Status Epilepticus

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Chapter 61 Status Epilepticus

Ala Nozari, MD, PhD , Corey R. Fehnel, MD , Lee H. Schwamm, MD, FAHA

1 What is the definition of status epilepticus (SE)?

SE has typically been defined as repetitive seizures lasting 30 minutes or longer, or seizures without full return of consciousness between episodes. This definition was recently challenged because it does not incorporate the practical considerations of patient management and because shorter periods of seizure activity can cause neuronal injury. Therefore others have recommended defining SE as seizures lasting ≥5 minutes or two or more seizures between which there is incomplete recovery of consciousness or function.

2 Name important features of SE

In patients with no prior seizure history, SE is usually a manifestation of cortical irritation or injury. Treatment of the underlying disorder is therefore critical. Relapse of seizure in patients with known seizure disorder, on the other hand, commonly reflects subtherapeutic levels of antiepileptic drugs (AED) and usually responds to a bolus of the maintenance drug. Most cases of convulsive SE in adults start as partial seizures that generalize.

3 Describe the classification and clinical presentation of SE

SE can be classified in several forms, including convulsive SE, focal SE, myoclonic SE, and nonconvulsive SE (NSE).

image Generalized convulsive SE involves tonic flexion of the axial muscles, flexion in the arms and legs followed by extension, clenching of teeth, forced expiration, dilation of the pupils or sluggish pupillary light responses, and upward or lateral eye deviation. The uninterrupted jerking or shivering during the clonic phase may gradually resolve, but tonic spasm may occur again with a similar pattern of jerking and resolution. As the duration of the seizures increases, the movements and muscle contractions may become reduced despite continued generalized electrical activity in the brain.

image Focal SE can be simple without loss of consciousness or complex with impaired consciousness. Jerking of one ipsilateral arm or leg or continuous clonic movements of one or two extremities can be observed. When confined to focal motor clonic seizures without Jacksonian march, it is often referred to as epilepsia partialis continua (EPC); the motor activity lasts for hours, days, weeks, or longer. Consciousness is not altered, but postictal weakness is frequent. In most cases, the ictal focus is cortical, and anticonvulsants help prevent generalization but are frequently ineffective at aborting the seizures. EPC is often caused by a structural lesion (e.g., tumor, chronic infarction) or a progressive neurodegenerative disease (particularly in children). Focal SE of all forms is often related to acute hemispheric lesions such as a hemorrhage or brain metastasis.

image Myoclonic SE is seen in patients after cardiac arrest or asphyxiation and consists of synchronous brief jerking of the limbs, face, or diaphragm. It can also be seen after electrical injury, drug intoxication, or decompression sickness and often denotes severe cortical laminar necrosis in association with thalamic and spinal cord injuries.

4 What defines NSE?

The same principles apply of prolonged duration (>5 minutes) or lack of return to baseline mental status in between seizures. However, NSE can be difficult to diagnose because of lack of pronounced motor activity. NSE is commonly divided into complex partial status and absence status, which are often mistaken for behavioral abnormalities or a psychiatric disorder. Clinical presentation is diverse and can involve blank staring or eye movement abnormalities and subtle periorbital, facial, or limb myoclonus. Absence SE is characterized by a reduction in vigilance, lack of attention, and automatism. Given the challenge of clinical diagnosis of NSE, electroencephalography (EEG) is often required to establish the diagnosis. Careful examination of the fully undressed patient with attention to the eye movements (versive saccades) and hands and face can often reveal subtle rhythmic movements of the mouth or digits suggestive of subtle generalized motor status, especially in patients who have received anticonvulsants.

5 Name common causes of convulsive SE

The most common cause of SE in a patient with a known seizure disorder is subtherapeutic AED levels. However in young patients, febrile seizure is a common precipitator, and central nervous system (CNS) infection with common pathogens such as Haemophilus influenzae and Streptococcus pneumoniae should be ruled out by lumbar puncture. Metabolic and electrolyte disturbances, traumatic brain injury, tumor, and drug intoxication are among other common causes. Ischemic strokes rarely produce seizures in the acute period, but chronically areas of encephalomalacia can provide substrate for intractable seizures. Proconvulsant drugs include β-lactam antibiotics and quinolones, bronchodilators, certain antidepressants, and immunosuppressants. SE caused by low AED levels or alcohol abuse is associated with a relatively good prognosis, whereas outcome is generally poor after cerebrovascular disease or anoxic injury.

6 Why is urgent treatment of SE a medical necessity?

SE can be life threatening with the development of pyrexia, deepening coma, and circulatory collapse. Aspiration is common and may result in respiratory failure with hypoxemia, systemic inflammatory response, and disseminated intravascular coagulation with multiple organ failure. Continuous seizures can result in rhabdomyolysis with risk for acute renal failure, lactic acidosis, and cardiac arrhythmias. Of importance, repetitive electric discharges can result in irreversible neuronal injury after as little as 5 to 20 minutes; cell death is common after 60 minutes. Neuronal injury can, understandably, also result from the acute insult that provoked the SE. A mortality rate of between 10% and 12% has been reported, of which the majority is related to the underlying process producing the SE. The highest mortality occurs in elderly patients and those with SE after a stroke or anoxia, whereas children, patients with SE related to subtherapeutic AED, or those who have unprovoked SE have usually a better outcome.

7 Name general treatment measures for SE

The immediate management of the patient should include measures to establish an airway, provide oxygenation, and stabilize circulation.

image An oral airway can be used if feasible, although most patients with prolonged SE may benefit from early endotracheal intubation.

image Supplemental oxygen should be provided, large-bore proximal intravenous (IV) access obtained, and liberal hydration with normal saline solution initiated.

image Vital signs should be recorded regularly.

image A blood sample should be collected as soon as possible to rule out hypoglycemia.

image A complete blood cell count, anticonvulsant levels, serum electrolytes, serum osmolarity, blood urea nitrogen, creatinine, calcium, magnesium, phosphate, a drug screen, blood alcohol level, and arterial blood gas analysis should also be ordered.

image If glucose testing reveals hypoglycemia, thiamine (100 mg IV) should be administered before the glucose bolus in patients with poor nutrition (e.g., patients with alcoholism).

image Whenever appropriate, vasopressor agents should be used to support the circulation.

image If CNS infection is suspected, empirical treatment followed by early lumbar puncture for cerebrospinal fluid analysis should be considered, especially in febrile children.

image EEG monitoring is particularly important in patients who have received neuromuscular blocking agents for intubation, as these agents may stop visible seizure manifestations despite electrical seizure activity in the brain.

8 What are the first-line treatment options for generalized convulsive SE?

There is no completely satisfactory approach to the treatment of SE, and the sequence of use of antiepileptic agents continues to evolve. Drugs should be given IV, but if IV access is not available, diazepam solution can be given rectally, intranasally, or via buccal mucosa. Lorazepam remains the first-line AED despite the risk for respiratory depression. A target total dose of 0.1 mg/kg can be given at a rate no faster than 2 mg/min and in 4-mg doses to a maximal adult dose of 10 mg.

9 What are the second-line treatments for SE?

Second-line drugs can be started simultaneously or, if seizure persists, 1 minute after the benzodiazepine dose. Phenytoin load with 18 to 20 mg/kg (if the patient is not already being given phenytoin) can be given only in normal saline solution to prevent precipitation and is usually administered at a maximum rate of <50 mg/minute. Blood pressure should be monitored for hypotension and electrocardiogram continuously recorded and monitored for arrhythmias. Sinus bradycardia is the most common cardiac arrhythmia, and the drug may also worsen any heart block. Asystole has been reported. If the patient is already receiving phenytoin but the phenytoin level is not known, 500 mg may be given at the preceding rate. Usually, 0.74 mg/kg to an adult raises the level by approximately 1 mcg/mL. Fosphenytoin is a water-soluble form of phenytoin and lacks the propylene glycol vehicle that has been implicated in the hypotension and cardiac arrhythmias that may be observed during traditional IV phenytoin loading. However, cardiac arrhythmias may still occur when fosphenytoin is infused at rates >150 mg phenytoin equivalent per minute. Phenytoin is albumin bound, and levels should be corrected for hypoalbuminemia.

10 What are the third-line treatments for SE ?

Only 7% of patients who have not responded to the above treatment will respond to a third-line drug, which is why many clinicians have proposed to skip the third-line drugs and proceed directly to continuous infusion therapy. Additional doses of 5 mg/kg phenytoin can be administered up to a total of 30 mg/kg. Traditionally, phenobarbital (15-20 mg/kg loading dose) has been recommended, given at a rate no faster than 50 to 100 mg/minute until the seizures stop. Maintenance therapy is then instituted at a dose of 1 to 4 mg/kg per day. Both phenobarbital and pentobarbital result in respiratory depression, which require close monitoring or sometimes intubation before initiation of treatment. Alternative treatments include sodium valproate at 15 to 30 mg/kg, followed by a maintenance dose of 500 mg three times a day, or levetiracetam 20 mg/kg IV bolus followed by a maintenance dose of 1500 mg twice a day.

If the preceding treatment fails to stop the seizures within 30 minutes, many physicians now recommend inserting an endotracheal tube and beginning continuous infusion therapy with midazolam, pentobarbital, or propofol. Midazolam has a shorter half-life than lorazepam and produces sedation of shorter duration in SE. A loading dose of 0.2 mg/kg is followed by an hourly infusion of 0.75 to 10 mcg/kg per minute and should be continued for at least 12 hours before the dose is tapered. The absence of propylene glycol solution in midazolam reduces the risk of hypotension, bradycardia, and electrocardiogram changes, which are seen with diazepam or lorazepam infusions. Pentobarbital is administered as a loading dose of 3 mg/kg at a rate of 25 mg/minute, followed by a maintenance dose of 0.3 to 3 mg/kg per hour until the seizures stop clinically or burst suppression is reached on the EEG. Alternatively, propofol can be used in anesthetic doses (loading dose of 1-3 mg/kg followed by maintenance of 1-10 mg/kg per hour).

These drugs are often associated with hemodynamic changes when administered in the doses mentioned and may require vasopressors to maintain adequate blood pressures. Prolonged infusion of high doses of propofol may also result in a rare complication known as the propofol infusion syndrome, with refractory bradycardia, metabolic acidosis, rhabdomyolysis, renal failure, and cardiovascular collapse. Treatment includes discontinuation of the propofol infusion and supportive care. Additional drugs that may be tried, if seizures continue, include carbamazepine, oxcarbazepine, topiramate, lamotrigine, and gabapentin. See Table 61-1.

Table 61-1 Drugs that are Typically Used in the Treatment of Status Epilepticus

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Other potential treatments include lidocaine infusion, inhalational anesthesia, electroconvulsive therapy, transcranial magnetic stimulation, and surgical intervention if a seizure focus is identified.

11 How can you treat SE when you are unable to achieve IV access?

If a peripheral IV access is difficult, initial management may include intramuscular or rectal administration of antiepileptic drugs. Benzodiazepines, such as rectal diazepam (0.2 mg/kg), or intramuscular midazolam (0.1 mg/kg), or lorazepam remain first-line agents. Intramuscular fosphenytoin at 20 mg/kg produces equal plasma concentrations of phenytoin as the oral dose within 1 to 2 hours of administration. An effective approach in patients with no IV access is the use of inhalational anesthetic agents, including isoflurane. In the past, placement of a central venous catheter or a brachial or saphenous vein cutdown was considered, but the advent of intraosseous cannulation makes this the access route of choice in emergency situations when traditional sites are unavailable.

12 Describe the management of seizures in patients with preeclampsia

Magnesium sulfate remains the standard in prevention and treatment of preeclamptic seizures or SE. It is given at a dose of 4 to 5 g IV, followed by an IV infusion of 1 g/hour, with the aim to reach a therapeutic level of 3.5 to 7 mEq/L, which corresponds to 4.2 to 8.4 mg/dL. Recurrent seizures can be treated with a bolus of 2 to 4 g of magnesium sulfate. Additional antiepileptic agents are usually not needed and may cause respiratory depression in the newborn. Clinical signs for magnesium toxicity should be monitored, and reduced tendon reflexes (corresponding to a serum concentration of 8-12 mg/dL) or respiratory depression should prompt immediate discontinuation of the infusion. The most effective treatment of seizures relating to eclampsia remains delivery of the fetus if possible.

13 Describe the pathogenesis and treatment of postanoxic myoclonic SE

Myoclonic SE is commonly seen in comatose patients who have survived asphyxia or cardiac arrest and indicates severe neurologic damage. It portends a very poor prognosis but must be distinguished from myoclonic jerks, which are often asynchronous and relate to muscle irritability rather than electrographic seizure activity. Myoclonic SE often consists of synchronous brief jerking in the limbs, face, or diaphragm and can be provoked by stimuli such as movement, touch, sound, or interventions such as intubation or placement of catheters. Myoclonic activity can be quite disconcerting to families and medical personnel.

Clonazepam has been advocated for treatment but is not consistently effective. Myoclonic status is also resistant to many other antiepileptic drugs such as phenobarbital, phenytoin, and benzodiazepines. Some anecdotal data suggest that valproate may be effective in treating this syndrome. Propofol infusion can be used when myoclonus causes marked contraction of diaphragm, hampering the ventilation of the lungs. Neuromuscular blocking agents may be considered to control the symptoms until the level of care has been discussed with the patient’s family. It must be kept in mind that treatment of myoclonic status does not affect outcome though it may ease the distress of family and medical staff.

14 What general measures should be considered after control of the seizures?

It is important to establish the cause of the seizure once it is controlled and the patient’s condition stabilized. Appropriate blood work and cultures should be completed. Lumbar puncture should be considered, if not already done, to rule out CNS infections and subarachnoid hemorrhage, and imaging with computed tomography or magnetic resonance imaging should be obtained to rule out structural CNS causes. Empirical antibiotics should be started if an infectious cause is suspected, and maintenance doses of anticonvulsants should be administered and adjusted on the basis of serum levels.

Key Points Status Epilepticusimage

1. SE is defined as seizures lasting ≥5 minutes or two or more seizures between which there is incomplete recovery of consciousness or function.

2. Morbidity and mortality are high in SE, and aggressive treatment strategies should be instituted immediately.

3. The most common cause of SE in a patient with known seizure disorder is low AED levels, whereas de novo SE is usually a manifestation of structural brain injuries or an illness that may require immediate diagnosis and treatment.

4. Treatment for SE is directed at stabilizing the patient’s condition, controlling the seizure, and identifying the cause. The underlying disease should be treated promptly.

5. First-line treatment to control the seizures often includes a benzodiazepine, for example, IV lorazepam. Second-line antiepileptic drug (phenytoin or fosphenytoin) can be given simultaneously with the first-line drug, or 1 minute after its administration if seizure persists. If third-line antiepileptic drugs (phenobarbital, valproate, or levetiracetam) do not stop the seizures, proceed to continuous infusion therapy with midazolam, pentobarbital, or propofol.

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