RSE) by the failure of SE to resolve with anesthesia. Around 15% of all those presenting to the hospital in SE, develop Super-refractory status epilepticus and the mortality is 30-50%.

31. Others measure used in SRSE:- Ketogenic die t has also been found to be effective in patients with FIRES, focal seizures and autoimmune encephalitis. Immunotherapy with IV steroids, immunoglobulins , and/or plasma exchange is often used in cases of SRSE of unclear etiology. In specific situations such as anti-NMDA receptor encephalitis or CNS vasculitis immunotherapy may be the first-line therapy. Inhaled anesthetics such as isoflurane have been used for SRSE but are associated with a number of adverse reactions. Induced hypothermia has also been used but further studies are needed to assess its safety and efficacy. The use of vagal nerve stimulation, electroconvulsive therapy, and transcranial magnetic stimulation has also been reported emergent neurosurgery such as hemispherectomy for Rasmussen encephalitis or focal resection if the seizures are secondary to an area of cortical dysplasia. Allopregnanolone , a neurosteroid , has shown promise in the treatment of pediatric and adult SRSE, and clinical trials are currently underway to better determine its efficacy

32. TAKE HOME MESSAGES: Status Epilepticus is a life threatening medical emergency that requires prompt recognition and management. Attention to airway,breathing and circulation simultaneously while treating seizure. Early Rx aborts SE faster and prevents neuronal damage. Initial management should consist of parenteral benzodiazepines ; any agent by any route may be used depending upon the availability and urgency. Aggressive therapy is required for management of SE as prolonged seizures are less responsive to therapy.