Catastrophic Neurologic Disorders in the Emergency Department , 2nd Edition

Chapter 10. Status Epilepticus and Recurrent Seizures

Status epilepticus is a multifaceted neurologic emergency. It may present suddenly in the setting of other clinical neurologic conditions (e.g., acute bacterial meningitis and herpes simplex encephalitis) for which therapeutic interventions are urgently indicated. The tasks at hand need to be well executed because long-standing morbidity in many patients has been linked to lapses in aggressive control of seizure activity. Thus, rapid termination of seizures and simultaneous treatment of the underlying illness are of utmost priority in tonic-clonic status epilepticus, and this undisputed urgency must be appreciated by any physician faced with this illness. Status epilepticus lasting 1 hour or more increases morbidity 10-fold. Furthermore, neurogenic pulmonary edema or life-threatening cardiac arrhythmia1 may occur, but more likely prolonged apnea and anoxia may result in an additional ischemic-anoxic injury and persistent coma, emphasizing the need for early intubation and airway control.

Concurrent destructive brain lesions are common in adult status epilepticus and, thus, in most cases are responsible for morbidity and mortality. Regrettably, outcome studies in status epilepticus include comatose patients with myoclonus status epilepticus, a phenomenon indicative of profound injury to the cortex and associated with cardiac arrest. These causes may account for 30%–40% of the cases, thus skewing the results toward an unfavorable outcome.1,2,3Conversely, albeit uncommonly, unprovoked status epilepticus may have an excellent neurologic outcome.

Status epilepticus in adults can be distinguished in several forms, each of which is discussed in detail. Potentially important differences in effect may exist with different antiepileptic agents. Why they differ in their ability to abort status epilepticus is not initially clear. In this chapter, an approach is presented that is based on the integration of position papers4,5,6 and systematic reviews.7,8

Classification and Presentation of Status Epilepticus

Convulsive status epilepticus can be divided into four major categories, and nonconvulsive status epilepticus can be further divided into complex partial and absence types (Fig. 10.1). The distinction has relevance because the initial choice of antiepileptic agents may be different, management may not involve antiepileptic agents (as in myoclonus status epilepticus and psychogenic seizures), and outcome may differ from category to category.

Persistence of seizure activity is an important discriminating factor because it is directly linked to cumulative development of neurological and medical complications. The risk of neuronal dropout resulting in morbidity is related not only to the duration of status epilepticus but also to age and systemic complications, such as severe hypoxemia from aspiration. Autonomic storm resulting in tachyarrhythmias and hyperthermia probably does not directly contribute to brain damage.

Figure 10.1 Classification of status epilepticus.

Tonic-Clonic Status Epilepticus

Tonic-Clonic status epilepticus has typically been defined as repetitive generalized tonic-clonic seizures lasting 30 minutes or longer or seizures without full return of consciousness between episodes. However, the evolution of seizures into status epilepticus often becomes clear within 10–15 minutes, and the time criterion should not be applied rigorously.

The tonic phase involves flexion of the axial muscles, upward gaze, and marked widening of the pupil diameter with sluggish light responses. Flexion occurs in the arms and legs and is soon followed by extension, clenching of teeth, and forced expiration for several seconds. Sweating may be profuse, with an increase in blood pressure and pulse. The clonic phase begins with a tremor or shivering but gives way to uninterrupted jerking, which dies out gradually and may result in urinary and fecal incontinence after the sphincter muscles relax from a forceful contraction during the clonic phase. Usually, a generalized tonic-clonic seizure lasts 1–2 minutes and is followed for up to 5 minutes by a dazed state or agitation resulting in labored breathing and deep sleep. Most patients gradually awaken but never to a point that conversation is understood or simple commands are followed. Then, tonic spasm may occur again with a similar pattern of jerking and resolution.

Electrographic recordings, if available, typically show rhythmic spike- or sharp-wave complexes or sharp- and slow-wave discharges with a generalized distribution. Clinically, the distinction between a postictal confusional state emerging from a generalized tonic-clonic seizure and convulsive status epilepticus is difficult in the emergency department. Subtle eyelid or limb twitching in a stuporous patient may indicate continuous epileptic activity, but the distinction may require electroencephalographic recording.

Typical clinical findings are tongue bite (large purple hematoma or erosion at the lateral border of the tongue, which should be carefully inspected while the tongue is pushed out or sideways with a tongue depressor) (Fig. 10.2) and, occasionally, petechial hemorrhages in the conjunctiva, chest, and neck. Other complications are tachycardia, hyperglycemia, bone fractures, posterior shoulder dislocation, pulmonary aspiration, and, rarely if ever, neurogenic pulmonary edema. Prolonged status epilepticus may produce fever (up to 42°C), even on the day after presentation. The most common causes of status epilepticus are shown in Table 10.1. Withdrawal of antiepileptic agents in patients with established seizure disorder is most common.9,10,11 In de novo status epilepticus, no overriding cause may be apparent, but an acute brain lesion is common. In one urban hospital study, the most common causes for status epilepticus were alcohol-related.10,12

Figure 10.2 Tongue bite much more evident when tongue pushed out.

Table 10.1. Causes of Status Epilepticus

Change in antiepileptic drugs
Withdrawal of benzodiazepines (NCSE)
Drugs or alcohol
Bacterial meningitis or intracranial abscess
Encephalitis
Intracranial tumor or metastasis
Stroke
Arteriovenous or cavernous malformation
Hyperglycemia
Hypoglycemia
Hyponatremia
Preeclampsia
Intravenous contrast agent (NCSE)
Electroconvulsive therapy (NCSE)
NCSE, nonconvulsive status epilepticus.

Nonconvulsive Status Epilepticus

Delayed diagnosis is common because behavioral abnormalities are mistaken for a postictal state or psychiatric disorder.13 Nonconvulsive status epilepticus is further divided into complex partial status and absence status.14,15,16 Complex partial status epilepticus is most prevalent in adults 20–40 years of age.17 It may occur after a single seizure and after replacement of antiepileptic drugs18 and is more likely in patients with prior brain injury.19

Clinical presentation is diverse, but clinical signs are not always suggestive and may be diagnostically confusing. Consciousness is always impaired. Nonconvulsive status epilepticus results in blank staring, sometimes with tremulousness and subtle periorbital, facial, or limb myoclonus or eye-movement abnormalities such as nystagmus or eye deviation.19 Patients have decreased or rambling speech output or are mute; thus, the distinction from aphasia with a structural lesion can be difficult. Aggressive behavior is uncommon,14 and more often patients are mildly agitated and easy to restrain. A waxing and waning state alternating between agitation and obtundation is characteristic. Inappropriate laughing, crying, or even singing may occur. Some patients express a feeling of imminent death. Absence status epilepticus is additionally characterized by reduction in vigilance rather than drowsiness. Attention is absent, and automatisms may occur. Complex status epilepticus can be characterized by hallucinations and a complete amnesia for the attacks.17

Focal Status Epilepticus

Focal status epilepticus can be simple (normal level of consciousness) or complex (impaired consciousness but no overt jerking). Focal status epilepticus is probably similar to epilepsia partialis continua. It involves continuous clonic movements of one or two extremities. Jerking of one arm or leg can be directly observed by the patient, who should be unable to influence its jerking frequency. Hemiparesis (which may last for days) may result if the condition is treated late. The disorder often is related to an acute hemispheric lesion (e.g., hemorrhage in cavernous hemangioma or metastasis, spontaneous lobar hematoma).

Psychogenic Status Epilepticus

Pseudoseizures can be very difficult to differentiate from true seizures and may occur comparatively frequently in patients with proven seizure disorder. The incidence was 40% in one referral hospital,20 but this appears inflated. The assessment of psychogenic seizures can be complicated because previous indiscriminate administration of a benzodiazepine may cloud the neurologic assessment, and electroencephalography often is not immediately available to verify the psychiatric origin of the convulsions.

Several clinical characteristics should increase the likelihood of psychogenic status epilepticus.21,22 Jerking movements are characteristically out of phase and asynchronous, with a highly typical forward thrusting of the pelvis. Screaming is common. Tongue biting is absent, pupils may be dilated but have retained light responses, and the gag reflex is present.21,22,23,24 Jerking of the extremities may rapidly alternate in tonic-clonic-like movements, and often the arms can be positioned above the patient's face while continuously jerking without falling on the face. The head turns from side to side, and more characteristically, both eyes are consistently deviated from the examiner, occasionally switching with the examiner's position. In between the jerking movements, the patient may speak brief sentences indicating major distress.

All of these manifestations, although very characteristic, may rarely be imitated by nonconvulsive status epilepticus due to a frontal epileptic focus.

Myoclonus Status Epilepticus

Myoclonus status epilepticus is common in emergency departments admitting comatose patients after asphyxia or cardiac arrest. The clinical manifestations of myoclonus status epilepticus are vastly different, but it is still misinterpreted as tonic-clonic seizures.

Myoclonus status epilepticus often consists of synchronous brief jerking in the limbs and face and may involve the diaphragm. Touch, intubation, and placement of catheters may provoke the movements, but continuous jerking is more commonly the rule. An episodic upward gaze of both eyes during a series of myoclonic jerks is typical. Myoclonus status epilepticus can be seen moments after cardiac resuscitation when the pulse has returned and the patient has failed to awaken. Pathologic withdrawal or extensor motor responses are common. Its presence denotes massive laminar cortical necrosis, often in association with ischemic damage to the thalamus and spinal cord.

Other conditions that cause myoclonus status epilepticus, such as environmental injuries (e.g., electrical injury, decompression sickness), are related to severe global anoxia produced by the insult. However, profound myoclonus status epilepticus in comatose patients may be caused by drug intoxication (predominantly lithium but also haloperidol, antiepileptic agents, tricyclic antidepressants, and penicillin), toxic exposure to industrial agents (pesticides) and heavy metals, renal or hepatic failure, or a degenerative condition such as Creutzfeldt-Jakob disease in the final stage.

Neuroimaging in Status Epilepticus

Because withdrawal of antiepileptic drugs remains a commonly recognized cause in adults with a prior seizure disorder, computed tomography (CT) scan or magnetic resonance imaging (MRI) findings are frequently normal in status epilepticus. In refractory epilepsy, the rate of detection of histopathologically proven abnormalities (glioma, hippocampal sclerosis, developmental lesions) is 95% with conventional MRI and much lower with CT scan, with a sensitivity of 32%. CT scan sensitivity for temporal lobe abnormalities is very low.25 However, CT or MRI may show acute destructive lesions, such as stroke or traumatic injury, metastatic disease, and glioma. CT scanning in myoclonus status epilepticus may show diffuse cerebral edema and, less often, thalamic or cerebral infarcts in watershed territories. An imaging study of cryptic seizures at the Mayo Clinic found mesial temporal sclerosis in 55%, brain tumor in 20%, nonspecific findings in 15%, and neuronal migration disorder, vascular malformation (Fig. 10.3), or head injury–associated sclerosis in 10%.26 Focal hyperintensities on T2-weighted images and decrease in apparent diffusion coefficients in complex partial status epilepticus—all reversible—may be seen as a consequence of edema associated with breakdown of the blood–brain barrier.27 As alluded to earlier, hippocampus or neocortical dropout abnormalities may emerge later and may be a direct correlate of seizures and not of hypoxemia (Box 10.1, Fig. 10.4).28,29

Miscellaneous Tests

Physiologic changes are observed in the aftermath of status epilepticus. A single generalized tonic-clonic seizure may produce similar laboratory changes if values are obtained within 1 hour of presentation. Most laboratory changes directly resulting from seizures or status epilepticus are self-limiting and rarely need intervention. However, abnormal laboratory values may suggest a competing systemic illness.

White cell counts may increase up to 30 × 109/L.33 Neutrophils usually remain dominant, but equally common is a lymphocyte increase in the differential count. Immature neutrophils can be present. Acute-phase hepatic proteins, glycoproteins, and globulins may transiently increase the erythrocyte sedimentation rate. Plasma glucose concentration may increase but remains in an indeterminate range of <150 mg/dL. Plasma osmolality should be normal or mildly increased in patients with dehydration but more significantly increased if recent alcohol abuse contributes to status epilepticus. Plasma osmolalities of 400–600 mOsm could be due to nonketotic hyperosmolar hyperglycemia. Hyponatremia may cause status epilepticus only when values are <120 mmol/L or have decreased at least 20–30 mmol/L within several hours.

Figure 10.3 Cavernous hemangiomas (arrows) (computed tomography and magnetic resonance imaging) in a patient with status epilepticus at presentation.

Spontaneous hypoglycemia possibly indicates a poison (see Chapter 8) or, less commonly, insulinoma. Acute renal failure should point to possible rhabdomyolysis and prompt measurement of serum creatine kinase, which may reach values in the thousands.

Arterial blood gas should be measured. Respiratory acidosis is as common as metabolic lactic acidosis, but the pH is rarely below 7.0 (Table 10.2).34 The abnormality is self-limiting and resolves within hours.35 Cardiac arrhythmias, such as sinus tachycardia, bradycardia, and supraventricular tachycardia, are rarely related to changes in the blood gases. Abnormal QRS complexes are not a manifestation of status epilepticus.

Laboratory results may be helpful in distinguishing between status epilepticus and pseudo-seizures. An entirely normal blood gas value while the patient is having convulsions supports pseudo-seizures. The serum concentration of prolactin is increased (peak value 15–20 minutes after onset of seizure) after a single epileptic generalized seizure but seldom after pseudoseizures.36 However, the discriminatory value in pseudo-status epilepticus has been debated,37 and prolactin may also be increased after syncope.38

Box 10.1. Neuronal Damage Associated with Status Epilepticus

Convulsive status epilepticus may greatly increase the excitatory amino acid glutamate, which in turn opens cation channels to calcium through N-methyl-D-aspartate receptors (“excitotoxic theory”). Whether this damage, with a proclivity for the hippocampus, thalamus, cerebellum, and neocortex, is also caused by additional hyperglycemia, anoxia, hyperpyrexia, or severe acidosis in humans remains unresolved. Neuronal dropout in the neocortex is predominantly apparent in inappropriately treated or unrecognized long-standing status epilepticus. It can take the form of dramatic MR changes (arrows in Fig. 10.4). Hippocampal cell damage does not occur after single seizures or nonconvulsive status epilepticus,30 but hippocampal edema has been demonstrated after febrile seizures.31 Paradoxically, one study found that hypoxemia protects against edema, possibly because of an early adaptive response involving stress-related transcription factors.32

Figure 10.4 MRI abnormalities consistent with long-standing status epilepticus.

Table 10.2. Acid-Base Disorders Associated with Status Epilepticus

Derangement

Number of Patients

pH

Respiratory acidosis

10

7.10–7.25

Respiratory and metabolic acidosis

6

7.11–7.15

Metabolic acidosis

8

7.05–7.13

Respiratory alkalosis

8

7.51–7.55

Normal

6

7.35–7.45

Source: Modified from Wijdicks and Hubmayr.34 By permission of Mayo Foundation for Medical Education and Research.

In any new-onset status epilepticus cerebro-spinal fluid (CSF) examination should be strongly considered, to exclude acute bacterial meningitis and encephalitis. White blood cell counts in the CSF may increase from seizures but not above 30 mononuclear cells/mL, and CSF protein rarely increase significantly.

Electroencephalography is particularly useful to confirm focal status epilepticus and detect non-convulsive status epilepticus. Electroencephalography may be helpful when the patient is sedated by antiepileptic drugs and clinical manifestations of electrographic discharges are difficult to detect.39 The findings should guide further use of antiepileptic agents or an increase in dose until epileptic activity is entirely suppressed. The patterns are shown in Figure 10.5.

Violent seizures may cause bone fractures but also injury to the shoulder. Apart from the typical posterior dislocation (such a characteristic feature that when seen by an orthopedic surgeon should result in referral to a neurologist for possible seizures), tendon injury may cause prolonged shoulder pain. Plain shoulder overviews are normal and in sharp contrast with abnormal MRI findings (Fig. 10.6).

Management of Status Epilepticus

Not only do patients with status epilepticus urgently need antiepileptic agents to reduce morbidity from injurious seizure activity but also the systemic effects are potentially harmful and may evolve into a complex medical emergency. It is important to immediately ventilate with oxygen, secure instruments to intubate quickly, and obtain intravenous access (Box 10.2).

Aspiration is very common in status epilepticus and may be the overriding cause of hypoxemia at presentation. In patients with altered pulmonary defenses, such as those with chronic obstructive pulmonary disease or alcohol abuse, pneumonia develops rapidly. Food particles may obstruct large airways and cause atelectasis and hypoxemia. Adult respiratory failure may follow rapidly and actually evolve in the emergency department. Dyspnea is profound from alveolar flooding, hypoxemia worsens within minutes, and patients with underlying chronic pulmonary disease have hypercapnia as well. These patients need intubation for airway protection and possibly fiberoptic bronchoscopy if early chest X-ray findings so indicate. Aspiration pneumonitis (Mendelson's syndrome) may be due to sterile gastric contents causing chemical injury. Empiric antibiotics are recommended (levofloxacin 500 mg/day, infusion over 1 hour).43 Neurogenic pulmonary edema from status epilepticus is uncommon but has been linked to sudden death, mostly in children and young adults. Chest X-ray findings are typically widespread “whiteout” infiltrates but resolve after several hours of positive end-expiratory pressure ventilation.

Cardiac arrhythmias may appear only if continuous seizures have resulted in prolonged significant lactic acidosis. Many patients have sinus tachycardia from the sympathetic overdrive state. Only cardiac arrhythmias causing measurable blood pressure reduction need correction with antiarrhythmic agents and bicarbonate infusion. Overzealous use of bicarbonate may cause alkalosis, which may perpetuate status epilepticus by lowering the seizure threshold.

Figure 10.5 Electroencephalographic patterns of different types of status epilepticus. A: Generalized tonic-clonic seizures (generalized high-frequency spikes and spike-and-wave discharges). B: Focal status epilepticus (rhythmic waves and spikes in one hemisphere). C: Nonconvulsive status epilepticus (episodes of spike-and-wave discharges coinciding with obtundation). D: Myoclonic status epilepticus (continuous epileptiform discharges with a burst-suppression pattern).

Figure 10.6 Plain X-ray (left) of shoulder following recurrent seizures. No evidence of posterior dislocation of fracture. Magnetic resonance image of shoulder (right) shows capsular edema, tear of the posterior labrum, and partial injury to subscapularis and biceps tendon.

 

Creatine kinase should be measured in each patient because rhabdomyolysis may result in acute renal failure, which can be entirely prevented by liberal intake of fluids.

The sequence of use of antiepileptic agents in status epilepticus continues to evolve.8 When patients with status epilepticus are referred to large institutions, approximately 30% have a recurrence of seizure after phenytoin loading, and seizures recurred in 40% of patients after a third-line agent. This demonstrates more difficult control with increasing duration. Morbidity will be substantial.44 An approach with additional precautionary measures is shown in Figure 10.7. Lorazepam 4 mg bolus is more effective than phenytoin for initial therapy.45 Up to 90% of patients are successfully managed with a combination of benzodiazepines and phenytoin.46,47 Failure to control seizures probably is related to inappropriate phenytoin loading (the popular “1g of phenytoin” is almost always inadequate) and to failure to appreciate that a second intravenous bolus of phenytoin may abort status epilepticus. A common sequence is phenytoin (Boxes 10.3, 10.4), midazolam or propofol49,50,51,52,53 (Boxes 10.5, 10.6), and pentobarbital and phenobarbital (Box 10.7). Newer drugs are ketamine (2 mg/kg bolus, 10–50 mg/kg per minute) or topiramate (300–1600 mg/day) and have aborted status epilepticus when all else fails.64,65 In addition, inhalation anesthetics can be used. Both isoflurane and desflurane are effective in controlling electroencephalographic activity, but improvement of the patient is rarely encountered.66

A particularly difficult situation is created by epilepsia partialis continua. Treatment is phenytoin loading followed by increasing doses of phenobarbital, starting with 40 mg or, in resistant cases, with intravenous administration of valproate (20 mg/min bolus and 20–50 mg/min infusion).67 In our experience, focal seizures are commonly treated well with valproate without need for endotracheal intubation due to respiratory depression. If valproate fails, additional doses of phenobarbital can be infused and could achieve control or at least a considerable decrease in manifestations.

Nonconvulsive status epilepticus, when documented by electroencephalography, can be treated under electroencephalographic monitoring with benzodiazepines (lorazepam, 4–8 mg, or diazepam, 10 mg).

The management of seizures in patients with preeclampsia is notably different. Magnesium sulfate remains the standard in prevention and treatment of seizures or status epilepticus.68,69 Magnesium sulfate is given at a beginning dose of 4–5 g intravenously or 10 g intramuscularly.70 An intravenous infusion of 1 g/hour is started. Additional antiepileptic agents are not warranted and may cause respiratory depression in the newborn. Magnesium toxicity may, however, also reduce mother and child respirations. Reduced tendon reflexes may occur and may indicate imminent toxicity; thus, they are a useful monitoring sign during titration of treatment.

Box 10.2. No Intravenous Access

Lack of intravenous access can be anticipated in long-term users of intravenous drugs. Intramuscular administration of fosphenytoin (12–20 mg/kg phenytoin equivalent) produces plasma concentrations of phenytoin equal to those with die oral dose within 30 minutes of administration, divided over different ejection sites. If intramuscular fosphenytoin is not available, diazepam should be used rectally (0.5 mg/kg) in repeated doses. Other options are intramuscular use of midazolam (5 mg) and observation for 3 minutes to allow absorption. Alternatively, the intranasal route can be considered for midazolam, with rapid absorption (within minutes, 0.1–0.2 mg/kg).40,41,42 Probably the last resort but the most effective way to counter status epilepticus is to use inhalation anesthetic agents. This should be followed by a saphenous vein cutdown at the ankle. The superficial location of the vein and large diameter make it suitable for placement of a large-bore cannula. Phenytoin can then be administered. Administration of isoflurane is started at 0.5% inspired concentration, with a gradual increase while end-tidal concentrations are monitored until a seizure-free electroencephalogram is obtained. Blood pressure most likely requires support with fluid infusions, the Trendelenburg position, and dopamine, phenylephrine, or dobutamine.

Antiepileptic therapy in myoclonus status epilepticus is usually not effective after cardiac arrest. Clonazepam has been advocated for treatment but has not been consistently effective in our experience. There is no rationale to aggressively treat these myoclonic jerks with a series of antiepileptic drugs. When myoclonus is forceful and causes marked contractions, even hampering normal ventilator cycling, propofol is needed (starting dose of 0.5 mg/kg per hour with 0.5 mg/kg per hour increments to effect) and is commonly successful. If myoclonus still cannot be controlled, neuromuscular blocking agents should be considered to eliminate the constant generalized jerks until the level of care has been assessed.

Figure 10.7 Algorithm for management of convulsive status epilepticus. IV, intravenous; WBC, white blood cells.

Box 10.3. Phenytoin

Phenytoin is rapidly distributed to body tissue and the brain. Respiratory depression does not occur in loading doses of 10–20 mg/kg. Sinus bradycardia is the most common cardiac arrhythmia. Transient diastolic pauses may occur and may worsen any heart block. Asystole has been reported. Phenytoin can be mixed only in isotonic saline because it precipitates in glucose. Oral dosage should resume 6–12 hours after infusion.

Box 10.4. Fosphenytoin

Fosphenytoin sodium (Cerebyx) is a prodrug of phenytoin that is rapidly (within minutes) converted by enzymes to phenytoin. Both intravenous and intramuscular administrations of 15–20 mg/kg produce therapeutic total (≥10 µg/mL) and free (≥ 1 µg/mL) plasma levels. Intramuscular loading (9–12 mg/kg phenytoin equivalent) produces therapeutic levels in 1 hour and can be considered in status epilepticus but only if intravenous access is not available. Fosphenytoin is completely water-soluble. Therefore, phlebitis, hypotension, and cardiac arrhythmias, typically associated with the propylene glycol–based intravenous phenytoin, are infrequent. However, cardiac arrhythmias may still occur when fosphenytoin is infused at rates >150 mg/minute. There is no pharmacokinetic drug interaction with intravenously administered diazepam or lorazepam. Major side effects are nystagmus, headache, ataxia, and drowsiness. Previously unrecognized and highly typical side effects (up to 30%) are transient but very annoying paresthesias and itching in the groin, genitalia, and head and neck.48

Box 10.5. Midazolam

It is not clear why midazolam works when benzodiazepines and phenytoin fail to control seizures. The drug is currently also being evaluated for initial management in outpatients.54 The half-life of midazolam (1–12 hours) is less than that of lorazepam (10–12 hours), and midazolam produces sedation of short duration in status epilepticus. Hourly infusion of 0.1–0.6 mg/kg should be continued for at least 12 hours before the dose is tapered. The cost, comparable with that of lorazepam, is high, approaching $800 for 24 hours of continuous infusion. The absence of propylene glycol solution in midazolam reduces the risk of hypotension, bradycardia, and electrocardiographic changes, which are more common with diazepam and lorazepam.55 High rates of infusion may produce cardiac depression and hypotension. Often, the mean dose to abolish seizure activity is three times the starting dose. When administration is discontinued, full consciousness is expected in 4–5 hours in most patients.56,57,58,59,60,61,62

Box 10.6. Propofol

Propofol has been considered controversial because of its association with myoclonic jerking and opisthotonos in humans. However, several studies have confirmed that it inhibits seizure activity. These animal studies included lidocaine-induced seizure activity or pentylenetetrazol-induced epilepsy. Propofol has been used in anesthetic doses to control status epilepticus and has reduced the risk of prolonged seizures in electroconvulsive therapy. A bolus of propofol may cause significant hypotension and is ill-advised. Only case series exist, but clinical experience is very favorable, with good control (1–5 mg/kg/hour). Bradycardia, hypotension, and lactic acidosis are side effects. The caloric intake with propofol is enormous.

Box 10.7. Barbiturates

Failure to control seizures with therapeutic levels of phenytoin (≥25 µg/mL) may justify intravenous administration of phenobarbital. Phenobarbital is much more potent than pentobarbital. Its major drawbacks are direct myocardial depression and vascular dilatation, but these are not treatment-limiting, Phenobarbital also has a very long elimination half-life (24–140 hours) but zeroorder elimination at high doses (constant amount of drug elimination per unit of time).

Intravenous pentobarbital (1–3 mg/kg per hour) virtually always controls status epilepticus, but relapse can be substantial, usually preceded by electrographic recurrence of seizure activity.63 Pentobarbital and phenobarbital are equal in effectiveness. Experience with propofol and midazolam will reduce the use of barbiturates greatly, but barbiturates remain very useful also in partial status epilepticus.

Psychogenic epilepticus typically lasts longer but may be aborted almost instantaneously with a supportive suggestion. The diagnosis can be confirmed by an electroencephalogram, but the jerking movements are often so bizarre that it is clear from the outset. A recent study found that psychogenic status epilepticus could be rapidly induced by administering saline intravenously and telling the patients (some of whom had visited many different emergency departments) that the saline solution will provoke seizures.71 However, the use of these deceptive provocative techniques is ethically questionable.72

Management of Recurrent Seizures

A clinical policy for the initial approach to patients with a seizure who do not have status epilepticus has been published by the American College of Emergency Physicians.73 Four major guidelines are highlighted. First, prolonged altered consciousness should not be attributed to a postictal state. Second, patients with prior epilepsy who are alert and have normal findings on neurologic examination do not require aggressive evaluation other than measurement of antiepileptic drug levels. Third, alcohol-related seizures may indicate serious underlying morbidity. Fourth, the patient should be implicitly told that driving and operation of machines should be restricted until a reasonable observation period has passed, to prevent future disasters.

Approximately 75% of patients with two or three unprovoked seizures have further seizures within 4 years.74 In contrast, the risk of a second seizure is approximately 35% in the subsequent 3–5 years.75 The risk of seizure recurrence is substantially increased (probably doubled) when an identifiable brain lesion is found.

Before a patient is sent out of the emergency department, several diagnostic tests should be done (Table 10.3); but in many instances, admission for intravenous phenytoin loading is advised. The above data suggest treatment in patients with two or more unprovoked seizures.

The recommended drugs for primary generalized tonic-clonic seizures or partial seizures with secondary generalization are phenytoin (300 mg/day in one dose; therapeutic level, 10–20 µg/mL), carbamazepine (300–1200 mg daily; therapeutic level, 4–12 µg/mL), and valproate (600–3000 mg/day; therapeutic level, 50–150 µg/mL). Valproate has notable side effects, particularly platelet dyscrasias and liver failure (1 in 20,000).76 The first-line agent for absence seizures is valproate (600–3000 mg/day; therapeutic level, 50–150, µg/mL), ethosuximide (20–30 mg/kg per day; therapeutic level, 40–100 µg/mL), or lamotrigine (100–400 mg/day in 2 divided doses). A combination of lamotrigine and valproate is often needed to control recurrent absences.

Table 10.3. Diagnostic Tests in Recurrent de Novo Seizures

Computed tomographic scan with contrast
Cervical spine radiograph (if trauma is suspected)
Cerebrospinal fluid (predominantly in immunosuppressed patients, human immunodeficiency virus)
Toxicologic screen, alcohol level
Sodium, calcium, magnesium, blood urea nitrogen,
creatinine, complete blood cell count, glucose

An alternative medication, mostly if seizures occur with first-line agents at therapeutic levels, could be gabapentin (900 mg/day in three gradually increasing doses) or other second-line antiepileptic drugs (e.g., lamotrigine, topiramate, tiagabine, or levetiracetam).

Specific concerns may arise when seizures are observed during pregnancy without evidence of eclampsia. Antiepileptic drugs for brief treatment of recurrent seizures should be well tolerated when pregnancy is beyond the first trimester and the risk to the infant seems unsubstantiated. Antiepileptic drugs in pregnancy double the risk of congenital malformations, including limb deformities, spina bifida (valproate), and growth retardation. Folic acid, 0.4 mg/day, should be added during pregnancy, but its effect on reducing birth defects probably takes place around conception.77 Monitoring phenytoin levels in pregnancy is complicated by a decrease in serum albumin levels; thus, the unbound fraction should be measured to manage dosage. In addition, the increased volume of distribution and increased clearance by liver and placenta may force an increase in the total daily dose.

Discontinuation of antiepileptic therapy is considered after a 2-year seizure-free interval, and if this can be achieved, recurrence is very low except in patients with documented brain lesions (e.g., cavernous angioma, cerebral contusion). Sudden withdrawal may increase the risk of recurrence and, in some instances, unfortunately, status epilepticus. Recurrence of seizures cannot be entirely excluded by a normal electroencephalogram before discontinuation is attempted.

References

1. Scholtes FB, Renier WO, Meinardi H: Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients. Epilepsia 35:1104, 1994.

2. Towne AR, Pellock JM, Ko D, et al.: Determinants of mortality in status epilepticus. Epilepsia 35:27, 1994.

3. Treiman DM: Generalized convulsive status epilepticus in the adults. Epilepsia 35:27, 1993.

4. Cascino GD: Generalized convulsive status epilepticus. Mayo Clin Proc 71:787, 1996.

5. Gemma M, Cipriani A, Mungo M: Management of status epilepticus. Intensive Care Med 20:611, 1994.

6. Runge JW, Allen FH: Emergency treatment of status epilepticus. Neurology 46(Suppl 1):S20, 1996.

7. Claasen J, Hirsch LJ, Emerson RG, et al.: Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 43:146, 2002.

8. Lawn ND, Wijdicks EFM: Progress in clinical neuro-sciences. Status epilepticus: a critical review of management options. Can J Neurol Sci 29:206, 2002.

9. DeLorenzo RJ, Hauser WA, Towne AR, et al.: A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 46:1029, 1996.

10. Lowenstein DH, Alldredge BK: Status epilepticus at an urban public hospital in the 1980s. Neurology 43:483, 1993.

11. Sung CY, Chu NS: Status epilepticus in the elderly: etiology, seizure type and outcome. Acta Neurol Scand 80:51, 1989.

12. Alldredge BK, Lowenstein DH: Status epilepticus related to alcohol abuse. Epilepsia 34:1033, 1993.

13. Fagan KJ, Lee SI: Prolonged confusion following convulsions due to generalized nonconvulsive status epilepticus. Neurology 40:1689, 1990.

14. Kaplan PW: Nonconvulsive status epilepticus in the emergency room. Epilepsia 37:643, 1996.

15. Baykan B, Gokyigit A, Gurses C, et al.: Recurrent absence status epilepticus: clinical and EEG characteristics. Seizure 11:310, 2002.

16. Agathonikou A, Panayiotopoulos CP, Giannakodimos S, et al.: Typical absence status in adults: diagnostic and syndromic considerations. Epilepsia 39:1265, 1998.

17. Cockerell OC, Walker MC, Sander JW, et al.: Complex partial status epilepticus: a recurrent problem. J Neurol Neurosurg Psychiatry 57:835, 1994.

18. Trinka E, Dilitz E, Unterberger I, et al.: Non-convulsive status epilepticus after replacement of valproate with lamotrigine. J Neurol 249:1417, 2002.

19. Husain AM, Horn GJ, Jacobson MP: Non-convulsive status epilepticus: usefulness of clinical features in selecting patients for urgent EEG. J Neurol Neurosurg Psychiatry 74:189, 2003.

20. Howell SJ, Owen L, Chadwick DW: Pseudostatus epilepticus. Q J Med 71:507, 1989.

21. Rosenberg ML: The eyes in hysterical states of unconsciousness. J Clin Neuroophthalmol 2:259, 1982.

22. Shen W, Bowman ES, Markand ON: Presenting the diagnosis of pseudoseizure. Neurology 40:756, 1990.

23. Jagoda A, Richey-Klein V, Riggio S: Psychogenic status epilepticus. J Emerg Med 13:31, 1995.

24. King DW, Gallagher BB, Murvin AJ, et al.: Pseudoseizures: diagnostic evaluation. Neurology 32:18, 1982.

25. Bronen RA, Fulbright RK, Spencer DD, et al.: Refractory epilepsy: comparison of MR imaging, CT, and histopathologic findings in 117 patients. Radiology 201:97, 1996.

26. Jack CR Jr: Magnetic resonance imaging in epilepsy. Mayo Clin Proc 71:695, 1996.

27. Calistri V, Caramia F, Bianco F, et al. Visualization of evolving status epilepticus with diffusion and perfusion MR imaging. Am J Neuroradiol 24:671, 2003.

28. Meierkord H, Wieshmann U, Niehaus L, et al.: Structural consequences of status epilepticus demonstrated with serial magnetic resonance imaging. Acta Neurol Scand 96:127, 1997.

29. Tien RD, Felsberg GJ: The hippocampus in status epilepticus: demonstration of signal intensity and morphologic changes with sequential fast spin-echo MR imaging, Radiology 194:249, 1995.

30. Bertram EH, Lothman EW, Lenn NJ: The hippocampus in experimental chronic epilepsy: a morphometric analysis. Ann Neurol 27:43, 1990.

31. Scott RC, Gadian DG, King MD, et al.: Magnetic resonance imaging findings within 5 days of status epileptics in childhood. Brain 125:1951, 2002.

32. Emerson MR, Nelson SR, Samson FE, et al.: Hypoxia preconditioning attenuates brain edema associated with kainic acid-induced status epilepticus in rats. Brain Res 825:189, 1999.

33. Barry E, Hauser WA: Pleocytosis after status epilepticus. Arch Neurol 51:190, 1994.

34. Wijdicks EFM, Hubmayr RD: Acute acid-base disorders associated with status epilepticus. Mayo Clin Proc 69:1044, 1994.

35. Yaffe K, Lowenstein DH: Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology 43:895, 1993.

36. Laxer KD, Mullooly JP, Howell B: Prolactin changes after seizures classified by EEG monitoring. Neurology 35:31, 1985.

37. Tomson T, Lindbom U, Nilsson BY, et al.: Serum prolactin during status epilepticus. J Neurol Neurosurg Psychiatry 52:1435, 1989.

38. Oribe E, Amini R, Nissenbaum E, et al.: Serum prolactin concentrations are elevated after syncope. Neurology 47:60, 1996.

39. Privitera MD, Strawsburg RH: Electroencephalographic monitoring in the emergency department. Emerg Med Clin North Am 12:1089, 1994.

40. Kendall JL, Reynolds M, Goldberg R: Intranasal midazolam in patients with status epilepticus. Ann Emerg Med 29:415, 1997.

41. Kofke WA, Young RS, Davis P, et al.: Isoflurane for refractory status epilepticus: a clinical series. Anesthesiology 71:653, 1989.

42. Rey E, Delaunay L, Pons G, et al.: Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration. Eur J Clin Pharmacol 41:355, 1991.

43. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665, 2001.

44. Mayer SA, Claassen J, Lokin J, et al.: Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 59:205, 2002.

45. Treiman DM, Meyers PD, Walton NY, et al.: A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 339:792, 1998.

46. Mitchell WG: Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 37(Suppl 1):S74, 1996.

47. Weise KL, Bleck TP: Status epilepticus in children and adults. Crit Care Clin 13:629, 1997.

48. Browne TR: Fosphenytoin (Cerebyx). Clin Neuropharmacol 20:1, 1997.

49. Borgeat A, Wilder-Smith OH, Jallon P, et al.: Propofol in the management of refractory status epilepticus: a case report. Intensive Care Med 20:148, 1994.

50. Kuisma M, Roine RO: Propofol in pre-hospital treatment of convulsive status epilepticus. Epilepsia 36:1241, 1995.

51. Mackenzie SJ, Kapadia F, Grant IS: Propofol infusion for control of status epilepticus. Epilepsia 36:1241, 1995.

52. Pitt-Miller PL, Elcock BJ, Maharaj M: The management of status epilepticus with a continuous propofol infusion. Anesth Analg 78:1193, 1994.

53. Stecker MM, Kramer TH, Raps EC, et al.: Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 39:18, 1998.

54. LeDuc TJ, Goellner WE, el-Sanadi N: Out-of-hospital midazolam for status epilepticus. Ann Emerg Med 28:377, 1996.

55. Labar DR, Ali A, Root J: High-dose intravenous lorazepam for the treatment of refractory status epilepticus. Neurology 44:1400, 1994.

56. Crisp CB, Gannon R, Knauft F: Continuous infusion of midazolam hydrochloride to control status epilepticus. Clin Pharmacol Ther 7:322, 1988.

57. Jawad S, Oxley J, Wilson J, et al.: A pharmacodynamic evaluation of midazolam as an antiepileptic compound. J Neurol Neurosurg Psychiatry 49:1050, 1986.

58. Kumar A, Bleck TP: Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 20:483, 1992.

59. Lai Koul R, Raj Aithala G, Chacko A, et al.: Continuous midazolam infusion as treatment of status epilepticus. Arch Dis Child 76:445, 1997.

60. Mayhue FE: IM midazolam for status epilepticus in the emergency department. Ann Emerg Med 17:643, 1988.

61. Nordt SP, Clark RF: Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 17:643, 1988.

62. Parent JM, Lowenstein DH: Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology 44:1837, 1994.

63. Krishnamurthy KB, Drislane FW: Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus. Epilepsia 37:863, 1996.

64. Sheth RD, Gidal BE: Refractory status epilepticus: response to ketamine. Neurology 51:1765, 1998.

65. Towne AR, Garnett LK, Waterhouse EJ, et al.: The use of topiramate in refractory status epilepticus. Neurology 60:332, 2003.

66. Sharpe MD, Young GB, Mirsattari S, et al.: Prolonged desflurane administration for refractory status epilepticus. Anesthesiology 87:261, 2002.

67. Kaplan PW: Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin Electroencephalogr 30:1, 1999.

68. Crowther C: Magnesium sulphate versus diazepam in the management of eclampsia: a randomized controlled trial. Br J Obstet Gynaecol 97:110, 1990.

69. Belfort MA, Anthony J, Saade GR, et al.: A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med 348:304, 2003.

70. Lucas MJ, Leveno KJ, Cunningham FG: A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 333:201, 1995.

71. Ney GC, Zimmerman C, Schaul N: Psychogenic status epilepticus induced by a provocative technique. Neurology 46:546, 1996.

72. Cohen RJ, Suter C: Hysterical seizures: suggestion as a provocative EEG test. Ann Neurol 11:391, 1982.

73. American College of Emergency Physicians: Clinical policy for the initial approach to patients presenting with a chief complaint of seizure who are not in status epilepticus. Ann Emerg Med 29:706, 1997.

74. First Seizure Trial Group: Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Neurology 43:478, 1993.

75. Hauser WA, Rich SS, Lee JR, et al.: Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 338:429, 1998.

76. Perucca E: Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 16:695, 2002.

77. Samren EB, van Duijn CM, Christiaens GC, et al.: Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 46:739, 1999.