Status Epilepticus

• Defined as a continuous convulsion lasting longer than 30 minutes or the occurrence of serial convulsions between which there is no return of consciousness.
• EPILEPSY FOUNDATION OF AMERICA
• It is a medical emergency that requires an organized and skillful approach to minimize the associated mortality and morbidity.

Newer Definition

• The definition has recently changed and continues to do so as new evidence emerges.
• A seizure that lasts longer than 5 minutes, or having more than 1 seizure within a 5-minute period, without returning to a normal level of consciousness between episodes.

Latest Definition

• Defined depending upon the classification as to whether it is:
• Convulsive (CSE) — 5 minutes
• Focal (FSE) — 10 minutes
• Absence status epilepticus (ASE) — 10–15 minutes for absent status epilepticus.
• This new definition considers the evidence that after these timelines the seizure activity is unlikely to stop spontaneously and therefore requires aggressive treatment for such complex pathology.
• The importance of this new definition is related to the type of seizure, as the time after which a patient has long-term consequences varies.

• The International League Against Epilepsy (ILAE) classification consists of 4 axes:
  • Semiology - presence or absence of prominent motor findings
  • Etiology - known and unknown causes
  • EEG correlates - description of the EEG
  • Age - neonatal, infancy, childhood, adolescent, adult, and elderly

The Treiman Classification of SE

• Generalized convulsive status epilepticus
• Subtle status epilepticus
• Non-convulsive status epilepticus (e.g., absence, complex partial)
• Simple partial status epilepticus

The Luders and Rona Semiologic Classification

• Consists of 3 axes, as follows:
  • The type of brain function predominantly compromised
  • The body part involved
  • The evolution over time

• There are three major subtypes of status epilepticus in children:
  • Prolonged febrile seizures
  • Idiopathic status epilepticus, in which a seizure develops in the absence of an underlying CNS lesion or insult
  • Symptomatic status epilepticus, when the seizure occurs as a result of an underlying neurologic disorder or a metabolic abnormality
• The idiopathic group includes epileptic patients who have had sudden withdrawal of AEDs followed by status epilepticus.
• Epileptic children who are given anticonvulsants on an irregular basis or who are noncompliant are more likely to develop status epilepticus.
• It may also be the initial presentation of epilepsy.
• Sleep deprivation and an intercurrent infection make epileptic patients more susceptible to status epilepticus.

Other Causes

• Encephalitis
• Meningitis
• Congenital malformations of the brain (e.g., lissencephaly or schizencephaly)
• Inborn errors of metabolism (especially in newborns)
• Electrolyte abnormalities (especially glucose, calcium)
• Drug intoxication
• Reye syndrome
• Lead intoxication
• Extreme hyperpyrexia
• Brain tumors, particularly in the frontal lobe

• Cell death may result from excessive release of the excitatory neurotransmitter glutamate and excessive stimulation of glutamate receptors, a process known as "excitotoxicity".
• The most vulnerable areas of the brain include the hippocampus, amygdala, cerebellum, middle cortical area, and thalamus.
• Prolonged generalized seizure activity may lead to dysfunction of the autonomic nervous system with hypotension and shock, as well as to lactic acidosis, myoglobinuria, elevated lactic acid levels, and acute tubular necrosis.

Systemic and Cerebral Pathophysiologic Changes
Compensation (< 30 minutes)	Decompensation (> 30 minutes)
Increased cardiac output	Falling of cardiac output and blood pressure
Increased cerebral blood flow	Failure of cerebral autoregulation
Increased catecholamine release	Hypoglycemia
Increased glucose concentration in the brain	Hypernatremia, Hypo/hyperkalemia
Cerebral energy requirements matched by supply of oxygen and glucose	Hypoxia, Acidosis
	Leukocytosis
	DIC

Goals of Management

• Supporting vital functions
  • (stabilizing the Airway, Breathing, and Circulation)
• Termination of seizure activities as fast as possible
• Diagnosis and treatment of life-threatening causes

Treatment

• Ideally should be in the ICU
• Initial treatment begins with an assessment of the respiratory and cardiovascular systems.
• The oral airway is secured.
• The vital signs should be recorded.
• Secretions should be suctioned.
• Assisted ventilation may be necessary.
• Physical and neurologic examination should be carried out concurrently to assess for:
  • Evidence of trauma
  • Papilledema
  • Bulging anterior fontanelle or lateralizing neurologic signs suggesting increased ICP
  • Manifestations of sepsis or meningitis
  • Retinal hemorrhages that may indicate a subdural hematoma
  • Kussmaul breathing and dehydration suggestive of metabolic acidosis
  • Irregular respirations signifying brainstem dysfunction
  • Evidence of failure to thrive
  • Peculiar body odor or abnormal hair pigmentation suggesting an inborn error of metabolism
  • Constriction or dilatation of pupils suggesting a toxin or drugs as the cause of the status epilepticus
• Investigations should be tailored along the possible causes.

Drugs

• Should always be administered IV.
• IM route is unreliable because some drugs are sequestered by muscle.
• One of the major problems in the management of status epilepticus is the inappropriate use of anticonvulsants.
• An unsuitably low drug dose is too often given, and with lack of response, another antiepileptic is introduced immediately.
• Care should be given with regard to how the anticonvulsant is administered.
• Phenytoin forms a precipitate in glucose solutions and is rendered ineffective.
• Other drugs interact with plastic containers or are altered by sunlight (e.g., paraldehyde).
• A benzodiazepine (diazepam, lorazepam, or midazolam) may be used initially.
• Diazepam should be given IV directly into the vein (not the tubing) in a dose of 0.1-0.3 mg/kg at a rate no greater than 2 mg/min for a maximum of three doses.
• Respiratory depression and hypotension can occur, especially if administered with a barbiturate.
• Benzodiazepines may be as effective as pentobarbital with fewer side effects.
• Diazepam is effective in the management of tonic-clonic status but has a short half-life and seizures may recur unless a longer-acting anticonvulsant is administered simultaneously.
• Lorazepam is an equally effective short-term anticonvulsant, with a greater duration of action and decreased likelihood of producing hypotension and respiratory arrest. The recommended dose is 0.05-0.1 mg/kg IV administered slowly.
• The dose of midazolam is 0.15-0.3 mg/kg IV.
• If an IV line cannot be established or the child is some distance from a medical center, rectal diazepam or lorazepam can be used safely:
  • Diazepam diluted in 3 mL 0.9% NaCl is placed into the rectum by a syringe and a flexible tube at a dose of 0.3-0.5 mg/kg.
  • Rectal lorazepam is given at a dose of 0.05-0.1 mg/kg.
• Therapeutic serum levels occur within 5-10 minutes.
• Sublingual lorazepam (0.05-0.1 mg/kg) may be used to treat children with serial seizures that tend to develop into status epilepticus while the children are at home.
• If the convulsive activity ceases after diazepam or lorazepam therapy or if the seizures persist, phenytoin is given immediately. The loading dose of phenytoin is 15 up to 30 mg/kg IV (given in 10 mg/kg increments) at the rate of 1 mg/kg/min.
• Electrocardiography is recommended during the loading phase to identify arrhythmias and bradycardia, a rare complication in children.
• Systemic hypotension may also complicate IV phenytoin.
• If the seizures do not recur, a maintenance dose of 3-9 mg/kg divided into two equal doses daily is begun 12-24 hours later.
• In some centers, phenobarbital is initiated before phenytoin. It is given in a loading dose of 15-20 mg/kg or in neonates 20-30 mg/kg IV during 10-30 minutes.
• With control of the seizures, the maintenance dose is 3-5 mg/kg/24 hours divided into two equal doses.
• If seizures persist after adequate treatment with benzodiazepines and phenytoin/phenobarbital, it is referred to as REFRACTORY STATUS EPILEPTICUS (RSE).
• The choices for further drug management include:
  • Paraldehyde
  • Diazepam infusion
  • Barbiturate coma
  • General anesthesia

Diagnostic work-up flowchart

Treatment flowchart

Check ABCs Insert IV STAT laboratory studies: Electrolytes, calcium, magnesium CBC Liver and renal FX test Toxicology screen Anticonvulsant levels Arterial blood gas Insert urinary catheter Urinalysis, urine toxicology Cardiac O2 saturation, monitors Consider the following during general and neurologic exam: Trauma Infection Stroke Drug ingestion As indicated: Chest x-ray CT scan or MRI Lumbar puncture Blood cultures Blood toxicology screen Treat underlying disorder(s) Admit to hospital

Intubate if necessary Control hyperthermia 50cc of 50% dextrose (D50) IV push Start anticonvulsant: Diazepam 0.15 mg/kg IV over 5 min or Lorazepam followed by fosphenytoin 20 mg PE / kg IV @ maximum rate of 150 mg PE/min If seizures continue after 20 min, give an additional 10 mg PE /kg of fosphenytoin If seizures continue after another 20 min, give phenobarbital 15 mg/kg IV If seizures continue, administer general anesthesia

Drug and Supportive Treatment Timeline
Time (Minutes)	Drug Treatment	Supportive Treatment
0		Clear airways, start oxygen, consider intubation
2-3		Set IV line, draw blood for glucose, LFT, RFT, FBC, electrolytes, blood gas Urine for urinalysis
3-5	Diazepam 0.3 mg/kg over 2 minutes	Second IV line
7-8	Phenobarbital/Phenytoin	D10, monitor BP
10	Repeat benzodiazepine if needed
15	Repeat benzodiazepine if needed. If seizure persists…..	Transfer to ICU
20	Diazepam (0.01-0.1 mg/kg/min) or Midazolam (2 µg/kg/min, increase by 2 µg/kg/min every 5 minutes until seizure is controlled) infusion	Cardi-respiratory monitoring, continuous EEG monitoring
60	Thiopental (Barbiturate Coma) load with 3-4 mg/kg over 2 minutes, then infusion at 0.2 mg/kg/min	Mechanical ventilation

Paraldehyde

• Relatively safe for administration to children.
• A 5% solution of paraldehyde is prepared by adding 1.75 mL of paraldehyde (1 g/mL) to D5W to a total volume of 35 mL.
• The loading dose is 150-200 mg/kg IV slowly for 15-20 minutes, and then seizure control is maintained with an infusion of 20 mg/kg/hr in a 5% concentration in a glass bottle, because the drug is incompatible with plastic.

General Anesthesia

• Is an alternative adjunct to the management of status epilepticus if conventional drug therapy is not effective or if barbiturate coma is not an option.
• Halothane, isoflurane, and some other GA agents have been used successfully.
• General anesthesia probably acts by reversing cerebral anoxia and the concomitant metabolic abnormalities, allowing the previously administered anticonvulsants to exert their effect.

Valproic Acid

• Has been an effective anticonvulsant in the management of several types of seizures.
• Has also been successfully used in Status Epilepticus (SE).
• Valproic acid is available as an injectable in some parts of the world.
• Not yet in Nigeria!!!

• Cerebral: Hypoxic injury, seizure-induced injury, cerebral oedema, cerebral haemorrhage and infarcts, cerebral venous thrombosis
• Cardiovascular: Hypertension, hypotension, bradycardia, arrhythmias, cardiac failure, shock
• Respiratory: Apnoea, Cheyne-Stokes breathing, respiratory acidosis, aspiration pneumonitis, pulmonary oedema
• Renal: Oliguria, acute renal failure, acute tubular necrosis, myoglobinuria
• Autonomic: Hyperpyrexia, failure of cerebral auto-regulation, vomiting, excessive secretion with airway obstruction, excessive sweating
• Metabolic: Hyperglycaemia, hypoglycaemia, hyperkalemia, hyponatremia, metabolic and lactic acidosis

• The greatest number of deaths occur in the symptomatic group, most of whom have a serious and life-threatening CNS disorder known before the onset of status epilepticus.
• Age, rapidity of control, and adequacy of care are important factors that determine prognosis.
• Periodic Lateralized Epileptiform Discharge (PLED) during or after the event is associated with poor prognostic outcome.
• Mortality ranges between 3-20%.