A seizure is a time-limited episode characterized by abnormal neurologic function associated with abnormal electrical discharges of neurons in the central nervous system (CNS). It is unclear exactly why seizures occur, but, in general, a seizure results from excessive neuronal excitation or impaired neuronal inhibition. It is generally thought that seizures are more easily provoked in children than in adults because of the immaturity of the brain at birth. Many seizure disorders, such as febrile seizures, are unique to childhood, as are several seizure types, such as infantile spasms. Epidemiologic studies on the incidence of seizures show a "U"shaped distribution, with higher incidences in the very young and the very old. The younger cases are related to developmental immaturity of the brain and the older cases are related to accumulated injuries to the brain. Further, there are generic factors that make one child more likely to have a seizure than another child when exposed to the same pathologic environment. This "seizure threshold" may change as the child matures so that a given pathologic environment may not produce a seizure in the same child at an older age.
A seizure is a single event. Epilepsy is recurrent, unprovoked seizures. Idiopathic epilepsy occurs in otherwise healthy children who have unprovoked, recurrent seizures. Symptomatic epilepsy is recurrent seizures caused by identifiable injury to the brain, such as seizures associated with tumor, malformation, or stroke. Symptomatic seizures (also called reactive seizures) are caused by specific, usually transient, pathophysiologic events that "trigger" a seizure by altering the microenvironment of the neuron such that excitation is facilitated or inhibition is impaired. Symptomatic seizures can be recurrent if the same pathophysiologic event recurs. Hypoglycemic seizures are a typical example. At times, the event that causes the acute, symptomatic seizure also injures the brain sufficiently enough to cause subsequent symptomatic epilepsy.
Because of the child's immature brain, some recurrent symptomatic seizures are specific to childhood. A single symptomatic seizure can be caused by a wide variety of disorders that may be related to significant systemic disease. The pediatrician must be aware of these various causes of symptomatic seizures to make an accurate diagnosis and to effectively manage them. It is implied that successful treatment or avoidance of the cause eliminates the need to treat the seizure. In general, acute symptomatic seizures are manifestations of transient stresses on the brain and the risk of later, unprovoked seizures is low.1 There is not an easy way to classify symptomatic seizures. Table 1 is one method based on the common events that occur in children that cause symptomatic seizures.
Classification of Symptomatic Seizures
Simple febrile seizures are unique to childhood. They occur in 1% to 3% of all children. In a prospective study of a large cohort of American children, criteria were established for the simple febrile seizure that predicted a benign outcome.2 The seizures occur between the ages of 3 months and 5 years, although it is rare for the first febrile seizure to occur after the age of 3 years. The seizures occur at the beginning of the febrile episode when the temperature is rapidly rising. Indeed, the seizure may be the first indication of a fever. The temperature is always above 101° F. The seizure is generalized and usually begins with a tonic component followed by clonic movements. The seizures are brief, rarely lasting longer than several minutes, and, by criteria, are never longer than 15 minutes. Prolonged, focal, or multiple seizures are atypical for a simple febrile convulsion. The neurologic examination shows no focal deficits immediately after the seizure or later when the child is back to normal. The results of an electroencephalogram (EEG), if obtained, are normal unless it has been performed shortly after the seizure, in which case nonspecific slowing may be shown. Exclusionary criteria are evidence of CNS infection, metabolic disturbances that could cause a seizure, or prior nonfebrile seizures. Often there is a family history of febrile seizures.
If a child fits the above criteria for a simple febrile seizure, the risk of subsequent epilepsy is less than 1.1%. This is greater than the risk for children who do not have febrile seizures. However, for children who were neurologically normal prior to the first febrile seizure, the risk of later neurologic or intellectual sequelae is the same as that of the general population.2 Approximately 30% will have a subsequent febrile seizure and few will have more than two. If the child does not meet the above criteria, the seizure is classified as a complicated febrile seizure and the risk of subsequent, unprovoked seizures (epilepsy) increases. For each abnormal feature, the risk is increased approximately 5%. A family history of epilepsy increases the risk of subsequent epilepsy.
Management of status epilepticus is described elsewhere in this issue. Usually, the child is evaluated at some point after the seizure has occurred. If the child is post-ictal, other causes for seizures should be considered. Foremost is a CNS infection. Infants younger than 9 months of age should probably have a lumbar puncture and examination and culture of the cerebrospinal fluid. After the age of 18 months, the clinical signs of meningitis should be sufficient to determine the need for lumbar puncture. When in doubt, the procedure is indicated especially for children who have been medically evaluated for the same febrile illness within the previous 48 hours. Routine serum electrolytes, glucose, and calcium are needed to exclude other treatable causes. An EEG is indicated for children who do not meet the criteria for a simple febrile convulsion. For both children who are post-ictal and children who have fully recovered, the suggestion of focal neurologic findings by history, examination, or EEG warrants a neuroimaging study. Magnetic resonance imaging is the study of choice when available. If the child has fully recovered and the history and physical examination findings are consistent with the diagnosis of a simple febrile convulsion, then no further studies are indicated.
Treatment to prevent subsequent seizures is usually not necessary. Only 30% have subsequent seizures. For the rare child who has multiple simple febrile seizures, prophylactic treatment with phenobarbital or valproate sodium is an option. Other anticonvulsant drugs usually are not effective. For the child who has prolonged or multiple, clustered febrile seizures, rectal diazepam gel is indicated.
For practical purposes, posttraumatic seizures can be divided into three groups depending on the timing of the seizure after the head injury and the severity of the trauma: impact seizures, early posttraumatic seizures, and late posttraumatic seizures.
Impact seizures occur within minutes of the head trauma. The injury itself is usually trivial, such as a minor fall, a collision with furniture or doors, and other frequent toddler accidents. The age of children who have impact seizures is similar to that of those who have breath-holding spells, and, indeed, impact seizures may be a variant of a complicated breath-holding spell.3 The seizures are brief and generalized and there is no evidence for significant head injury. An EEG and neuroimaging studies are indicated after the first seizure, but should not be obtained if subsequent, typical impact seizures occur. For frequent recurrences, anticonvulsant prophylaxis with carbamazepine and other medications can be beneficial in some patients.
Early posttraumatic seizures occur within 7 days of the head injury. The risk of seizures following all head injuries, within this time period, is 2.6% in children. Those with serious injuries (concussion, intracranial hematoma, prolonged unconsciousness, or prolonged amnesia) have a 30% incidence. The incidence among children hospitalized for trauma is approximately 5%, and approximately 20% of this 5% have late posttraumatic seizures.4 Early posttraumatic seizures are probably symptomatic of the injury itself. It is reasonable to acLminister anticonvulsant medication to children who have significant head injury during the first week after the accident. It is unclear whether children who have early posttraumatic seizures are at greater risk of later epilepsy or whether early therapy alters this prognosis.
Late posttraumatic seizures occur after the first 7 days following a head injury in 5% to 7% of children. There is a correlation between the severity/type of injury and subsequent epilepsy. Intracranial hematoma, depressed skull fracture, and especially a penetrating missile wound are more likely to cause late posttraumatic seizures than are less severe injuries. The seizure type is usually a partial seizure with secondary generalization. A late posttraumatic seizure should be evaluated with neuroimaging if a complication from the injury or surgery is suspected. An EEG is also indicated. If the seizures recur or if there is a focal epileptiform abnormality on the EEG, prophylactic anticonvulsant therapy with carbamazepine or phenytoin should be considered.
Seizures associated with infection parallel posttraumatic seizures. Approximately 30% of children with bacterial meningitis have one or more seizures during the first week of the illness, usually in the first few days. These seizures are often symptomatic of the complications of bacterial meningitis: vasculitis with infarction, electrolyte imbalance, and extra-axial fluid. Some children will have a febrile seizure at the onset of the infection. Most children with early, symptomatic seizures do not have subsequent epilepsy.
During a 20-year period, subsequent unprovoked seizures occur in 6.8% of patients with CNS infections, excluding brain abscess.5 The incidence is highest for those with viral encephalitis and lowest for those with aseptic meningitis. For those with bacterial meningitis without early symptomatic seizures, the incidence is 2.4%. This compares with 13% for those who had early seizures. Children with brain abscesses are at high risk for early-onset and lateonset seizures. Approximately 70% have unprovoked seizures.6
Symptomatic Seizures In Metabolic Disorders and Intoxications
METABOLIC AND TOXIC SEIZURES
Many metabolic perturbations and intoxications can provoke seizures. Some of the more common causes are listed in Table 2. These disturbances transiently alter the microenvironment of the neuron such that excitation is facilitated or inhibition is impaired. Normally, correction of the underlying disorder or removal of the toxin corrects the problem. The risk of subsequent unprovoked seizures is low unless there is a secondary complication that alters the structure of the brain. For example, severe dehydration with hyponatremia that causes seizures can also cause cerebral sinovenous thrombosis and stroke. This becomes a secondary cause for acute symptomatic and later unprovoked seizures.
Rarely is the seizure the first or the only manifestation of the metabolic or toxic event. Electrolyte abnormalities and other metabolic disturbances severe enough to cause seizures almost always have other clinical findings from the abnormality or its cause. Severe hypoglycemia will induce a generalized or focal seizure in almost all children. Preceding signs and symptoms are nervousness, sweating, tremor, lethargy, and often coma. Children with hyponatremia often have nausea, incoordination, and altered consciousness prior to having seizures. Hyponatremia causes seizures in children who are dehydrated or water intoxicated. Seizures associated with hypernatremia are more likely when there is a related vascular thrombosis, or too vigorous hydration has produced cerebral edema. In the neonate, hypocalcemia causes jitteriness, hyperreflexia, and seizures. In older children, the classic features of tetany, such as carpopedal spasm, usually precede seizures. Hypophosphatemia and hypomagnesemia often accompany hypocalcemia and, when present, must also be treated. Isolated hypomagnesemia causes clinical features similar to those of hypocalcemia. Disorders of acid-base metabolism and chloride ion rarely cause seizures unless associated with other metabolic disturbances. Management of symptomatic seizures associated with metabolic disturbances is directed toward correcting the underlying problem. Anticonvulsants may be less effective.
Seizures associated with organ failure, such as from renal or liver disease, are usually associated with the accompanying metabolic and electrolyte disturbances, as late manifestations. Often the patient is in a coma at the time the seizures occur. Hepatic encephalopathy is characterized by progressive obtundation often punctuated with delirium. Tremor or asterixis, posturing, and other abnormal movements usually precede seizures. Severe azotemia can be the only identifiable cause for seizures in some patients in renal failure. Uremia more often causes altered mental status, movement disorders, myoclonus, and peripheral neuropathy. Seizures are also associated with dialysis, especially hemodialysis, probably because of water shifts within the brain.
Malignant hypertension from acute renal disease is not uncommon in children. Generalized seizures often present early in the course and may be the cause for seeking medical attention.7 Severe hypertension causes microinfarction, edema, and loss of cerebral autoregulation. The seizures, encephalopathy, and multifocal neurologic signs may be the result of ischemia, microinfarcts, or other pathology. Subsequent symptomatic epilepsy is rare. Some patients with hyperthyroidism have generalized seizures. Rarely, seizures are the presenting clinical feature of thyrotoxicosis.8
Ordinarily, seizures are not the only manifestation of inborn errors of metabolism. Seizures usually occur within the context of acute encephalopathy with acidosis, hypoglycemia, hyperammonemia, and other derangements. The exception is pyridoxine dependency in which seizures are the primary neurologic complication.
Similarly, drug-induced seizures are preceded by the clinical signs of intoxication. The seizure that results from such events is more a sign of severity. Withdrawal seizures are uncommon in children, except in the neonate born to an addicted mother. The two most common drugs associated with withdrawal seizures are narcotics9 and barbiturates, especially the latter.10 The clinical signs preceding these seizures are jitteriness, irritability, hypertonicity, and high-pitched cry. Seizures usually occur 2 to 3 days after birth. The most common biologic toxin that causes seizures is Shiga's toxin, associated with Shigella gastroenteritis. These children also have meningismus.
Hypoxemia is the state of depressed oxygenation to the brain. It is usually, but not always, associated with brain ischemia. The latter refers to impaired blood circulation such that oxygen, glucose, and other nutrients are deficient. Seizures often follow hypoxemia. The pattern is similar to that of head trauma, with immediate, delayed, and late onset of seizures.
Seizures can follow relatively brief periods of hypoxemia in susceptible children. The best example of this is the complicated breath-holding spell.3 Approximately 15% of children with breath-holding spells have seizure-like activity during these events. The longer the period of apnea, the more likely the child is to have a seizure. At the end of the apnea, the child stiffens and may have incontinence. At times, there is generalized clonic activity that coincides with rhythmic EEG slow wave activity. Generalized seizures can also follow cyanotic spells in children with cyanotic congenital heart disease. Probably related are impact seizures (discussed above with trauma), venipuncture fits, and immersion seizures that some infants have when their head is immersed in water.
Seizures often follow more severe and prolonged periods of hypoxia and ischemia. This is most common in the first hours after resuscitation. As such, these seizures are more of an indication of the severity of the hypoxic or ischemic event than a sign of subsequent epilepsy. These seizures should be managed with intravenous anticonvulsants during the period of encephalopathy. Unless the seizures persist beyond this period, the medications should be withdrawn at the time of discharge. Seizures that occur after the first 7 days following the hypoxic or ischemic event are rare, but when they occur, they are usually associated with sufficient brain injury that subsequent symptomatic epilepsy is likely. Children with late-onset seizures should be treated with oral anticonvulsant medications.
Cerebrovascular accidents (CVAs) are rare in children. But when they occur, they are often associated with acute, symptomatic seizures. This is especially true for newborns. CVAs can be divided into thrombotic stroke, hemorrhagic stroke, embolic stroke, sinovenous occlusive disease, and intracranial hemorrhages. The latter are subdivided into subdural, subarachnoid, intracerebral, and intraventricular hemorrhages.
Arterial thrombotic stroke occurs in a number of clinical settings, including the hemoglobinopathies, vasculitis, hypercoagulable disease, and idiopathic causes. Arterial thrombosis is the most common cause of stroke in children. In a group of children with sickle cell disease, approximately 20% of those with a stroke had a symptomatic seizure with the CVA.11 On the other hand, sinovenous occlusive disease, with thrombosis of cortical veins or the venous sinuses, is relatively uncommon. But seizures, often refractory, are a prominent feature here. Embolic and hemorrhagic strokes are more likely to cause a seizure than are thrombotic ones. Children who have seizures associated with stroke are more likely to have an adverse outcome. Overall, the risk of subsequent epilepsy following stroke is approximately 20%.
Intracranial hemorrhage, regardless of location, is often heralded by a symptomatic seizure. Seizures associated with traumatic causes of intracranial hemorrhage may be related to the trauma, hemorrhage, or both. Blood in the subarachnoid space does cause seizures by itself. Approximately 5% of all patients with subarachnoid hemorrhage have a seizure in the acute phase. This is somewhat higher in children.12 Approximately 15% of patients with subarachnoid hemorrhage have subsequent symptomatic epilepsy, most likely related to accompanying ischemic injury.
Most symptomatic seizures are brief. For those that are prolonged, the usual steps for the management of status epilepticus are indicated, as discussed elsewhere in this issue. Patients presenting in the emergency department with a newonset seizure or in the post-ictal state without a previous history of seizures need a thorough history and examination to identify causes of a symptomatic seizure. As opposed to those with unprovoked seizures, children with symptomatic seizures may have life-threatening causes that need immediate attention. Many metabolicrelated seizures cannot be controlled unless the underlying disturbance and its cause are managed appropriately. Preceding illness, medications and physical findings can often help the pediatrician identify the underlying disease. Routine electrolytes, glucose, blood urea nitrogen, calcium, and magnesium should be obtained if the cause is not obvious. An abnormal laboratory result requires determination of its etiology, and then appropriate management. The febrile child with seizures must be considered as having a CNS infection until proven otherwise. Lumbar puncture, with an examination and culture of the cerebrospinal fluid, is recommended for children younger than 9 months of age. If the pre-seizure history suggests a diagnosable cause, such as a toric ingestion, trauma, or hypoxemia, the appropriate diagnostic studies can then be performed.
A neuroimaging study is indicated if there (1) is no readily identifiable cause; (2) are localizing signs on the examination; or (3) is altered consciousness. Computerized tomography is generally satisfactory in this setting because it is likely to identify surgically correctable lesions. An EEG is not usually necessary immediately unless needed to exclude nonconvulsive seizures. An EEG is always indicated in the child who has persistent seizures after the underlying disturbance is corrected or if there is a late recurrence of seizures after the acute event has resolved. Referral to a pediatric neurologist should be considered under these circumstances as well. Persistent abnormalities on the EEG, in a child with a late recurrence of seizures, would be a consideration for prophylactic anticonvulsant therapy.
Children who have recurrent symptomatic seizures (eg, those with complicated breathholding spells or impact seizures) should have a trial of prophylactic anticonvulsants. Carbamazepine or phenytoin is often useful. Phenobarbital can be considered, but its effects on behavior could be a problem and could exacerbate some situations.
For those children who are encephalopathy with seizures, it is desirable to control the seizures to both improve the ability to clinically monitor the patient and avoid complications the seizures may have for the clinical course and its management. Two examples are that intracranial hemorrhage and increased intracranial pressure are adversely affected by generalized convulsions, and it is difficult to adequately ventilate a patient who is actively having a seizure. In this setting, phenytoin is probably the drug of choice because it can be given intravenously and is generally nonsedating at therapeutic levels. Prophylactic therapy for children with serious head trauma is indicated to reduce the risk of early posttraumatic seizures. However, prophylactic therapy does not prevent posttraumatic epilepsy.13
1. Wolf SM, Ochoa JG, Conway EE. Seizure management Ln pediatric patients for the nineties. Pediatr Ann. 1998;27: 653-667.
2. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics. 1978;61:720-727.
3. Evans OB. Breath-holding spells. Pediatr Ann. 1998;26: 410-414.
4. Jennett B. Post-traumatic epilepsy. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology, vol. 24. Amsterdam, The Netherlands: North Holland; 1976.
5. Annegers JF, Hauser WA, Beghi E, et al. The risk of unprovoked seizures after encephalitis and meningitis. Neurology. 1988;38:1407-1410.
6. Legg NJ, Gupta PC, Scott DF. Epilepsy following cerebral abscess: a clinical and EEG study in 70 patients. Brain. 1993;96:259-268.
7. Trompeter RS, Smith RL, Hoare RD, et al. Neurologic complications of arterial hypertension. Arch Dis Child. 1982;57:913-917.
8. Jabbari B, Huott AD. Seizures in thyrotoxicosis. Epilepsia. 1980;21:91-95.
9. Zelson C, Rubir E, Wasserman E. Neonatal narcotic addiction. Pediatrics. 1971;48:178-183.
10. Bleyer WA, Marshall RE. Barbiturate withdrawal syndrome in a passively addicted infant. JAMA. 1972;221: 185-187.
11. Balkaran B, Char G, Morris JS, et al. Stroke in a cohort of patients with homozygous sickle cell disease. Pediatrics. 1992;120:360-366.
12. Crisotomo EA, Leaton E, Rosenblum EL. Features of intracranial aneurysms in infants and a report of a case. Dev Med Child Neurol. 1986;28:62-67.
13. Tempkin NR, Dikman SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323: 497-502.
Classification of Symptomatic Seizures
Symptomatic Seizures In Metabolic Disorders and Intoxications