Status Epilepticus : Pathophysiology, Symptoms and Treatments
Status epilepticus (SE) is recurrent seizures without an intervening period of consciousness before the next seizure or any seizure lasting longer than 30 minutes whether or not consciousness is impaired. The most common manifestation of SE is tonic-clonic or generalized convulsive SE (GCSE).
Pathophysiology of Status epilepticus (SE):
- An increase in excitatory (e.g., glutamate, acetylcholine) or a decrease in inhibitory (e.g., Î³-aminobutyric acid [GABA]) neurotransmitters can cause sustained seizures with subsequent neuronal death.
- During SE, the GABA system does not function to inhibit seizures. There is evidence that GABAA receptors are modified during SE in a way that contributes to persistent seizures. However, it is unlikely that loss of GABA inhibition is the sole mechanism for SE.
- Two phases of GCSE have been identified. During phase I, each seizure produces marked increases in plasma epinephrine, norepinephrine, and steroid concentrations that may cause hypertension, tachycardia, and cardiac arrhythmias. Acidosis, hypotension, shock, rhabdomyolysis, secondary hyperkalemia, and acute tubular necrosis may ensue.
- Phase II begins 60 minutes into the seizure, and the patient begins to decompensate. The patient may become hypotensive and cerebral blood flow may be compromised. Glucose may be normal or decreased, and hyperthermia, respiratory deterioration, hypoxia, and ventilatory failure may develop.
- In prolonged seizures, motor activity may cease, but electrical seizures may persist.
- Age, seizure duration, and severe preexisting brain disease are related to SE-induced morbidity. The younger the child, the greater is the risk for sequelea. Seizures exceeding 60 minutes can cause neuronal damage.
- Morbidity may be higher in patients with preexisting epilepsy.
- Mortality from GCSE depends on etiology, time from onset of SE to initiation of treatment, seizure duration, and patient age. More frequently, death is a result of the illness that precipitated the attack of SE, not the SE itself. The longer the duration of SE, the worse the prognosis. Recent estimates suggest a mortality rate up to 10% in children, up to 20% in adults, and up to 38% in the elderly.
CLINICAL PRESENTATION AND DIAGNOSIS
Status epilepticus (SE) is a medical emergency that may be associated with significant morbidity and mortality.
- Impaired consciousness (e.g., lethargy to coma)
- Disorientation once GCSE is controlled
- Pain associated with injuries (e.g., tongue lacerations, shoulder dislocations, head trauma, facial trauma)
- Acute injuries or CNS insults that cause extensor or flexor posturing
- Fever or intercurrent illnesses (signs of sepsis or meningitis)
- Evidence of head or other CNS injury (bradycardia, tachypnea, and hypertension; poor pupillary response; asymmetry on neurologic examination; abnormal posturing
- Generalized convulsions
- Hypothermia or fever suggestive of intercurrent illnesses
- Muscle contractions, spasms
- Normal blood pressure or hypotension
- Respiratory compromise
- Pulmonary edema with respiratory failure
- Cardiac failure (dysrhythmias, arrest, cardiogenic shock)
- Disseminated intravascular coagulation, multi-organ failure
INITIAL LABORATORY TESTS
- Complete blood count (CBC) with differential
- Serum chemistry profile (e.g., electrolytes, calcium, magnesium, glucose, serum creatinine, ALT, AST)
- Urine drug/alcohol screen
- Blood cultures
- Arterial blood gas to assess for metabolic and respiratory acidosis
- Serum drug concentration if previous anticonvulsant suspected or known
OTHER DIAGNOSTIC TESTS
- Lumbar puncture if CNS infection suspected
- EEGâ€”should be obtained on presentation and once clinical seizures are controlled
- CT with and without contrast (to assess for bleeding, infection, arteriovenous malformations, neoplasm)
- MRI later
- X-ray if indicated to diagnose fractures
- ECG, especially if ingestion confirmed
- ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; CNS, central nervous system; CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalograph; GCSE, generalized convulsive status epilepticus; MRI, magnetic resonance imaging; SE, status epilepticus
- Most patients have altered consciousness ranging from obtunded to marked lethargy and somnolence with pronounced eyes-open unresponsiveness and waxy rigidity.
- After seizures have stopped, it is important to determine if the patient is febrile or has a systemic or central nervous system (CNS) infection.
The goals of treatment are (1) patient stabilization (e.g., adequate oxygenation, preservation of cardiorespiratory function, and management of systemic complications), (2) correct diagnosis of the subtype and identification of precipitating factors, (3) stopping clinical and electrical activity as soon as possible, and (4) preventing seizure recurrence.
TREATMENT of Status Epilepticus
- For any tonic-clonic seizure that does not stop automatically or when doubt exists regarding the diagnosis, treatment should begin during the diagnostic workup.
- Concurrent with initiation of anticonvulsants, vital signs should be assessed and an adequate airway with ventilation should be established and maintained.
- Oxygen should be administered. If there is poor air exchange, the patient should be intubated and ventilated mechanically. Temperature should be monitored frequently.
- Normal to high blood pressure should be maintained.
- All patients should receive glucose, and thiamine (100 mg) should be given prior to glucose in adults.
- Metabolic and/or respiratory acidosis should be assessed by arterial blood gas measurements to determine pH, Pao2, Paco2, and HCO3. If pH is less than 7.2, secondary to metabolic acidosis, sodium bicarbonate should be given.
A benzodiazepine (BZ) should be administered as soon as possible if the patient is actively seizing. If seizures have stopped, a longer-acting anticonvulsant should be given.
Diazepam is extremely lipophilic and quickly distributed into the brain but redistributes rapidly into body fat, causing a very short duration of effect (0.25 to 0.5 hours). Therefore, a longer-acting anticonvulsant (e.g., phenytoin, phenobarbital) should be given immediately after the diazepam.
The recommended initial diazepam dose in children and adults is shown in Table 54-2. The maximum total dose is 5 mg in children under age of 5 years, 10 mg in children 5 years and older, and 40 mg in adults.
Lorazepam is currently considered the BZ of choice. It takes slightly longer to reach peak brain levels than diazepam but has a longer duration of action (greater than 12 to 24 hours); thus, fewer patients require additional anticonvulsants for seizure termination. One dose provides seizure protection for 24 hours. The initial dosing of lorazepam is shown in Table 54-2. If the seizure continues after 5 minutes, a second dose may be given. If there is no response in another 5 minutes, a third (final) dose can be given. Patients chronically on BZs may require larger doses. The administration of diazepam and lorazepam should not exceed 5 and 2 mg/min, respectively.
Midazolam is water soluble and diffuses rapidly into the central nervous system (CNS) but has a very short half-life (0.8 hours). It must be given by continuous infusion when given chronically. There is increasing interest in using it buccally, intranasally, and intramuscularly when intravenous access cannot be obtained readily.
With BZ administration, a brief period of cardiorespiratory depression (less than 1 minute) may occur and can necessitate assisted ventilation or require intubation, especially if BZs are used with a barbiturate. Hypotension may occur with high doses of BZs.
Phenytoin has a long half-life (20 to 36 hours), but it cannot be delivered fast enough to be considered a first-line agent. It takes longer to control seizures than do the BZs because it enters the brain more slowly. It is also associated with administration-related cardiovascular toxicity and is ineffective in some forms of nonconvulsive SE (NCSE).
If the patient has been on phenytoin prior to admission and the phenytoin concentration is known, this should be considered in determining a loading dose.
A reduction in the loading dose is recommended for elderly patients, and a larger loading dose is required in obese patients.
For seizures continuing after the initial loading dose, some practitioners have recommended an additional loading dose of 5 mg/kg (after waiting 60 minutes for response), but additional phenytoin may result in toxicity and exacerbation of seizures. There is no evidence that a total loading dose greater than 20 mg/kg will be of benefit in these patients.
Maintenance dosing should be started within 12 to 24 hours of the loading dose.
The propylene glycol vehicle may cause hypotension and arrhythmias, especially in older patients with heart disease and critically ill patients with marginal blood pressures. The maximum rate of infusion is 50 mg/min in adults, 25 mg/min in the elderly and those with atherosclerotic heart disease, and 1 mg/kg/min in children weighing less than 50 kg. Vital signs and an electrocardiogram (ECG) should be obtained during administration.
Phenytoin is associated with pain and burning during infusion. Phlebitis may occur with chronic infusion, and tissue necrosis is likely on infiltration. Intramuscular administration is not recommended.
Fosphenytoin, the water-soluble phosphate ester of phenytoin, is a phenytoin prodrug.
The dose of fosphenytoin sodium is expressed as phenytoin sodium equivalents (PE).
Adverse reactions include nystagmus, dizziness, pruritus, paresthesias, headache, somnolence, and ataxia.
In adults, the rate of administration should be 100 to 150 mg PE/min. Pediatric patients should receive fosphenytoin at a rate of 1 to 3 mg PE/kg/min.
Continuous ECG, blood pressure, and respiratory status monitoring is required for all loading doses of fosphenytoin. Serum phenytoin concentrations should not be obtained for at least 2 hours or more following fosphenytoin dosing.
The Working Group on Status Epilepticus recommends that phenobarbital be given after a benzodiazepine plus phenytoin has failed. Most practitioners agree that phenobarbital is the long-acting anticonvulsant of choice in patients with hypersensitivity to the hydantoins or in those with cardiac conduction abnormalities. Some clinicians, especially in pediatric institutions feel that phenobarbital should be the drug of choice after the benzodiazepines have been administered.
There is no maximum dose beyond which further doses are likely to be ineffective.
The dosing guidelines are given in Table 54-2. In order to avoid overdosing, estimated lean body mass should be used in obese patients.
Peak brain concentrations occur 12 to 60 minutes after intravenous dosing. On average, seizures are controlled within minutes of the loading dose.
If the initial loading dose does not stop the seizures within 20 to 30 minutes, an additional 10- to 20-mg/kg dose may be given. If seizures continue, a third 10-mg/kg load may be given. Once seizures are controlled, the maintenance dose should be started within 12 to 24 hours.
Medical personnel should be ready to provide respiratory support whenever phenobarbital and the BZs are used together. If significant hypotension develops, the infusion should be slowed or stopped.
EVALUATION OF THERAPEUTIC OUTCOMES
An EEG is a very important tool that allows practitioners to determine when abnormal electrical activity has been aborted and may assist in determining which anticonvulsant was effective. Vital signs must be monitored during the infusion. It may also be necessary to monitor the ECG in some patients. The infusion site must be assessed for any evidence of infiltration before and during administration of phenytoin.