Chapter 3. Seizures and Epilepsy

A general simplified definition of a seizure is a sudden temporary change in brain function caused by an abnormal rhythmic electrical discharge. Epilepsy is, simply put, a state of recurrent seizure activity. The mechanism whereby a seizure turns into epilepsy, a process known as epileptogenesis, is controversial.

Seizures are common in humans, with an incidence of approximately 80/100,000 per year and an overall risk of epilepsy of 1% to 3%.1 Status epilepticus is a less common form of severe prolonged seizure activity with a high morbidity and mortality.

Seizures arise secondary to a number of etiologies. Idiopathic seizures, or "cryptogenic" seizures, are fairly common. Contrary to what many patients and families might think, the inability to find a cause for the seizure is not necessary "bad." In fact, this may portend a somewhat better prognosis for long-term seizure control. Febrile seizures are common in children and are covered in detail in Chapter 4.

Trauma contributes to the risk of seizures in two fairly distinct fashions. Early posttraumatic seizures are typically associated with intracranial hemorrhage, focal neurological deficits, posttraumatic amnesia exceeding 24 hours, and linear skull fractures. Late posttraumatic seizures are also associated with intracranial hemorrhage and posttraumatic amnesia exceeding 24 hours, but are usually seen in patients with depressed skull fractures and with the injury after age 16 years.2-4

A number of congenital malformations increase the risk for epilepsy. Disorders associated with migrational disorders and structural anomalies often increase the risk of subsequent seizures. The genetic diseases listed in Table 3-1 also increase the risk of epilepsy whether or not they are associated with structural malformations.5-7

Infections are also common causes of seizure activity in the pediatric population. Meningitis and encephalitis can result in seizures either related to the fever or to the direct effects of the infection. These are covered in detail in the chapters on infectious disease. Bacterial infections can result in meningitis, encephalitis, and abscess formation. Herpes simplex virus (HSV) is a well known cause of seizures and can be catastrophic.8 Other viral infections including cytomegalovirus (CMV) infection and various viral encephalitides can result in seizures. Fungal infections and toxoplasmosis also raise the risk of developing seizures.

A wide array of toxic and metabolic disorders can result in seizures. These derangements can cause seizures to occur de novo but can also worsen a pre-existing epilepsy. The common metabolic and toxic causes of seizures are listed in Table 3-2.

Cerebral ischemia is a common cause of seizures in the neonate and in the older adult but is relatively uncommon in the older pediatric population.

Seizures usually occur in the more slowly growing tumors. Tumors located in the supratentorial region cause seizures more frequently than do cerebellar or brainstem tumors.

Epilepsy is divided into several categories with significant differences in the characteristics of the electrical discharges as well as the clinical manifestations. Localization-related epilepsy or partial epilepsy has a primary focus from which the electrical discharges arise. Complex partial seizures occur with alteration of awareness while simple partial seizures have no alteration of awareness. Jacksonian motor seizures, Rolandic epilepsy, temporal lobe epilepsy, and frontal lobe epilepsy are all examples of partial epilepsy.

The Revised International Classification of Epilepsies, Epileptic Syndromes and Related Seizure Disorders divides the localization-related epilepsies as follows:10

• Idiopathic localization-related epilepsy
• Symptomatic or secondary localization-related epilepsy
• Cryptogenic localization-related epilepsy

Generalized seizures are the other major seizure type. In this category of epilepsy, the seizure affects the entire cortex electrically. Several subtypes of generalized seizures have also been identified, including absence epilepsy with 3-Hz spike and wave activity, generalized tonic-clonic seizures, juvenile myoclonic epilepsy, and progressive myoclonic epilepsy.

The Revised International Classification of Epilepsies, Epileptic Syndromes and Related Seizure Disorders divides the generalized epilepsies as follows10:

• Primary generalized epilepsy
• Symptomatic generalized epilepsy
• Cryptogenic epilepsy

A number of seizures and epilepsies may be very difficult to categorize. The Revised International Classification of Epilepsies, Epileptic Syndromes and Related Seizure Disorders groups these disorders in the "undetermined" category. These seizures may be divided as follows10:

• Both focal and generalized
• Situation-related epilepsy
• Febrile convulsions
• Isolated seizure
• Isolated status epilepticus
• Toxic/metabolic

In each of these cases, the electroencephalographic (EEG) findings may be different. The EEG serves as a vitally important tool in the correct diagnosis of the various epilepsy subtypes and syndromes.

Seizure Types

Generalized Tonic-Clonic Seizures

Generalized tonic-clonic seizures typically have no preceding aura but may have a prodrome of apathy or irritability. During the tonic phase, the jaw snaps shut followed by 10 to 15 seconds or longer of tonic spasms, apnea, and cyanosis. The clonic phase usually consists of 1 to 2 minutes of rhythmic generalized muscle contractions and increased blood pressure. The postictal phase lasts for minutes to hours, with confusion, somnolence, and possibly agitation.

The ictal EEG usually consists of generalized spike and wave or polyspike activity. The interictal EEG is highly variable with a normal background in some patients and slowing present in others.

Generalized seizures are rare in newborns. Generalized seizures occur most frequently in children secondary to fevers and metabolic derangements.

Absence Seizures

Absence seizures typically have no preceding aura or prodrome. An absence seizure usually lasts for only several seconds to minutes. There is a sudden interruption of consciousness, staring, 3-Hz blinking, and less frequently automatisms. There is no postictal confusion.11

The ictal EEG usually consists of 3-Hz generalized spike and wave activity with some slowing of the discharge frequency during the seizure. The interictal EEG usually has a normal background. Atypical absence seizures have generalized spike and wave activity but usually have a frequency less than 3 Hz.12

Absence seizures typically start between ages 4 and 10 years and resolve by age 20 years. Atypical absence epilepsy usually occurs in children who are neurologically or developmentally abnormal.13

Febrile Seizures

Febrile seizures occur with a prodromal fever. A simple febrile seizure occurs as a brief generalized tonic clonic seizure occurring after the onset of fever. A complicated febrile seizure has prolonged seizure activity or focal seizure activity. Febrile seizures are covered in detail in Chapter 4.

Juvenile Myoclonic Epilepsy

The seizures associated with juvenile myoclonic epilepsy typically have no preceding aura but may have a prodrome of morning myoclonus. The seizures may consist of generalized tonic-clonic activity; however, absence seizures may also occur. The postictal phase is variable depending on the seizure type.11

The ictal EEG usually consists of generalized polyspike and slow wave activity. The interictal EEG is typically unremarkable.12

The age of onset of juvenile myoclonic epilepsy is typically 10 to 20 years. Patients are usually developmentally and neurologically normal.13

Progressive Myoclonic Epilepsy

The family of disorders known as the progressive myoclonic epilepsies (Table 3-3) consists of a number of loosely related disorders. These epilepsy subtypes are quite rare and have complex presentations and diagnostic findings. Most of these disorders have a genetic basis, though sporadic cases have occurred in some cases (Table 3-4). The EEG associated with these disorders is variable. The background is often slow. The seizures are typically generalized.11

Infantile Spasms

West syndrome typically begins between 3 months and 3 years of age.14-16 The seizures associated with West syndrome consist of a jack-knifing movement and myoclonus. The EEG consists of a hypsarrhythmia pattern with bursts of asynchronous slow waves; spikes and sharp waves alternate with a suppressed EEG.17 The clinical features of West syndrome include infantile spasms and mental retardation, which varies according to the etiology of the spasms.

Aicardi syndrome is an X-linked disorder present from birth that is associated with infantile spasms. The seizures are described as infantile spasms, but alternating hemiconvulsions may also be seen. The clinical features of Aicardi syndrome include coloboma, chorioretinal lacunae, agenesis of the corpus callosum, vertebral anomalies, and seizures.18

Lennox–Gastaut Syndrome

Lennox–Gastaut syndrome typically begins between 1 and 10 years of age. There are multiple seizure types, associated with variable degrees of mental retardation.

The EEG reveals a slow spike wave complex with a frequency of 1 to 2.5 Hz, multifocal spikes, and generalized paroxysmal fast activity (GPFA).19

Partial Seizures: Localization-Related Epilepsy

Jacksonian motor seizures are simple partial seizures with no alteration of consciousness. These seizures begin with tonic contractions of the face, fingers, or feet and transform into clonic movements that march to other muscle groups on the ipsilateral hemibody. There is no alteration in consciousness, but postictal aphasia may occur if the primary epileptogenic zone involves the dominant hemisphere. Simple partial seizures may involve autonomic (Table 3-5), sensory, motor, or psychic functions.

Complex Partial Seizures

Benign Rolandic Epilepsy

Benign Rolandic epilepsy usually begins between ages 5 and 10 years and is transmitted in an autosomal dominant pattern with variable penetrance. It is fairly common, with an incidence of 21/100,000 children.20 The clinical features include a single nocturnal seizure with clonic movement of the mouth and gurgling. Secondary generalization is common. Alteration in consciousness, aura, and postictal confusion are rare. The seizures resolve by age 16 years.21,22

The interictal EEG consists of central and mid-temporal high-amplitude spike and wave with a characteristic dipole. The ictal EEG usually consists of a focal central or mid-temporal ictal onset, with the possibility of secondary generalization.23,24

Temporal Lobe Epilepsy

Temporal lobe epilepsy accounts for approximately 70% of partial seizures. Many patients have a prior history of febrile seizures or head trauma. A prodrome consisting of lethargy is common. Auras are also common but not universal and include an array of findings such as déjà vu. The ictal findings or semiology include oral or motor automatisms, alteration of consciousness, head and eye deviation, contralateral twitching or tonic–clonic movements, and posturing. Right temporal lobe seizures are often hypermobile. Left temporal lobe seizures often result in behavior arrest. Versive head movements are relatively common, and 90% of patients with versive head movements had a primary epileptogenic zone in the contralateral hemisphere. Ipsiversive movements are less common but occur most commonly in patients with temporal foci. The postictal phase consists of minutes to hours of confusion and somnolence.24-30

Frontal Lobe Epilepsy

Frontal lobe epilepsy accounts for approximately 20% of partial seizures. A prodrome is rare. Auras are unusual. The seizures typically consist of combinations of behavior alteration and automatisms of very brief duration. Frontal seizures often have atypical presentations and vary widely depending on the region of the frontal lobe from which the seizures arise (Table 3-6). Postictal confusion is rare.31-36

Occipital Lobe Epilepsy

Occipital lobe epilepsy is rare, accounting for less than 10% of partial seizures. Prodromes are rare with occipital lobe seizures and auras are unusual. As with the frontal lobe seizures, the seizure characteristics are dependent on the area of the occipital lobe involved. When the striate cortex is involved, there are typically elemental visual hallucinations. Involvement of the lateral occipital lobe results in twinkling, pulsing lights. Seizures arising from the temporo-occipital are usually associated with formed visual hallucinations.37-39

Parietal Lobe Epilepsy

Parietal lobe seizures are also relatively uncommon. The may be seen as simple partial seizures but they will often propagate. The initial features can include contralateral paresthesias, contralateral pain, idiomotor apraxia, and limb movement sensations. As the seizure progresses and propagates, asymmetric tonic posturing and automatisms may develop.40-42

Landau–Kleffner Syndrome

Landau–Kleffner syndrome is a rare, invariably progressive, idiopathic acquired aphasia related to a focal epileptic disturbance in the area of the brain responsible for verbal processing.43 The syndrome begins between ages 3 and 10 in a child with normally acquired language abilities. The child then develops a verbal auditory agnosia and infrequent nocturnal partial or secondarily generalized seizures. The syndrome has a pathognomonic EEG pattern consisting of high-voltage multifocal spikes, predominating in the temporal lobes.44 Treatment is usually with valproic acid and benzodiazepines.45 Sometimes corticosteroids and IV Ig or even surgery with subpial transection46 are used in refractory cases. The outcome for overall language and cognitive function depends in part on how early the syndrome is recognized and treated, but over 2/3 of children are left with significant language or behavioral deficits.47

Rasmussen Encephalitis

Rasmussen encephalitis is a syndrome of diffuse lymphocytic infiltration of the brain associated with partial seizures and progressive neurological deterioration with hemiparesis. This disorder typically affects children 1 to 14 years old. The syndrome is associated with perivascular cuffing on pathologic sections, and antibodies to the glutamate subunit GluR3 are commonly identified. The disorder is usually unilateral. Rasmussen encephalitis is very difficult to treat and frequently requires surgical management with hemispherectomy.

As with many facets of neurology, the history is the most important diagnostic tool and should include information on each of the items in Table 3-7. The history should be obtained from family and eyewitnesses, if possible. Many patients are unable to provide accurate descriptions of the seizure and the postictal period.

MRI of the head with temporal lobe protocol (thin coronal slices through hippocampi) is the preferred imaging modality for most patients. The MRI sequences are much more sensitive to the causes of epilepsy than is CT imaging. CT can, however, be of help in the emergency department setting. EEG is a vital component of the evaluation to categorize the seizure type and assist with planning of the treatment strategy. The need for laboratory testing is highly variable depending on the history. Initial evaluation with fluid balance profile (FBP), Ca++, Mg++, and liver function tests (LFTs) is important for both the search for a potential cause of the seizures and for medication selection. Urine drug screening should be obtained for patients with new-onset seizures.

Physicians and families often agonize over the decision about whether to initiate therapy after a single seizure. In the absence of a structural cause for the seizures or a typical syndrome of epilepsy, most patients do not require long-term treatment with an antiepileptic medication. The patient selection criteria for treatment after a single seizure are listed in Table 3-8.48,49

Stopping the antiepileptic medication can also be a challenge. The prognostic factors used for making the decision regarding discontinuation are listed in Table 3-9.49

The selection of a particular antiepileptic medication for a given subtype of epilepsy has long been the subject of controversy. When selecting a given drug, the concomitant medical disorders such as headache, bone marrow dysfunction, and liver insufficiency should be considered. Guidelines for the selection of antiepileptic drugs, the pharmacology of the common antiepileptic drugs, and potential interactions are reviewed in Tables 3-10, 3-11, 3-12, and 3-13.50-53

Surgery for epilepsy is an important but often underutilized treatment option. The surgical option provides an opportunity for some patients to become seizure free. However, this is a complex discussion and beyond the scope of this book.

Non-Epileptic Events

Non-epileptic events are unusual in the pediatric population, especially in the younger child. Several categories of non-epileptic events (thrashing, staring, etc.) have different natural histories and variable prognosis. Etiologies include conversion disorder, malingering, and medical conditions, especially cardiac disorders. Symptoms suggesting non-epileptic events include closed eyes, resisted eyelid opening, non-physiologic progression, pelvic thrusting, lack of cyanosis, lack of tongue biting, variable semiology, crying, and rapid reorientation following the event.54-56

Neonatal Seizures

Neonatal seizures are poorly classified, under-recognized, especially in sick neonates, and often difficult to treat. Neonatal seizures are often the presenting clinical manifestation of underlying neurological conditions such as hypoxic-ischemic encephalopathy, stroke, intraventricular or intraparenchymal hemorrhages, meningitis, sepsis, or metabolic disorders. Of these, hypoxic ischemic encephalopathy is the most common etiology, accounting for 50% to 60% of patients with neonatal seizures.57

The neonatal brain is particularly vulnerable to seizure activity as a result of an imbalance of excitatory to inhibitory circuitry. The imbalance favors excitation, and does so to facilitate important developmental processes that occur during the neonatal period (synaptogenesis, apoptosis, progressive integration of circuitry, synaptic pruning). The imbalance occurs anatomically and physiologically by an overexpression of NMDA receptor in the hippocampus and neocortical regions of the neonatal brain, a delay in the maturation of the inhibitory system, and neurons in such regions as the hippocampus are excited rather than inhibited by the neurotransmitter GABA (normally the primary inhibitory neurotransmitter in the brain).

Clinical Presentation

Subtle

Subtle seizures are more common in premature infants. As the name suggests, the seizures may be difficult to identify with only tonic horizontal eye movements, sustained eye opening, chewing, or apnea. In some cases there may be "boxing" movements. These seizures may have limited EEG changes correlating with the seizure activity. 58-61

Clonic

Clonic seizures typically present as rhythmic, slow movements. The movements have a frequency of 1 to 3 Hz. Focal clonic seizures involve one side of the body, and the infant is not clearly unconscious. Multifocal clonic seizures involve several body parts, often in a migrating pattern. Generalized clonic seizures are rarely observed in newborn because of the incomplete myelination of the brain.58-61

Tonic

Focal tonic seizures result in sustained posturing of a limb, the trunk, or the neck. These seizures are usually accompanied by EEG changes. Generalized tonic seizures exhibit tonic extension of all limbs (mimicking decorticate posturing) or tonic flexion of upper limbs and tonic extension of lower limbs (mimicking decerebrate posturing). There are no EEG changes in 85% of cases.58-61

Myoclonic

Focal myoclonic seizures usually involve flexor muscles of an upper extremity. Often, there are no EEG changes. Conversely, generalized myoclonic seizures exhibit bilateral jerks of both upper and lower limbs, and may resemble infantile spasms. These generalized seizures are more likely to have EEG changes.58-61

Syndromes

Benign Familial Neonatal Seizures

Benign familial neonatal seizures occur as a genetic disorder with an autosomal dominant inheritance pattern associated with chromosome 20q. The seizures typically start on day of life 2 or 3. The neonate may have as many as 10 to 20 seizures per day. The syndrome is usually self-limited and benign, but approximately 10% of cases progress to an antiepileptic drug-requiring seizure disorder. Neurological development is normal.58-61

Fifth-Day Fits

Fifth-day fits usually begin on day of life 4 to 6. The seizures are typically multifocal clonic seizures and are frequently associated with apnea. The seizures usually last for less than 24 hours. Fifth-day fits progress to status epilepticus in 80% of cases.58-61

Benign Neonatal Sleep Myoclonus

Benign neonatal sleep myoclonus begins during the first week of life. The seizures are usually bilateral myoclonic jerks that last for several minutes and occur only during NREM sleep. The EEG is normal or slow. The seizures worsen with the administration of benzodiazepines. The seizures usually resolve within 2 months and neurological outcome is normal.58-61

Benign Myoclonus of Early Infancy

Benign myoclonus of early infancy has an onset at age 3 to 9 months but it can be much earlier. The seizures resemble infantile spasms but the EEG is normal. The seizures usually occur while the patient is awake. The seizures disorder may continue for 1 to 2 years but neurological outcome is normal.58-61

Treatment

The clinician should first search for underlying etiologies producing the seizures and treat (hypoglycemia, hypocalcemia, sepsis). If the clinician cannot find a readily identifiable and treatable etiology, the frontline agent of choice for treating seizures is phenobarbital (see Table 3-14 for dosing suggestions).61 Phenobarbital as a single agent will stop seizure activity in 42% of patients. When the seizure does not respond to a single agent, phenytoin is added with an increase in efficacy to 65%. Currently, fosphenytoin, the salt ester of phenytoin, is preferred in the neonate because it is an aqueous solution that is soluble in glucose-containing solutions, can be administered more quickly than phenytoin, and will not cause "purple glove syndrome."61 Purple glove syndrome is necrosis or injury of the soft tissue that can occur with intravenous infusion of the highly alkaline phenytoin. The drug of choice for neonates in status is lorazepam. This agent has several properties that make it ideal—a long half-life and a small volume of distribution, which prolongs its retention at high levels in the brain.