A previously healthy 9 year old boy is brought to the emergency department because of the sudden onset of left-sided paralysis. His parents were aroused at night by a thrashing noise from his bedroom. They rushed to his room and found his bedsheets awry. He was lying in bed, breathing deeply, difficult to arouse, and could not stand or move his left arm or leg. There was no prior history of trauma, but he was noted to have a small tongue laceration. There is no history of toxic ingestions, fever, emesis or incontinence. EMS was called and he became more arousable during transport.
PMH is negative for any seizures or other serious medical conditions. His development has been normal. Family history is negative for seizures, strokes or brain tumors. His social history is negative for any problems at home. He is doing well in school.
Exam: Vital signs are normal. He is now alert, oriented, lying supine and not moving his left extremities. He appears non-dysmorphic and non-toxic. His head appears normal and without trauma other than the tongue laceration. Neck is supple with full range of active motion. No Brudzinski or Kernig signs. Pupils are equally round and reactive to light. Extraoccular movements are intact. No facial asymmetry. His heart is regular without murmurs. Lungs are clear. Abdominal exam is unremarkable. Skin is without neurocutaneous stigmata or signs of trauma. Neurologic evaluation reveals decreased strength (grade 2 out of 5) on the left. No sensory loss. Deep tendon reflexes are more brisk on the left and a Babinski sign is present on the left as well. Coordination is intact on the right. Coordination on the left and gait are not tested.
Labs: CBC and electrolytes are normal. Glucose is slightly elevated. CT scan of his head is normal.
He is hospitalized for observation. The next day, his left-sided weakness and neurologic abnormalities on exam are resolved. An EEG reveals centrotemporal spikes. After a discussion with his parents, it is decided to discharge him on no anticonvulsant medications. It is concluded that his lethargic episode was due to an unwitnessed seizure with subsequent post-ictal drowsiness.
A second nocturnal seizure occurs a year later, and he is started on carbamazepine. Over the next two years, he experiences no further seizures. He is treated until age 12 when his medication is weaned off and he does very well thereafter.
A seizure is a sudden, involuntary, stereotypical, repetitive alteration in behavior, including a change in motor activity, in autonomic function, in consciousness, and/or in sensation, which is caused by hypersynchronous discharges from a group of cerebral neurons (1,2). Epilepsy is a condition in which an individual is predisposed to recurrent seizures because of a central nervous system disorder (although about two-thirds have no identifiable cause). Recurrent seizures are the symptomatic expression of underlying brain pathology, not a disease in the usual sense (3).
While all people with epilepsy have seizures by definition, not everyone who has a seizures has epilepsy. Four to six percent of all children will have at least one seizure in the first 16 years of life; however, most of these are benign febrile seizures, and the cumulative risk of epilepsy during this time is only about 1-2% (4,5). In other words, less than one third of children who experience a seizure ever develop epilepsy. Over one half of first-time seizures are simple febrile seizures (see the chapter on febrile seizures) and another third are single isolated seizure events or seizures associated with a non-epileptic medical illness. Overall, about half of the lifetime risk of developing epilepsy is realized during the pediatric period, and it is the most common chronic neurologic disorder seen in children. Rates are highest during the first year of life.
As described, seizures are the clinical manifestations of epilepsy. Although other clinical manifestations may also be relevant, such as the neurologic exam, development, etc., this chapter will focus on general classifications and characteristics of epileptic seizures as proposed by the International League Against Epilepsy. Patients with epilepsy usually have a characteristic seizure type although some may have combinations of the following seizure types. The simplest classification is partial versus generalized. Partial seizures can be simple or complex. Generalized seizures can be absence or tonic-clonic. More classifications exist, but this chapter will focus on these four basic categories.
Partial or focal seizures are often caused by identifiable focal brain lesions which are related to the seizure activity expressed. They may be associated with an aura which is an altered sensation heralding or characterizing partial seizure activity. Any partial seizure can secondarily generalize into a tonic-clonic seizure which is discussed further below.
A simple partial seizure does not have an associated alteration of consciousness. Seizure manifestations may include tonic and/or clonic motor activity (e.g., originating from a contralateral motor cortex lesion), somatosensory phenomena (e.g., feeling a breeze, seeing light flashes, hearing buzzing, smelling odors, sensation of vertigo), and/or autonomic symptoms (e.g., gastric sensations, sweating, flushing). Of these, partial tonic-clonic seizures are the easiest to recognize. The others may be attributable to some other process and thus, are frequently not diagnosed as seizures.
Complex partial seizures also have focal origins but include an impairment of consciousness which implies alteration of functioning in the mesial temporal lobes, orbito frontal lobes, or in more widespread areas of the brain. The impaired consciousness is usually associated with a lack of understanding and memory of the brief event. They may involve more complicated behaviors such as frantic running, uncontrollable laughing, partial undressing, or facial automatisms. Partial complex seizures used to be called temporal lobe seizures because they often originate in the temporal lobes. Partial complex seizures also used to be called psychomotor seizures because they frequently include behavioral symptoms (e.g., auras, fear, déjà vu, facial grimacing).
Generalized seizures typically involve a loss of consciousness and/or a stereotypic motor activity. Absence seizures involve a few seconds of impairment of consciousness with eye blinking or staring which may occur as clustered events. Myoclonic seizures are usually seen in specific epilepsy syndromes and involve quick muscle jerks usually without associated impairment of consciousness. Tonic, clonic, or tonic-clonic seizures involve the abrupt onset of the described muscle activity for several minutes, often followed by post-ictal confusion and fatigue. Atonic seizures involve a sudden loss of postural tone, usually resulting in an abrupt collapse, which may not have any loss of consciousness. Generalized absence seizures are still called by their old name, petit mal seizures. These occur most commonly in the elementary school age group. Generalized tonic clonic seizures are still called by their old name, grand mal seizures.
Epileptic Seizure Classifications (1,5)
. . . . . A. Partial simple: Previous names include partial elementary seizures, focal motor seizures. Typical onset at any age.
. . . . . B. Partial complex: Previous names include temporal lobe seizures, psychomotor epilepsy. Typical onset at any age.
. . . . . C. Partial with secondary generalization: Previous names include Jacksonian march. Typical onset at any age.
. . . . . A. Generalized tonic clonic: Previous names include grand mal seizures. Typical onset at any age.
. . . . . B. Generalized absence: Previous names include petit mal seizures. Typical onset at elementary school age.
. . . . . C. Other types including: myoclonic, tonic, clonic, atonic (akinetic, drop attacks).
III. Epilepsy syndromes: Seizure syndromes including: infantile spasms (also known loosely as West's syndrome, Salaam attacks, hypsarrhythmia on EEG), benign epilepsy of childhood (Rolandic), Lennox-Gastaut, and juvenile myoclonic epilepsy.
The differential diagnosis of seizures requires consideration on several levels. The first question needing to be answered is whether a seizure truly occurred. The history of the event may classically characterize seizure activity, or a patient may present in status epilepticus (see chapter on status epilepticus), in which case the answer to this question is clear. However, often times with non-medical personnel observing what seems to be seizure activity and the emotional anxiety that accompanies it, whether a seizure truly occurred may be unclear. Phenomena which may seem to be partial seizure-like activity include: tics, paroxysmal REM sleep behavior, benign sleep myoclonus (jerks as one falls asleep), night terrors, migraine, benign paroxysmal vertigo, etc. Phenomena which may seem to be generalized seizure-like activity include: syncope, breath-holding spells, panic attacks, psychogenic seizures/pseudoseizures/conversion reaction, gastroesophageal reflux, staring spells, startle reflex (infants), etc.
Syncope is a common presentation which may be mistaken for a seizure. In general, syncope tends to be more gradual in onset, may be posturally related, and is without post-event focal neurologic findings or confusion. Seizures, however, are usually associated more with an abrupt onset, secondary injury, and may have post-ictal confusion, headache, incontinence or focal nerurologic signs (e.g., Todd paralysis) as well as an abnormal EEG. Syncope may have some brief clonic or myoclonic extremity movements associated with it which can add to the confusion between the two types of events. In general, true seizure motor activity does not have a reproducible trigger (e.g., a slamming door) and if the seizing body part is restrained, the seizure activity will persist.
If a seizure did occur, an important second question to be determined in evaluating a seizure is whether there were acute and reversible provocative causes such as: excessive stimulant medication or stimulant drug abuse, withdrawal from sedative drugs or alcohol, high fever (see chapter on febrile seizures), hypoglycemia, electrolyte imbalance (e.g., sodium, calcium, magnesium), hypoxia, or hypertensive encephalopathy. Answers to this question will play a pivotal role in selecting immediate therapy and determining future prognosis. Although a patient may have more than a single seizure attributed to these problems, these types of seizures would not typically be classified as epileptic.
A third question to be answered in the evaluation of what is now determined to be a first-time, not acutely reversible seizure, is whether further seizures are expected to occur. This includes an evaluation to determine if the seizure is symptomatic of other pathology and could result in recurrent seizures (i.e., symptomatic epilepsy). These include the following:
. . . . . Arteriovenous malformation
. . . . . Aneurysm, subarachnoid hemorrhage
. . . . . Stroke
. . . . . Venous thrombosis
. . . . . Blood dyscrasias (eg sickle cell anemia)
. . . . . Vasculitides (e.g., SLE)
. . . . . Abscess
. . . . . Encephalitis, meningitis
. . . . . Rasmussen's syndrome (presumed viral)
Tumors and Congential etiologies:
. . . . . Heterotopias (refer to the chapter on developmental brain anomalies)
. . . . . Cortical dysplasias
. . . . . Neurocutaneous syndromes (e.g., Sturge-Weber, Neurofibromatosis, Tuberous Sclerosis, Ataxia-Telangiectasia, von Hippel-Lindau)
. . . . . Other intracranial neoplasms
. . . . . Prenatal and perinatal (refer to the chapter on neonatal seizures)
. . . . . Child abuse
. . . . . Other head injuries
Less than 50% of patients with epilepsy have an identifiable cause. Those without a known underlying pathology are described as "cryptogenic" (likely an undetectable pathologic explanation) or "idiopathic" (presumed genetic) (1,4). Further consideration is also required to determine whether the seizure may be part of an epileptic syndrome which, by definition, would imply expected recurrent seizure activity without treatment. Epileptic syndromes in pediatrics are defined by known ages of onset, seizure patterns, EEG findings, and/or prognosis. These include: benign neonatal familial convulsions, infantile spasms (West's syndrome), benign childhood epilepsy with centrotemporal spikes, childhood epilepsy with occipital spikes, childhood absence, juvenile myoclonic epilepsy, and the Lennox-Gastaut syndrome. With all that has been mentioned, there are still numerous other epilepsy syndromes as well as combinations of seizures and EEG patterns which may not fit into the categories noted above.
All seizures involve abnormal paroxysmal hypersynchronous neuronal excitation. Cerebral manifestations include increased blood flow, increased oxygen and glucose consumption, and increased carbon dioxide and lactic acid production. If a patient can maintain appropriate oxygenation and ventilation, the increase in cerebral blood flow is usually sufficient to meet the initial increased metabolic requirements of the brain; however, prolonged seizures may result in permanent neuronal injury (2).
Systemic manifestations of massive sympathetic discharge may occur with seizures and include: pulse increase, BP increase, pupil dilatation, and increased blood glucose. Salivation may increase secondary to parotid stimulation with masseter muscle contraction. Respirations may cease or be irregular and the patient may have facial cyanosis due to a tonic increase in intrathoracic pressure and impeded venous return associated with maximal muscle group contractions. Failure of adequate ventilation can lead to hypoxia, hypercarbia, and respiratory acidosis. Prolonged skeletal muscle activity can lead to lactic acidosis, rhabdomyolysis, hyeperkalemia, and hyperthermia.
Postictally (after the seizure event), effects of the massive neuronal depolarization and metabolic activity may include confusion, lethargy or a comatose state. Vomiting may occur, and patients with impaired consciousness may be unable to protect their airway and are at risk for aspiration. Impaired consciousness may also be associated with airway obstruction from the tongue or respiratory secretions. Head trauma may have precipitated a seizure event, but traumatic falls may also occur interictally and contribute to postictal altered mental status and other injuries.
Transient postictal focal deficits, e.g., Todd paralysis (transient paralysis which occurs after a seizure), may occur, but typically do not last beyond 24 hours. The mechanism is not well understood, but it may be attributed to neuronal dysfunction or neurotransmitter exhaustion. The duration and severity of the seizure do not correlate with the degree of postictal paralysis, and the paralysis usually, but not always, is noted in the area of the focal seizure activity. (6).
Systemically in the postictal state, deep respirations may be present to compensate for respiratory and metabolic acidosis, and blood pressure and temperature quickly return to normal. Due to the catecholamine surge noted above, patients are usually mildy hyperglycemic. Headache and muscle soreness may also occur in association with muscle fatigue and acidosis.
The diagnosis of epileptic seizures involves determining: 1) if seizures occurred, 2) the type of seizures, 3) the cause of the seizures, and 4) if they are characteristic of an epileptic syndrome. Furthermore, any life-threatening causes of seizures (e.g., intracranial hemorrhage, meningitis/encephalitis, toxic ingestions), should be ruled-out or addressed in a timely fashion.
The history is the most important part of the diagnostic evaluation of a patient's seizure disorder. This may include:
Source: Reliable witnesses?
HPI: Seizure or not seizure? If a seizure, what type? Any complications?
Etiology: Provoked (trauma, drugs, fever)/unprovoked? Underlying seizure disorder, history of previous seizures or other neruologic disorder? If on an anticonvulsant drug (anti-epileptic drug, AED), has there been change in dosing/compliance? Other signs of systemic illness or reasons for provocative causes: headache, vomiting, diarrhea, ataxia, altered mental status.
Onset: Prodromal symptoms (aura)? Rapid/gradual?
Characteristics: Partial/generalized? Duration (see chapter on status epilepticus if prolonged)? Evolution, motor activity of head, eyes, face, trunk, extremities, other complicating factors (cyanosis, trauma, emesis).
Postictal state: Incontinence, confusion/sleepy, headache, focal neurologic deficits, time to recovery of normal function (nearly immediate for syncope, minutes to hours for postictal, but usually less than 24hours)?
Past medical history (predisposing factors): Chronic illnesses (endocrine, hepatic, neoplastic, renal), history of seizures, CVA, CNS infection, autoimmune disease, head trauma, medications.
Development: Appropriate for age?
Family history: Seizures, epilepsy, neurocutaneous syndromes, other neurologic disorders?
Social history: Risk of physical abuse? Drug/alcohol abuse?
Physical examination should note the following: General appearance (dysmorphic features, associated injury pattern, signs of infection), vital signs, growth and head circumference percentiles, head (trauma, VP shunt), eyes (pupils, papilledema, retinal hemorrhages, angiomatosis, pigmentation), ears (hemotympanum, otitis media), nose (CSF rhinorrhea), mouth (drooling indicates aspiration risk, tongue laceration is suggestive of a seizure), neck (injury, meningeal signs), lungs (aspiration pneumonia), heart (rhythm abnormalities, congenital heart disease), incontinence, extremities (injuries), and skin (trauma, neurocutaneous stigmata). Neurologic evaluation should include: time to recovery, retrograde amnesia, speech difficulty, cranial nerves function, herniation signs, posturing, postictal deficits such as Todd paralysis, sensory loss, pathological reflexes, coordination or gait changes
Diagnostic tests for seizures are usually low-yield without historical or exam findings to suggest possible abnormalities. Routine screening labs, depending on the setting, may include electrolytes, glucose, Ca and Mg. Hyponatremia and hypoglycemia can cause seizures, whereas hypocalcemia and magnesium abnormalities resulting in hypocalcemia may cause tetany which resembles seizures. If the patient is on chronic AEDs for seizure control, then obtaining blood levels provides valuable information regarding compliance, drug efficacy, and possible toxicity. CBC, BUN/Creatinine, liver function tests, PT/PTT are particularly of low yield unless the clinical circumstances suggest a specific problem related to these. ABG and CPK , potassium and bicarbonate may have some benefit if the seizure was prolonged (see chapter on status epilepticus) and if there is a risk of rhabdomyolysis. Drug screens may be considered based on the social history. Toxicology can be used to screen for cocaine, amphetamines, PCP, TCA (tricyclic antidepressants) as well as possible withdrawal from benzodiazepines, alcohol, and barbiturates. Other drugs in overdose may cause seizures such as antipsychotics, methylxanthies, INH, antihistamines, and narcotics. If brain hemorrhage or infection is suspected, a lumbar puncture is indicated once elevated intracranial pressure (ICP) has been ruled out by history, exam, and possibly an imaging study.
Structural imaging studies of the brain, computed tomography (CT) and/or magnetic resonance imaging (MRI), are typically indicated in afebrile seizures and non-simple febrile seizures of unclear etiology. An emergent CT scan may be indicated in the following situations: 1) signs of symptoms of elevated ICP, 2) focal seizure or persistent focal neurologic deficit, 3) seizures with head trauma, 4) status epilepticus of unclear etiology. The CT is appropriate for detection of intracranial vascular lesions, acute bleeding and certain tumors larger than 1 cm. The MRI has better resolution for smaller and isodense lesions (e.g., low-grade gliomas). MRI may also provide better images in some areas (e.g., posterior fossa) and for some lesion types (e.g., neuronal migration disorders, lesions of the neurocutaneous syndromes, AVM). The trade-off with MRI is that they are typically more difficult to schedule acutely, they take more time to complete and they require deeper sedation levels for young children. On the order of 50% or more of neuroimaging studies may be normal in patients with epilepsy (5).
The electroencephalogram (EEG) is a crucial tool in the diagnosis of seizures. It consists of a systematic measurement of electric potentials emanating from the brain's cortical surface which are less than 1/100th that of cardiac voltage on ECG. Numerous channels are recorded simultaneously from standard electrode placements to map brain electrical activity. Potentially provacative maneuvers (procedures known to provoke seizure potentials), known as activation procedures, such as hyperventilation, photic stimulation (e.g., blinking lights), and spontaneous sleep induction and emergence are employed to increase the yield of positive EEG findings by helping to trigger seizure potentials during the study. Because epileptiform activity may be present only at brief intervals, only 50-60% of routine EEGs are positive even in patients with known epilepsy. Activation procedures increase this yield. Seizure activity on EEG does not always accompany a visible seizure clinically. In general, although normal EEGs have low utility because they may be falsely negative, positive findings can be very helpful in determining the presence and classification of epilepsy to help direct treatment.
There are a wide variety of positive EEG findings. The classic epileptiform EEG abnormality is the sharp spike or wave which may be focal or generalized. Generalized spiking is usually large and obvious, while focal spikes (especially temporal lobe spiking) may be smaller and more subtle to see. Focal spikes or waves may help define an epileptic syndrome (e.g., benign childhood epilepsy with centrotemporal spikes). Other generalized patterns may also be definitive such as the 3-per-second spike and slow waves of childhood absence epilepsy (petit mal). Other mixtures of signals may also display characteristically defined patterns such as the mixture of spikes and slow waves that are different in each hemisphere described as hypsarrhythmia which is typical of infantile spasms. Postictal slowing may suggest a previous epileptic event if similar changes are not seen in a preseizure EEG. After a diagnosis of epilepsy is made, follow-up EEGs may sometimes be helpful in assessing response to therapy.
The yield on an EEG is dependent on multiple factors. Increasing positive findings with provocative measures was discussed previously. False negative results can be associated with epileptogenic foci that are deep to the cerebral surface, discharges that are orthogonal to the cerebral surface, excessive muscular artifact, and simply due to limitations in monitoring duration in comparison with the frequency of epileptiform EEG activity. Although there may be a variety of other abnormal EEG findings, such as focal slow waves or asymmetries of signals, they are non-specific regarding a diagnosis of epilepsy and are more useful in providing general information about cerebral function, encephalopathies, focal lesions, etc.
Epileptic seizure classifications by EEG are generally as follows: Partial simple seizures display spikes in a localized portion of the brain. Partial complex seizures display small spikes, usually in the temporal lobes. Partial seizures with secondary generalization demonstrates focal spikes progressing to generalized spiking. Generalized absence seizures display a 3 per second spike and slow wave pattern which is often preciptated by hyperventilation. Generalized tonic-clonic seizures display generalized spiking (photic stimulation may be a useful activation procedure). Infantile spasms, sometimes seen in severe developmental brain anomalies and tuberous sclerosis, display a hypsarrhythmia pattern (disorganized mixture of spikes and slow waves, different in each hemisphere). Benign epilepsy of childhood (Rolandic seizures) displays centrotemporal spikes or sharp waves ("Rolandic discharges") against a normal background. The Lennox-Gastaut syndrome displays slow spike and waves on an abnormal slow background.
Therapy for the acutely seizing patient is described in the chapter on status epilepticus. The decisions on whether to start chronic anti-epileptic drug (AED) therapy, involves weighing risks and benefits of therapy with an in-depth discussion with the patient and family. If a seizure occurs secondary to an acutely reversible provoking factor (e.g., fever, hyponatremia, hypoglycemia, benzodiazepine withdrawal, post-impact, etc.), the treatment is directed toward the underlying cause and short-term anti-seizure medication, as needed. No long-term anticonvulsant medication is typically employed.
Chronic therapy with AEDs should be started for seizures associated with any known structural lesion (e.g., brain tumor, AVM, intracranial bleeding, or infection such as HSV encephalitis). If there is no known underlying pathology, chronic AED therapy is also indicated for seizures associated with: 1) A family history of epilepsy in siblings (not if in parents). 2) EEG with definite epileptic pattern. 3) History of prior acute unprovoked seizure(s). 4) Status epilepticus at onset. 5) Remote history of head trauma, stroke, CNS infection, or static encephalopathy from birth with mental retardation or cerebral palsy. All of these factors suggest a higher risk of recurrence. The decision to start chronic AED therapy is less clear if there is a first-time unprovoked seizure without the above risk factors. The risk for a second seizure in five-years is approximately 30% whereas it is approximately 46-73% for a seizure with any one of the above risk factors (7). The risks/costs of treatment include the side-effect profile of the intended AED, financial cost, impact of implementation on daily routine, and the chance that even with good compliance, the medication may not definitively prevent a seizure recurrence. For example, if a child's first seizure occurs at age 6 years, it is difficult to predict whether the next seizure will occur, tomorrow, next year, in another 6 years, or never at all. It is not beneficial for children to take daily medication for years to prevent an incident that may not be destined to occur during that time period.
The benefits of treatment include reducing the risk of recurrent seizures and their potential consequences such as associated injury, effects on self-esteem, and numerous restrictions such as loss of driving license privileges. In general, AED therapy is not indicated for the child who experiences a brief first seizure if the history confirms that the episode is truly an initial event, there is no family history of epilepsy, the neurologic examination is normal, and the EEG does not confirm a specific epileptic syndrome. The patient must be educated about the risk of subsequent seizures and should be advised about state driving regulations (8).
The initial selection of AED is typically based on seizure type. Carbamazepine (Tegretol) and phenytoin (Dilantin) are considered the initial medications to consider in all partial seizures and in generalized tonic-clonic seizures (with the exception of infants). Infants are usually treated with phenobarbital, since this drug is less toxic and the other drugs have some unattractive characteristics in infants such as poor GI absorption, poor oral formulations, etc. Generalized absence seizures are treated with ethosuximide (Zarontin). Valproic acid (Depakene, Depakote) may be effective both for partial and generalized seizures including absence seizures, but it is typically used only if initial therapy is not successful due to its side-effect profile. Oral benzodiazepines are also used as AEDs in some instances, usually in combination with other AEDs. Other newer AEDs cleared by the FDA since 1993 include felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide (9). The reader is referred to the reference list for further information on these medications and therapy for other epileptic syndromes. Approximately 80% of all persons with primary generalized seizure epilepsy and 65% of patients with partial seizure epilepsy achieve satisfactory control of seizures with AED therapy (10). The indications, pharmacology, and adverse effects of carbamazepine, phenytoin, phenobarbital, and valproic acid will be discussed briefly:
Carbamezepine is a first-line AED for the treatment of simple partial, complex partial, and general tonic-clonic seizures. The mechanism of action of carbamazepine is thought to be through use-dependent blockade of voltage sensitive sodium channels which results in stabilization of neuronal membranes and inhibition of repetitive firing of neurons. It may be orally or rectally absorbed, has a half-life of 12 to 17 hours and is extensively metabolized in the liver via the cytochrome P450 system. Dose-related side effects of carbamazepine include vertigo, ataxia, diplopia, and drowsiness. Approximately 4% of people treated with carbamazepine develop dermatologic reactions including erythematous and pruritic rashes, toxic epidermal necrolysis, erythema multiforme and Stevens-Johnson syndrome. The onset is usually within the first month of treatment but can be delayed up to 6 months. Serious blood dyscrasias, such as aplastic anemia and agranulocytosis have been reported, and although rare, occur at a freaquency 5 to 8 times higher than that of the general population (11).
Phenytoin is used for the treatment of simple partial, complex partial, and generalized tonic-clonic seizures. The mechanism of action is similar to carbamazepine by use-dependent blockade of voltage-sensitive sodium channels. Phenytoin may be administered orally or intravenously. Because intravenous infusion rates of phenytoin are limited due to associated cardiac side-effects, fosphenytoin (an ester of phenytoin which is cleaved to phenytoin in the body) is commonly used for emergent loading (refer to the status epilepticus chapter). Phenytoin is metabolized in the liver in a concentration dependent, non-linear fashion. As a result, the half-life and time to steady state are dose dependent. Dose related side effects include nystagmus, ataxia, sedation, mental status changes, ophthalmoplegia and increased seizure frequency. Cosmetic side effects, including gingival hyperplasia, hirsutism and acne, are commonly seen and can be barriers to compliance in adolescent patients. A rash is the most common idiosyncratic reaction seen in 5-10% of people treated with phenytoin. It is typically morbilliform, may be accompanied by fever, and usually occurs in the first 3 months of treatment. Serious side effects such as agranulocytosis, aplastic anemia, hepatitis, and nephritis are rare (11).
Phenobarbital is frequently used in the treatment of neonatal seizures (see chapter on neonatal seizures) and seizures that occur in the first year of life. It is effective for both generalized tonic-clonic seizures, and partial seizures at all ages, but unfavorable cognitive side effects and concerns about the potential for adverse effects on the developing brain limit its use. Phenobarbital acts by various mechanisms including potentiating inhibitory neurotransmission by increasing the duration of time that gamma-aminobutyric acid (GABA) mediated chloride channels remain open. It is absorbed enterally and can also be given intravenously or intramuscularly. Phenobarbital is metabolized in the liver by the cytochrome P450 system, and it can induce the rate of metabolism of itself and other drugs that are metabolized thought this system. The clearance of phenobarbital is slow, with a half-life of 1 to 5 days. The dose-related adverse effects of phenobarbital include sedation, slowed thinking and ataxia. In children, however, paradoxic irritability and hyperactivity are also common side effects. (11).
Valproic acid has a broad spectrum of AED activity which includes generalized seizures such as myoclonic, tonic, atonic, absence, generalized tonic-clonic seizures and partial onset seizures. The mechanism of action of valproic acid is not completely understood. It has several different actions in vitro which may contribute to its AED effect including enhanced GABA-mediated inhibition and blockage of voltage-activated sodium currents. Valproic acid is orally administered, hepatically eliminated, and has a half life of 8 to 9 hours. Dose-related adverse effects of valproic acid include tremor, sedation, fatigue, and ataxia. Valproic acid can produce local gastrointestinal irritation that can lead to abdominal pain, nausea, diarrhea, or pancreatitis. Potentially fatal hepatotoxicity has been observed, usually within the first 6 months of therapy, and typically in children under 2 years of age. Valproic acid should be used with caution in women of child bearing age due to its teratogenic effects and association with polycystic ovaries (11).
All of the above AEDs have extensive protein binding and are hepatically metabolized. As a result, their levels are significantly affected by conditions and other medications which may affect protein binding and hepatic enzyme function.
Reasons for failure to respond to single AED therapy include noncompliance, inadequate serum AED levels, incorrect classification of seizure type, and continued exposure to seizure precipitants. If AED therapy is changed, the transition should include a slow wean off the original AED. If two trials of AEDs as monotherapy are ineffective, the chances of obtaining seizure control with additional medication trials are less than 15% (5). Trials of combinations of AEDs with different mechanisms of action are is also an alternative although this increases the risk of drug-drug interactions. About 30% of all patients with epilepsy continue to have seizures that appear to be resistant to all pharmacologic manipulations (1,4).
Nonpharmacological therapies for seizure control are usually reserved for medically refractory cases of epilepsy. These modalities include epilepsy surgery, vagus nerve stimulation, and the ketogenic diet.
Epilepsy surgery may be considered for patients with medically refractory seizures that interfere significantly with their lifestyle. Medical refractoriness is not well defined, but it can generally begin to be considered when seizures continue despite adequate monotherapy trials of two AEDs. Patients with simple partial seizures alone are generally not considered for surgery because the risk is likely to exceed the benefit. However, patients with complex-partial seizures or generalized motor seizures occurring as infrequently as once every few months can be candidates if these sufficiently impede academic or job performance, driving, and employment opportunities (12). Epilepsy surgery is contraindicated in children with benign focal epilepsy of childhood, idiopathic generalized epilepsy, and progressive medical or neurologic disorders (12). Presurgical evaluation is focused upon delineation of the epileptogenic zone (the region of cortex capable of generating seizures). The evaluation includes clinical history, ictal and interictal video, EEG, possibly invasive EEG, neuroimaging (MRI, SPECT, PET, magnetic resonance spectroscopy), and neuropsychologic assessment. A recommendation for surgery is made when the epileptogenic zone has been adequately defined, and the proposed procedure is believed to be associated with a high likelihood of seizure relief and a low risk of neurologic and cognitive morbitidy (12).
The types of surgery performed in patients for refractory epilepsy included corticectomy, lobectomy, lesionectomy, hemispherectomy, corpus callosotomy, multiple subpial transection , and newer procedures including gamma knife surgery and deep brain stimulation (11). Early consideration for surgery is important to capitalize on the plasticity of the developing brain and to minimize lost developmental and behavioral milestones.
Vagus nerve stimulation (VNS) is FDA approved for use as adjunctive therapy for adolescents over 12 years of age and adults whose partial-onset seizures are refractory to AEDs (1,5). These patients are also usually not epilepsy surgery candidates. The mechanism of action of VNS is uncertain. A generator is placed surgically and it delivers programmed electrical pulses which may help to interrupt seizures or reduce seizure severity. Patients who experience auras warning them of an impending seizure can stop or shorten the length of the seizure by activating the VNS.
The ketogenic diet is a high fat, low protein and low carbohydrate diet used to treat intractable epilepsy. It was originally developed in the 1920s at the Mayo Clinic and was widely used until the 1940s when more effective and easier to use AEDs were developed. The ketogenic diet is still used by some neurologists today; however for children who endure multiple daily seizures. The diet places the body in a state of starvation which forces it to utilize more fat than usual for energy, which results in more ketone by-products (hence the name "ketogenic") which serve as an alternative energy source for the brain. The exact mechanism for the ketogenic diet's efficacy is unclear, and it is on the FDA list of "experimental treatments" (1).
Lifestyle factors can contribute to seizure control and attempts should be made to manage them while encouraging normal development. Some lifestyle modifications may include: 1) Taking chronic AED medications regularly. 2) Getting enough sleep, avoiding alcohol, drugs other interacting medications. 3) Emergency plan of access to medical care, medical condition identification bracelet, and possibly rectal diazepam to be used in an emergency for a prolonged seizure. 4) Ongoing monitoring of AED levels, side-effects, adequacy of seizure control. 5) Ongoing monitoring of development, school performance. 6) Water and fall precautions. 7) Restrictions, especially as they relate to a driver's license. 8) Maintaining previous normal activity and disciplinary measures as much as possible and avoiding over-protection.
About 60-70% of patients with newly diagnosed epilepsy enter long-term remission, usually on a single AED. Patients who remain seizure-free for several years may be considered for weaning off AED therapy. Factors affecting the decision to wean AEDs and when to do this depend primarily on the type of epilepsy syndrome present (e.g., benign epilepsy with centrotemporal spikes tends to be "outgrown" while a structural lesion such as a brain tumor or AVM may have a perpetually high risk of seizures despite good control). Other factors that favor successful withdrawal include: single type of seizure, normal neurologic examination, normal IQ, and normal EEG following treatment. The benefits of withdrawal (freedom from daily medication, reduction of side effects, decreased risk of teratogenic effects) must be balanced against an approximately 20-30% probability of seizure recurrence (loss of job, possible injury, effects on self-esteem) (1). If the decision to discontinue AED therapy is made, the medication should be gradually weaned over weeks to months to avoid withdrawal seizures.
Short occasional seizures are not felt to be associated with additional brain injury of long-term significance. About 30% of patients with epilepsy continue to have seizures that appear to be resistant to all pharmacologic manipulations (7). The response to the first AED is the most powerful predictor of long-term prognosis. Presuming that the correct type of seizure was diagnosed and therapeutic levels of the correct AED are obtained, a patient may be considered to have refractory epilepsy if seizure control is not achieved after the first two to three AEDs used. These patients are usually treated with multiple AEDs, which in combination, may produce sedative and adverse behavioral effects. However, high seizure frequency, prolonged seizures, and episodes of status epilepticus can lead to cognitive decline. In some patients, excessive seizure activity may be associated with detrimental cerebral histologic changes such as dendritic sprouting, synaptic reorganization, glial proliferation, and cell death (7). Also associated with AED toxicity and/or excessive seizure activity are psychosocial dysfunction, poor academic achievement, diminished self-esteem, dependent behavior, and a restricted lifestyle.
In the case at the beginning of the chapter, this is a developmentally normal boy with no personal or family history of seizures who had an acute event that is suggestive of a seizure given its abrupt onset and description as well as the persisting focal neurologic deficit which gradually resolves (which is likely a Todd paralysis). The exam finding of a tongue laceration is also suggestive of a seizure. The transient left hemiplegia and hyperreflexia are consistent with Todd paralysis. The elevation in blood glucose is normal postictal hyperglycemia. The CT was indicated due to persisting focal neurologic deficits in the patient although he did not have a history suggestive of trauma, infection, or focal structural lesions.
The patient is appropriately hospitalized for observation given his persisting neurologic deficit. The EEG confirms the diagnosis of benign Rolandic epilepsy with centrotemporal spikes, an idiopathic epileptic condition with characteristic EEG findings. Given this diagnosis and the fact that the patient experienced a first-time seizure, observation without AED therapy is reasonably employed. Although he has a recurrent seizure, he does well on carbemazepine and is successfully weaned off therapy after adolescence which is consistent with the good prognosis of this particular epileptic syndrome.
1. List 4 basic types of seizures (hint: two are partial and two are generalized).
2. List some of the old names that correlate to each of the above 4 seizure types and indicate the reason these old names were used.
3. A 14 year old girl is found unconscious. Witnesses say that she had some facial twitching. She gradually awakens and tells you that she smelled some burning rubber just prior to feeling faint. She tried to call for help, but couldn't speak. She now seems to be normal. A CT scan demonstrates a left temporal lobe arteriovenous malformation. What seizure type is she likely to have had and why?
4. Can the term petit mal be used to describe a seizure of small jerking movements of one arm?
5. Name some tests/studies which would be ordered for a 7 year-old girl who presents to the emergency department actively having a generalized seizure which stops spontaneously. She is afebrile and was brought in by her babysitter who is unaware of any history except that she may have been on some kind of medicine.
6. Why would an eventual MRI be useful for the patient in questions 5 if there are no obvious reasons for the seizure?
7. If a patient has no epileptiform activity on an EEG does that rule-out epilepsy? Why?
8. What are typical EEG findings in generalized absence seizures? In infantile spasms?
9. What AEDs (anti-epileptic drugs) are used for treatment of generalized absence seizures?
10. What percent of children with epilepsy eventually enter long-term remission? What percent of children with epilepsy never become seizure free on AEDs?
1. Gumnit RJ, Leppik IE. The epilepsies. In: Rosenberrg R (ed). Comprehensive Neurology. 1991, New York: Raven Press, pp. 311-356.
2. Chiang VW. Chapter 70-Seizures. In: Fleisher GR, Ludwig S (eds). Textbook of Pediatric Emergency Medicine, fourth edition. 2000, Philadelphia: Williams & Wilkins, pp. 573-579.
3. Glaze DG. Epilepsy. In: Johnson KB, Oski FA (eds). Oski's Essential Pediatrics. 1997, Philadelphia: Lippincott-Raven, pp. 607-611.
4. Berg AT, Testa FM, Levy SR, Shinnar S. The Epidemiology of Epilepsy. Neurologic Clinics 1996;14(2):383-398.
5. Schachter SC. Epilepsy. Neurologic Clinics 2001;19(1):57-78.
6. Dhaliwal HS. Index of suspicion, Case 3, Diagnosis Todd paralysis. Pediatr Rev 1998:19(11):387-388.
7. Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology 2002:58(8):S2-S8.
8. Consensus statements (Southern Clinical Neurological Society). Medical management of epilepsy. Neurology 1998;51(5):S039-S043.
9. Pellock JM. Managing Pediatric Epilepsy Syndromes With New Antiepileptic Drugs. Pediatrics 1999;104(5):1106-1116.
10. Devinsky O. Patients with Refractory Seizures. New Engl J Med 1999;340(20):1565-1570.
11. Holland KD. Efficacy, pharmacology, and adverse effects of antiepileptic drugs. Neurologic Clinics 2001;19(2):313-345.
12. Foldvary N, Bingaman WE, Wyllie E. Surgical treatment of epilepsy. Neurologic Clinics 2001;19(2):491-515.
Answers to questions
1. Partial simple (also called "partial elementary" or "focal motor"), partial complex, generalized tonic-clonic, generalized absence.
2. Focal motor seizures (partial simple) because only one part of the body exhibits tonic clonic seizures. "Jacksonian seizures" describe focal motor seizures, while "Jacksonian march" describes a partial simple with secondary generalization because of gradual spread of motor activity. Temporal lobe epilepsy (partial complex) due to lesions in the temporal lobe. Psychomotor seizures (partial complex) because they display behavioral changes in addition to facial motor abnormalities, such as twitching and grimacing. Grand mal (generalized tonic-clonic) because they exhibit grand abnormalities as manifested by generalized jerking. Petit mal (generalized absence) because they exhibit smaller abnormalities limited to the eyes and face in most instances, and also because these patients are generally in elementary school and thus petit in size.
3. Partial complex seizures. She has experienced an aura (burning rubber smell). The witnesses suggest mostly facial motor symptoms. She lost consciousness. The temporary expressive aphasia suggests a temporal lobe origin which is confirmed on CT scan which identifies a lesion in the left temporal lobe (which is why this used to be called temporal lobe seizures). Students will often confuse this presentation with generalized absence seizures, which usually occurs in elementary school aged children who have just a few seconds of impaired/loss of consciousness. This is not a partial simple seizure because there are motor, aura, aphasia and olfactory symptoms, in addition to loss of consciousness.
4. No, petit mal refers to generalized absence seizures. Jerking of one arm (even if they are small jerks) are partial simple seizures (focal motor), not generalized absence (petit mal).
5. Electrolytes, glucose, toxicology, AED levels, CT of the head, lumbar puncture would be a basic set of initial tests. An eventual EEG would be in order if no obvious precipitating factors were found.
6. The MRI has better resolution for smaller and isodense lesions (e.g., low-grade gliomas). MRI may also provide better images in some areas (e.g., posterior fossa) and for some lesions types (e.g., neuronal migration disorders, lesions of the neurocutaneous syndromes, AVM).
7. No, a negative EEG does not rule out epilepsy. False negative results can be associated with epileptogenic foci that are deep to the cerebral surface, discharges that are orthogonal to the cerebral surface, excessive muscular artifact, and simply due to limitations in monitoring duration in comparison with the frequency of epileptiform EEG activity. Of all the seizure types, partial complex seizure foci are the most difficult to reliably identify on EEG.
8. Generalized absence seizures typically have a generalized 3 per second (Hertz) spike and slow wave EEG pattern, often provoked by hyperventilation. Infantile spasms have a hypsarrhythmia pattern on EEG which has an asymmetric disorganized mixture of spikes and slow waves.
9. Ethosuximide and valproic acid are used to treat generalized absence seizures.
10. 60-70% of children with epilepsy eventually have good seizure control on AEDs and enter into long-term remission, but 30% won't ever become seizure free on AEDs.