Genetic Factors

The genetic contribution to incidence of febrile seizures is manifested by a positive family history for febrile seizures. In many families the disorder is inherited as an autosomal dominant trait, and multiple single genes causing the disorder have been identified. In most cases the disorder appears polygenic, and the genes predisposing to it remain to be identified. Identified single genes include FEB 1, 2, 3, 4, 5, 6, and 7 genes on chromosomes 8q13-q21, 19p13.3, 2q24, 5q14-q15, 6q22-24, 18p11.2, and 21q22. Only the function of FEB 2 is known: it is a sodium channel gene, SCN1A.

Almost any type of epilepsy can be preceded by febrile seizures, and a few epilepsy syndromes typically start with febrile seizures. These are generalized epilepsy with febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (SMEI, also called Dravet syndrome), and, in many patients, temporal lobe epilepsy secondary to mesial temporal sclerosis.

GEFS+ is an autosomal dominant syndrome with a highly variable phenotype. Onset is usually in early childhood and remission is usually in mid-childhood. It is characterized by multiple febrile seizures and several types of afebrile generalized seizures, including generalized tonic-clonic, absence, myoclonic, atonic, or myoclonic astatic seizures with variable degrees of severity.

Dravet syndrome is considered to be the most severe of the phenotypic spectrum of febrile seizures plus. It constitutes a distinctive separate entity that is one of the most severe forms of epilepsy starting in infancy. Its onset is in the 1st yr of life, characterized by febrile and afebrile unilateral clonic seizures recurring every 1 or 2 mo. These early seizures are typically induced by fever, but they differ from the usual febrile convulsions in that they are more prolonged, are more frequent, and come in clusters. Seizures subsequently start to occur with lower fevers and then without fever. During the 2nd yr of life, myoclonus, atypical absences, and partial seizures occur frequently and developmental delay usually follows. This syndrome is usually caused by a new mutation, although rarely it is inherited in an autosomal dominant manner. The mutated gene is located on 2q24-31 and encodes for SCN1A, the same gene mutated in GEFS+ spectrum. However, in Dravet syndrome the mutations lead to loss of function and thus to a more severe phenotype.

The majority of patients who had had prolonged febrile seizures and encephalopathy after vaccination and who had been presumed to have suffered from vaccine encephalopathy (seizures and psychomotor regression occurring after vaccination and presumed to be caused by it) have Dravet syndrome mutations, indicating that their disease is due to the mutation and not secondary to the vaccine. This has raised doubts about the very existence of the entity termed vaccine encephalopathy.

Work-Up

The general approach the patient with febrile seizures is delineated in Figure 586-1. Each child who presents with a febrile seizure requires a detailed history and a thorough general and neurologic examination. These are the cornerstones of the evaluation. Febrile seizures often occur in the context of otitis media, roseola and human herpesvirus 6 (HHV6) infection, shigella, or similar infections, making the evaluation more demanding. Several investigations need to be considered.

Figure 586-1 Management of febrile seizures.

(Modified from Mikati MA, Rahi A: Febrile seizures: from molecular biology to clinical practice, Neurosciences 10:14–22, 2004.)

Treatment

In general, antiepileptic therapy, continuous or intermittent, is not recommended for children with one or more simple febrile seizures. Parents should be counseled about the relative risks of recurrence of febrile seizures and recurrence of epilepsy, educated on how to handle a seizure acutely, and given emotional support. If the seizure lasts for >5 min, then acute treatment with diazepam, lorazepam, or midazolam is needed (see Chapter 586.8 for acute management of seizures and status epilepticus). Rectal diazepam is often prescribed to be given at the time of recurrence of febrile seizure lasting >5 min (see Table 586-12 for dosing). Alternatively, buccal or intranasal midazolam may be used and is often preferred by parents. Intravenous benzodiazepines, phenobarbital, phenytoin, or valproate may be needed in the case of febrile status epilepticus. If the parents are very anxious concerning their child’s seizures, intermittent oral diazepam can be given during febrile illnesses (0.33 mg/kg every 8 hr during fever) to help reduce the risk of seizures in children known to have had febrile seizures with previous illnesses. Intermittent oral nitrazepam, clobazam, and clonazepam (0.1 mg/kg/day) have also been used. Other therapies have included intermittent diazepam prophylaxis (0.5 mg/kg administered as a rectal suppository every 8 hr), phenobarbital (4-5 mg/kg/day in 1 or 2 divided doses), and valproate (20-30 mg/kg/day in 2 or 3 divided doses). In the vast majority of cases it is not justified to use these medications owing to the risk of side effects and lack of demonstrated long-term benefits, even if the recurrence rate of febrile seizures is expected to be decreased by these drugs. Other antiepileptic drugs (AEDs) have not been shown to be effective.

Antipyretics can decrease the discomfort of the child but do not reduce the risk of having a recurrent febrile seizure, probably because the seizure often occurs as the temperature is rising or falling. Chronic antiepileptic therapy may be considered for children with a high risk for later epilepsy. Currently available data indicate that the possibility of future epilepsy does not change with or without antiepileptic therapy. Iron deficiency has been shown to be associated with an increased risk of febrile seizures, and thus screening for that problem and treating it appears appropriate.

History and Examination

Acute evaluation of a first seizure includes evaluation of vital signs and respiratory and cardiac function and institution of measures to normalize and stabilize them as needed. Signs of head trauma, abuse, drug intoxication, poisoning, meningitis, sepsis, focal abnormalities, increased intracranial pressure, herniation, neurocutaneous stigmata, brain stem dysfunction, and/or focal weakness should all be sought because they could suggest an underlying etiology for the seizure.

The history should also include details of the seizure manifestations, particularly those that occurred at its initial onset. These could give clues to the type and brain localization of the seizure. One should question whether there were other previous signs or symptoms that might signify the occurrence of seizures that the parents overlooked or did not report. In some instances, if the events have been going on for a time and there is a question about their nature (e.g., sleep myoclonus versus seizures), then the family can video record the patient and make the video available to the health care provider. Having the parents imitate the seizure can also be helpful. Seizure patterns (e.g., clustering), precipitating conditions (e.g., sleep or sleep deprivation, television, visual patterns, mental activity, stress), exacerbating conditions (e.g., menstrual cycle, medications), frequency, duration, time of occurrence, and other characteristics need to be carefully documented. Parents often overlook, do not report, or underreport absence, complex partial, or myoclonic seizures. A history of personality change or symptoms of increased intracranial pressure can suggest an intracranial tumor. Similarly, a history of cognitive regression can suggest a degenerative or metabolic disease. Certain medications such as stimulants or antihistamines can precipitate seizures. A history of prenatal or perinatal distress or of developmental delay can suggest etiologic congenital or perinatal brain dysfunction. Details of the spells can suggest nonepileptic paroxysmal disorders that mimic seizures (Chapter 587).

Differential Diagnosis

The various types of seizures, as classified by the International League Against Epilepsy (ILAE), are enumerated in Table 586-1. Some seizures might begin with an aura. Auras are sensory experiences reported by the patient and not observed externally. These can take the form of visual (e.g., flashing lights or seeing colors or complex visual hallucinations), somatosensory (tingling), olfactory, auditory, vestibular, or experiential (e.g., déjà vu, déjà vécu feelings) sensations, depending upon the precise localization of the origin of the seizures.

Motor seizures can be tonic (sustained contraction), clonic (rhythmic contractions), myoclonic (rapid shocklike contractions, usually <50 msec in duration, that may be isolated or may repeat but usually are not rhythmic), atonic, or astatic. Astatic seizures often follow myoclonic seizures and cause a very momentary loss of tone with a sudden fall. Atonic seizures, on the other hand, are usually longer and the loss of tone often develops more slowly. Sometimes it is difficult to distinguish among tonic, myoclonic, atonic, or astatic seizures based on the history alone when the family reports only that the patient “falls”; in such cases, the seizure may be described as a drop attack. A mechanistically similar seizure can involve the tone of only the head and neck; this seizure morphology is referred to as a head drop. Tonic, clonic, myoclonic, and atonic seizures can be focal (including one limb or one side only), focal with secondary generalization, or primary generalized. Spasms (axial spasms) consist of flexion or extension of truncal and extremity musculature that is sustained for 1-2 sec, shorter than what is seen in tonic seizures, which last >2 sec. Focal motor seizures are usually clonic and/or myoclonic. These seizures sometimes persist for days, months, or even longer. This phenomenon is termed epilepsia partialis continua.

Absence seizures are generalized seizures consisting of staring, unresponsiveness, and eye flutter lasting usually for few seconds. Typical absences are associated with 3 Hz spike–and–slow wave discharges and with petit mal epilepsy, which has a good prognosis. Atypical absences are associated with 1-2 Hz spike–and–slow wave discharges, with head atony and myoclonus during the seizures and with Lennox-Gastaut syndrome, which has a poor prognosis. Seizure type together with the other nonseizure clinical manifestations helps determine the type of epilepsy syndrome with which a particular patient is afflicted (Table 586-7; Chapters 586.3 and 586.4).

Family history of epilepsy can suggest a specific one of the known familial epilepsy syndromes. More often, different members of a family with a positive history of epilepsy have different types of seizures and of epilepsy. Head circumference can indicate the presence of microcephaly or of macrocephaly. Eye exam could show papilledema, retinal hemorrhages, chororetinitis, colobomata (associated with brain malformations), a cherry red spot, optic atrophy, macular changes (associated with genetic neurodegenerative and storage diseases) or phakomas (associated with tuberous sclerosis). Skin exam could show a trigeminal V-1 distribution capillary hemangioma (associated with Sturge-Weber syndrome), hypopigmented lesions (sometimes associated with tuberous sclerosis and detected more reliably by viewing the skin under UV light), or other neurocutaneous manifestations such as Shagreen patches and adenoma sebaceum (associated with tuberous sclerosis), or whorl-like hypopigmented areas (hypomelanosis of Ito, associated with hemimegalencephaly). Subtle asymmetries on the exam such as drift of one of the extended arms, posturing of an arm on stress gait, slowness in rapid alternating movements, small hand or thumb and thumb nail on one side, or difficulty in hopping on one leg relative to the other can signify a subtle hemiparesis associated with a lesion on the contralateral side of the brain.

Guidelines on the evaluation and treatment of a first unprovoked nonfebrile seizure include a careful history and physical examination and brain imaging by head CT or MRI. Emergency head CT in the child presenting with a first unprovoked nonfebrile seizure is often useful for acute management of the patient. Laboratory studies are recommended in specific clinical situations: Spinal tap is considered in patients with suspected meningitis or encephalitis, in children without brain swelling or papilledema, and in children in whom a history of intracranial bleeding is suspected without evidence of such on head CT. In the second of these, examination of the CSF for xanthochromia is essential. CSF tests can also confirm with the appropriate clinical setup the diagnosis of glucose transporter deficiency, cerebral folate deficiency, pyridoxine dependency, pyridoxal dependency, mitochondrial disorders, nonketotic hyperglycemia, and neurotransmitter deficiencies. Electrocardiography (ECG) to rule out long QT or other cardiac dysrhythmias and other tests directed at disorders that could mimic seizures may be needed (Chapter 587).

Patients with recurrent seizures with 2 seizures spaced apart by >24 hr warrant further work-up directed at the underlying etiology. Often, particularly in infants, a full metabolic work-up including amino acids, organic acids, biotinidase, and CSF studies is needed. In infants who do not respond immediately to antiepileptic therapy, vitamin B₆ (100 mg intravenously) is given as a therapeutic trial to rule out pyridoxine-responsive seizures, with precautions to guard against possible apnea. The trial is best done with continuous EEG monitoring, including a preadministration baseline recording period. Prior to the B₆ trial, a pipecolic acid level can be drawn, because it is often elevated in this rare syndrome. Pyridoxal phosphate given orally up to 50 mg/kg and folinic acid (up to 3 mg/kg) over several weeks can change pyridoxal dependency and cerebral folate deficiency.

Approach to the Patient and Additional Testing

The approach to the patient with epilepsy is based on the diagnostic scheme proposed by the ILAE Task Force on Classification and Terminology, presented in Table 586-8. This emphasizes the total approach to the patient, including identification, if possible, of the underlying etiology of the epilepsy and the impairments that result from it. The impairments are very often just as important as, if not more important than, the seizures themselves. There are now many epilepsy syndromes that have been associated with specific gene mutations (see Table 586-2). Different mutations of the same gene can result in different epilepsy syndromes, and mutations of different genes can cause the same epilepsy syndrome phenotype. The clinical use of gene testing in the diagnosis and management of childhood epilepsy has been limited to patients manifesting specific underlying malformational, metabolic, or degenerative disorders, patients with severe named epilepsy syndromes (such as West and Dravet syndromes and progressive myoclonic epilepsies), and, rarely, patients with familial syndromes (see Table 586-2).

Additional testing in infants and children with recurrent seizures, depending on the clinical findings, can include measurement of serum lactate, pyruvate, acyl carnitine profile, creatine, very long chain fatty acids, and guanidino-acetic acid. Blood and serum are tested for white blood cell lysosomal enzymes, serum coenzyme Q levels, and serum copper and ceruloplasmin levels (for Menkes syndrome). Serum isoelectric focusing is performed for carbohydrate deficient transferrin.

CSF glucose testing looks for glucose transporter deficiency, and CSF can be examined for cells and proteins (for parainfectious and postinfectious syndromes, and for Aicardi Goutieres syndrome which also shows cerebral calcifications). Other laboratory studies include immunoglobulin G (IgG) index, NMDA (N-methyl-D-aspartate) receptor antibodies, and measles titers.

Urine is tested for urinary sulfite indicating molybdenum cofactor deficiency and for oligosaccharides and mucopolysaccharides.

MR spectroscopy is performed for lactate and creatine peaks.

Gene testing looks for specific disorders that can manifest with seizures, including SCN1A mutations in Dravet syndrome; ARX gene for infantile spasms in boys; MECP2, CDKL5, and protocadeherin 19 for Rett syndrome and similar presentations; syntaxin binding protein for Ohtahara syndrome; and polymerase G for infantile spasms and other seizures in infants. Gene testing can also be performed for other dysmorphic or metabolic syndromes.

Other tests include neurotransmitter metabolites for neurotransmitter disorders including pyridoxal-responsive seizures, cerebral folate deficiency, adenylsuccinate lyase deficiency, and specific neurotransmitter disorders. Muscle biopsy can be performed for mitochondrial enzymes, and skin biopsy for inclusion bodies seen in neuronal ceroid lipofuschinosis and Lafora body disease is sometimes needed.

Most patients do not require a work-up anywhere near this extensive. The pace and extent of the work-up must depend critically upon the clinical nonepileptic features that accompany the seizures, the family and antecedent personal history of the patient, the medication responsiveness of the seizures, the likelihood of identifying a treatable or palliable condition, and the wishes of the family to assign a specific diagnosis to the child’s illness.

Deciding on Long-Term Therapy

After a first seizure, if the risk of recurrence is low and the patient has normal neurodevelopmental status, EEG, and MRI (risk about 20%), then treatment is usually not started. If the patient has abnormal EEG, MRI, development, and/or neurologic exam and/or a positive family history of epilepsy, then the risk is higher and often treatment is started. Other considerations are also important, such as motor vehicle driving status and type of employment in older patients or the parents’ ability to deal with recurrences or AED drug therapy in children. The decision is therefore always individualized. All aspects of this decision-making process should be discussed with the family. An overview of the approach to the treatment of seizures and epilepsy is presented in Figure 586-4.

Figure 586-4 An approach to the child with a suspected convulsive disorder.

Counseling

An important part of the management of a patient with epilepsy is educating the family and the child about the disease, its management, and the limitations it might impose and how to deal with them. It is important to establish a successful therapeutic alliance. Some restrictions on driving (in adolescents) and on swimming are usually necessary (Table 586-9). In most states, the physician is not required to report the epileptic patient to the motor vehicle registry; this is the responsibility of the patient. Also in most states, a seizure-free period of 6 mo, and in some states longer, is required before driving is allowed. Often swimming in rivers, lakes, or sea, and underwater diving are prohibited but swimming in swimming pools may be allowable. When swimming, patients with epilepsy, even if the epilepsy is under excellent control, should be under the continuous supervision of an observer who is aware of their condition and capable of lifeguard-level rescue.

Table 586-9 SPORTS AND SPECIAL CONSIDERATIONS FOR THE CHILD WITH EPILEPSY*

* Specific advice should be individualized depending on the patient’s clinical condition. Many patients actually have fewer seizures when they are active than when they are idle.

Based on Committee on Children with Handicaps: The epileptic child and competitive school athletics, Pediatrics 42:700–702, 1968.

The American Academy of Pediatrics recommends that the physician, parents, and child jointly evaluate the risk of involvement in athletic activities. To participate in athletics, proper medical management, good seizure control, and proper supervision are crucial to avoid significant risks. Any activity where a seizure might cause a dangerous fall should be avoided; these activities include rope climbing, use of the parallel bars, and high diving. Participation in collision or contact sports depends on the patient’s condition. Epileptic children should not automatically be banned from participating in hockey, baseball, basketball, football, or wrestling. Rather, individual consideration should be based on the child’s specific case (see Table 586-9).

Counseling is helpful to support the family and to educate them about the resources available in the community. Educational and, in some cases, psychological evaluation may be necessary to evaluate for possible learning disabilities or abnormal behavioral patterns that might coexist with the epilepsy. Epilepsy does carry risk of increased mortality (2 or more times the standardized mortality rates of the general population) and of sudden unexpected death. This is mostly related to the conditions associated with or underlying the epilepsy (e.g., metabolic diseases), to poor seizure control (e.g., in patients with severe epileptic encephalopathies), and to poor compliance with prescribed therapies. Thus, family members can be usually be informed about this increased risk without inappropriately increasing their anxiety. Many family members feel they need to observe the patient continuously in wakefulness and sleep and have the patient sleep in the parent’s rooms to detect seizures. This has never been shown to improve outcome and should generally be discouraged because it will affect the psychology of the child with no proven benefits. Education about what to do in case of seizures, the choices of treatment or no treatment and of medications and their side effects, and potential complications of epilepsy should be provided to the parents and, if he or she is old enough, to the child.

Mechanisms of Action of Antiepileptic Drugs

Current AEDs reduce excitability by interfering with the sodium or calcium ion channels, by reducing glutamate induced excitatory function, or by enhancing GABAergic inhibition. Most medications have multiple mechanisms of action, and the exact mechanism responsible for their activity in human epilepsy is usually not fully understood. Often, medications acting on sodium channels are effective against partial seizures, and medications acting on T-type calcium channels are effective against absence seizures. Voltage-gated sodium channels are blocked by felbamate, valproate, topiramate, carbamazepine, oxcarbazepine, lamotrigine, phenytoin, rufinamide, lacosamide, and zonisamide. T-type calcium channels, found in the thalamic area, are blocked by valproate, zonisamide, and ethosuximide. Voltage-gated calcium channels are inhibited by lamotrigine, felbamate, gabapentin and pregabalin. N-type calcium channels are inhibited by levetiracetam.

GABA_A receptors are activated by phenobarbital, benzodiazepines, topiramate, felbamate, and levetiracetam. Tiagabine, by virtue of its binding to GABA transporters 1 (GAT-1) and 3 (GAT-3), is a GABA reuptake inhibitor. GABA levels are increased by vigabatrin via its irreversible inhibition of GABA transaminases, and valproate inhibits GABA transaminases, acts on GABA_B presynaptic receptors (also done by gabapentin), and activates glutamic acid decarboxylase (the enzyme that forms GABA).

Glutaminergic transmission is decreased by felbamate that blocks NMDA and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid)/kainate receptors. Topiramate also blocks AMPA/kainate receptors. Levetiracetam binds to the presynaptic vesicle protein SV2A found in all neurotransmitter vesicles and possibly results in inhibition of presynaptic neurotransmitter release in a use-dependent manner.

Choice of Drug According to Seizure Type and Epilepsy Syndrome

Drug therapy should be based on the type of seizure and the epilepsy syndrome. In general, the drugs of first choice for focal seizures and epilepsies are oxcarbazepine and carbamazepine; for absence seizures, ethosuximide; for juvenile myoclonic epilepsy, valproate and lamotrigine; for Lennox-Gastaut syndrome, valproate, topiramate, lamotrigine, and, most recently, as add on, rufinamide; and for infantile spasms, adrenocorticotropic hormone (ACTH). Lamotrigine has been shown to be effective for partial seizures, and valproate has been shown to be effective for generalized and unclassified epilepsies. There is significant controversy about these choices, and therapy should always be individualized (see the next section and Table 586-10).

West syndrome is best treated with adrenocorticotropic hormone (ACTH). There are several protocols that range in dose from high to intermediate to low. The increase in price of ACTH gel in the USA has led many physicians to use the lowest dose even though a better response usually occurs with the higher doses. The initial ACTH dose in one high-dose protocol is 150 IU/m²/day of ACTH gel intramuscularly in 2 divided doses for 1 wk. During the 2nd wk, the dose is 75 IU/m²/day in 1 daily dose for 1 wk. For the 3rd wk, the dose is 75 IU/m² every other day for 1 wk. ACTH is gradually tapered over the next 9 wk. The lot number of the ACTH gel is recorded. Response is usually observed within the first 7 days; however, if no response is observed within 2 wk, the lot is changed. During the tapering period, and especially in symptomatic patients, relapse can occur. Remediation entails increasing the dose to the previously effective dose for 2 wk and then beginning the taper again. If seizures persist after this, the dose is increased to 150 IU/m²/day and the protocol is initiated again. Synthetic ACTH has also been used: Synacthen Depot intramuscular 0.25 mg/mL or 1 mg/mL is used; 1 mg is considered to have the potency of 100 IU in stimulating the adrenal. Other protocols include the use of 110 IU/m² per day for 3 wk with a subsequent taper over 6 wk. A third protocol is to use 20 IU/day (low dose) and to taper and discontinue therapy immediately after achieving a response.

Awake and asleep EEG is often done 1, 2, and 4 wk after the initiation of ACTH to monitor the patient’s response. Side effects, more common with the higher doses, include hypertension, electrolyte imbalance, infections, hyperglycemia and/or glycosuria, and gastric ulcers. All should be carefully monitored for. ACTH is generally thought to offer an added advantage over prednisone or other steroids alone. There is often amelioration of the seizures and of the EEG findings. The majority of patients have a poor prognosis despite ACTH. Cryptogenic cases have a better chance for a response.

In August 2009, vigabatrin was approved by the FDA for use in children with infantile spasms. Where available, it is considered by some as an alternative to ACTH as the drug of first choice. Its principal side effect is its retinal toxicity, with resultant visual field defects that can persist despite withdrawal of the drug. The level of evidence for its efficacy is weaker than that for ACTH and stronger than that of other alternative medications, including valproate, benzodiazepines like nitrazepam, and clonazepam, topiramate, lamotrigine, zonisamide, pyridoxine, ketogenic diet, and intravenous gamma globulin (IVIG). None of these alternative drugs offers uniformly satisfactory results. However, they are useful for decreasing the frequency and severity of seizures in patients with symptomatic infantile spasms and as adjunctive therapy in patients with cryptogenic infantile spasms who do not respond completely to ACTH or vigabatrin.

Lennox-Gastaut syndrome is another difficult-to-treat epilepsy syndrome. Treatment of seizures in Lennox-Gastaut syndrome varies according to the preponderant seizure type. For drop attacks (tonic, atonic, or myoclonic astatic seizures), valproate, lamotrigine, or topiramate have been found to be especially effective. These drugs might control other types of seizures (partial, generalized tonic-clonic, atypical absence, other tonic, myoclonic), as well. For patients who have a preponderance of atypical absence seizures, lamotrigine or ethosuximide are often suitable drugs to try because they are relatively less toxic than many of the alternative drugs. Lamotrigine or valproate should be used if other seizures coexist with absences. Clonazepam and other benzodiazepines are also often helpful for all seizure types but produce significant sedation and often tolerance to their antiepileptic effects develops in a few months. In resistant cases of Lennox-Gastaut syndrome and related epilepsies, rufinamide, zonisamide, felbamate, levetiracetam, acetazolamide, methsuximide, corticosteroids, ketogenic diet, or IVIG can be used.

Dravet syndrome is usually treated with valproate and benzodiazepines such as clonazepam; the ketogenic diet can also be useful in patients with this syndrome. In some countries clobazam and stiripentol are available, and these appear to result more commonly in successes, particularly if used in combination with valproate. Other medications include zonisamide and topiramate. Lamotrigine has been reported to exacerbate seizures in Dravet syndrome and other myoclonic epilepsies.

Very rare cases of patients who have neonatal, infantile, or early childhood epilepsy who have pyridoxine-dependent epilepsy (demonstrated to be due to antiquitin gene mutation) respond to pyridoxine 10-100 mg/day orally (up to 600 mg/day has been used) within 3-7 days of the initiation of oral therapy and almost immediately if given parenterally. Seizure types include myoclonic, partial, or generalized seizures. Some patients have seizures that are intractable from onset, but other seizures show an initial but transient response to traditional AEDs. Some of these patients also require concurrent folinic acid (5-15 mg/day). Rarely, patients require the active form of vitamin B₆, specifically, pyridoxal phosphate (50 mg/day initial dose that can be increased gradually up to 15 mg/kg every 6 hr) owing to the patient’s deficiency of pyridoxamine phosphate oxidase (PNPO). In both the PNPO-deficient/pyridoxal phosphate-dependent and the pyridoxine-dependent forms, hypotonia and hypopnea can occur after initiation of vitamin therapy. Pyridoxine has also been used by some, specifically in Japan, early in the treatment of West syndrome. Patients with cerebral folate deficiency can respond to folinic acid supplementation (usually started at low doses of 0.5-1 mg/kg/day). Traditionally these entities have been diagnosed by giving the vitamin B₆ or folinic acid in therapeutic trials. There are biologic markers for the different forms of the disorder. One is elevation of pipecolic acid and of α-amino adipic semialdehyde (AASA) in vitamin B₆–dependent epilepsy due to a defect in the enzyme AASA dehydrogenase; another is abnormal metabolites in the CSF of patients with cerebral folate deficiency and PNPO deficiency.

Absence seizures are most often initially treated with ethosuximide, which is as effective as and less toxic than valproate and more effective than lamotrigine. Alternative drugs of first choice are lamotrigine and valproate, especially if generalized tonic-clonic seizures coexist with absence seizures. Patients resistant to ethosuximide might still respond to valproate or to lamotrigine. In absence seizures, the EEG is usually helpful in monitoring the response to therapy and is often more sensitive than the parents’ observations in detecting these seizures. The EEG often normalizes when complete seizure control is achieved. This is usually not true for partial epilepsies. Other medications that could be used for absence seizures include acetazolamide, zonisamide, or clonazepam.

Benign myoclonic epilepsies are often best treated with valproate, particularly when patients have associated generalized tonic-clonic and absence seizures. Benzodiazepines, clonazepam, lamotrigine, and topiramate are alternatives for the treatment of benign myoclonic epilepsy. Severe myoclonic epilepsies and Dravet syndrome (see earlier) are treated with topiramate, clobazam, valproate, and stiripentol.

Partial and secondary generalized tonic and clonic seizures can be treated with oxcarbazepine, carbamazepine, phenobarbital, topiramate, valproic acid, lamotrigine, clobazam, clonazepam, or levetiracetam (see Table 586-8). Oxcarbazepine, levetiracetam, carbamazepine (USA) or valproate (Europe) are often used first. One study favored lamotrigine as initial monotherapy for partial seizures and valproate for generalized seizures. Almost any of these medications has been used as first or second choice depending on the individualization of the therapy.

Choice of Drug: Other Considerations

Because there are many options for each patient, the choice of which drug to use is always an individualized decision based on comparative effectiveness data from randomized controlled trials and several other considerations.

Comparative effectiveness and potential for paradoxical seizure aggravation by some AEDs (e.g., precipitation of absence seizures and myoclonic seizures by carbamazepine and tiagabine) must be considered (see Table 586-10).

Comparative tolerability: Adverse effects can vary according to the profile of the patient. The most prominent example is the increased risk of liver toxicity for valproate therapy in children <2 yr of age, on polytherapy, and or with metabolic disorders. Thus, if metabolic disorders are suspected, other drugs should be considered first and, in any case, valproate should not be started until these are ruled out by normal amino acids, organic acids, acylcarnitine profile, lactate, pyruvate, liver function tests, and perhaps other tests. The choice of an AED can also be influenced by the likelihood of occurrence of nuisance side effects such as weight gain (valproate, carbamazepine), gingival hyperplasia (phenytoin), alopecia (valproate), hyperactivity (benzodiazepines, barbiturates, valproate, gabapentin), and others. Children with behavior problems and/or with attention deficit disorder can become particularly hyperactive with GABAergic drugs such as benzodiazepines and barbiturates or even valproate. This often affects the choice of medications.

Cost and availability: The cost of the newer AEDs often precludes their use, particularly in developing countries where cost is a major issue. Also, many drugs are not available in many countries either because they are too expensive, because, paradoxically, they are too inexpensive, or because of regulatory restrictions. In general, AEDs have a narrow therapeutic range, and thus switching from brand name to generic formulations or from one generic to another can result in changes in levels that could result in breakthrough seizures or side effects. Thus, generic substitution is generally best avoided if a brand name drug has already proved efficacious.

Ease of initiation of the AED: Medications that are started very gradually such as lamotrigine and topiramate may not be chosen in situations when there is a need to achieve a therapeutic level quickly. In such situations, medications that have intravenous preparations or that can be started and titrated more quickly such as valproate, phenytoin, or levetiracetam may be chosen instead.

Drug interactions and presence of background medications: An example is the potential interference of enzyme-inducing drugs with many chemotherapeutic agents. In those cases, medications like gabapentin or levetiracetam are used. Also, valproate inhibits the metabolism and increases the levels of lamotrigine, phenobarbital, and felbamate. It also displaces protein-bound phenytoin from protein-binding sites, increasing the free fraction, and thus the free and not the total level needs to be checked when both medications are being used together. Enzyme inducers like phenobarbital, carbamazepine, phenytoin, and primidone reduce levels of lamotrigine, valproate, and, to a lesser extent, topiramate and zonisamide. Medications exclusively excreted by the kidney like levetiracetam and gabapentin are not subject to such interactions.

The presence of comorbid conditions: For example, the presence of migraine in a patient with epilepsy can lead to the choice of a medication that is effective against both conditions such as valproate or topiramate. In an obese patient, a medication such as valproate might be avoided, and a medication that decreases appetite such as topiramate might be used instead. In adolescent girls of child-bearing potential, enzyme-inducing AEDs should be avoided because they can interfere with birth control pills; other AEDs, particularly valproate, can increase risks for fetal malformations (see Table 586-9).

Coexisting seizures: In a patient with both absence and generalized tonic-clonic seizures, a drug that has a broad spectrum of antiseizure effects such as lamotrigine or valproate could be used rather than medications that have a narrow spectrum of efficacy, such as phenytoin.

History of prior response to specific AEDs: For example, if a patient or a family member with the same problem had previously responded to carbamazepine, carbamazepine could be a desirable choice.

Mechanism of drug actions: At present, the understanding of the pathophysiology of epilepsy does not allow specific choice of AEDs based on the assumed pathophysiology of the epilepsy. However, in general, it is believed that it is better to avoid combining medications that have similar mechanisms of action, such as phenytoin and carbamazepine (both work on sodium channels). A number of medications, such as lamotrigine and valproate or topiramate and lamotrigine, have been reported to have synergistic effects, possibly because they have different mechanisms of action.

Ease of use: Medications that are given once or twice a day are easier to use than medications that are given 3 or 4 times a day. Availability of a pediatric liquid preparation, particularly if such a preparation is palatable, also plays a role.

Ability to monitor the medication and adjust the dose: Some medications are difficult to adjust and to follow, requiring frequent blood levels. The prototype of such medications is phenytoin, but many of the older medications require blood level monitoring. This helps physicians gauge efficacy and avoid potential toxicity. However, monitoring in itself can represent a practical or patient satisfaction disadvantage as compared to the newer AEDs, which generally do not require blood level monitoring.

Patient’s and family’s preferences: All things being equal, the choice between two or more acceptable alternative AEDs might also depend on the patient’s or family’s preferences. For example, some patients might want to avoid gingival hyperplasia and hirsutism as side effects but might tolerate weight loss, or vice versa.

Genetics and genetic testing: A genetic predisposition to developing AED-induced side effects is another factor that may be a consideration. For example, there is a strong association between the human leukocyte antigen HLA-B*1502 allele and severe cutaneous reactions induced by carbamazepine, phenytoin, or lamotrigine in Chinese patients; hence these AEDs should be avoided in genetically susceptible persons. Mutations of the SCN1A sodium channel gene indicating Dravet syndrome could also lead to avoiding lamotrigine because it can exacerbate seizures in this syndrome.

Teratogenic profiles: Some AEDs, including valproate and to a lesser extent carbamazepine, phenobarbital, and phenytoin, are associated with teratogenic effects (Table 586-11).

Table 586-11 TERATOGENESIS AND PERINATAL OUTCOMES OF ANTIEPILEPTIC DRUGS

Levels of recommendation: A: strongest recommendation; based on Class 1 data, B and C: lower levels of recommendations.

Types of malformations: Prior studies had reported the occurrence of spina bifida with valproate and carbamazepine therapy, and of cardiac malformation and cleft palate after carbamazepine phenytoin and phenobarbital exposure. There is variability from study to study. However, in general the relative incidence of major malformations of about 10% for valproate monotherapy, higher with valproate polytherapy, and in the range of 5% for monotherapy with the other above three AEDs and higher with polytherapy.

FDA categories: Valproate, phenobarbital, carbamazepine, and phenytoin are classified by the FDA as category D. Ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide are category C. Category C: Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women. Category D: Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy might outweigh the potential risk.

AED, antiepileptic drug; VPA, valproate.

Data from Harden CI, Meador KJ, Pennell PB, et al: Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and American Epilepsy Society, Neurology 73(2):133–141, 2009.

Some of these considerations can be addressed by resorting to expert opinion surveys (see Table 586-10) or to guidelines developed by concerned societies such as the ILAE, National Institute for Clinical Excellence (NICE) in England, Scottish Intercollegiate Guidelines Network (SIGN), or the American Academy of Neurology (AAN). Some guidelines are totally evidence based (AAN, ILAE), and others (NICE, SIGN) incorporate other considerations as well. However, no guideline is able to incorporate all the considerations relevant to each patient. Thus, the process of choosing an AED involves incorporating the evidence from randomized controlled trials, guidelines, expert opinion surveys, and all of the other considerations inherent in individualizing therapy and in tailoring therapy to the patient’s specific condition.

Initiating and Monitoring Therapy

In nonemergency situations or when loading is not necessary, the maintenance dose of the chosen AED is started (Table 586-12). With some medications (e.g., carbamazepine and topiramate), in many cases even smaller doses are initially started then gradually increased up to the maintenance dose to build tolerance to adverse effects such as sedation. For example, the starting dose of carbamazepine is usually 5-10 mg/kg/day. Increments of 5 mg/kg/day can be added every 3 days until a therapeutic level is achieved and a therapeutic response is established or until unacceptable adverse effects occur. With other medications such as zonisamide, phenobarbital, phenytoin, or valproate, starting at the maintenance dose is usually tolerated. With some, such as levetiracetam and gabapentin, either approach can be used. Patients should be counseled about potential adverse effects, and these should be monitored during follow-up visits (Table 586-13).

Table 586-13 SOME COMMON ADVERSE EFFECTS OF ANTIEPILEPTIC DRUGS

Essentially all AEDs can cause CNS toxicity and potentially rashes and serious allergic reactions. Lacosamide has recently been approved as add-on therapy for partial seizures for patients ≥17 yr of age and requires a baseline EEG before starting it.

AED, antiepileptic drug; CNS, central nervous system; EEG, electroencephalogram.

Approach to Epilepsy Surgery

If a patient has failed 3 drugs, the chance of achieving seizure freedom using AEDs is generally <10%. Therefore, proper evaluation for surgery is necessary as soon as patients fail 2 or 3 AEDs, usually within 2 yr of the onset of epilepsy and often sooner than 2 yr. Performing epilepsy surgery in children at an earlier stage (e.g., <5 yr) allows transfer of function in the developing brain. Candidacy for epilepsy surgery requires proof of resistance to AEDs used at maximum, tolerably nontoxic doses; absence of expected unacceptable adverse consequences of surgery, and a properly defined epileptogenic zone (area that needs to be resected to achieve seizure freedom). The epileptogenic zone can be identified by seizure semiology, interictal EEG, video-EEG long-term monitoring, and MRI. Other techniques such as invasive EEG (depth electrodes, subdurals), single photon emission CT (SPECT), magnetoencephalography (MEG), and positron emission tomography (PET) are used when the epileptogenic zone is difficult to localize or when it is close to eloquent cortex. To avoid resection of eloquent cortex, several techniques can be used including the Wada test. In this test, intracarotid infusion of amobarbital is used to anesthetize one hemisphere to lateralize memory and speech by testing them during that unilateral anesthesia. Other tests to localize function include functional MRI, MEG, or subdural electrodes with cortical stimulation. Developmental delay or psychiatric diseases need to be considered in assessing the potential impact of surgery on the patient. The usual minimal presurgical evaluation includes EEG monitoring, imaging, and age-specific neuropsychologic assessment.

Epilepsy surgery is often used to treat refractory epilepsy of a number of etiologies including cortical dysplasia, tuberous sclerosis, polymicrogyria, hypothalamic hamartoma, and hemispheric syndromes, such as Sturge-Weber syndrome, hemimegalencephaly, Rasmussen encephalitis, and Landau-Kleffner syndrome. Patients with intractable epilepsy resulting from metabolic or degenerative problems are not candidates for resective epilepsy surgery. Focal resection of the epileptogenic zone is the most common procedure. Hemispherectomy is used for diffuse hemispheric lesions; multiple subpial transection, a surgical technique in which the connections of the epileptic focus are partially cut without resecting it, is sometimes used for unresectable foci located in eloquent cortex. In Lennox-Gastaut syndrome, corpus callosotomy is used for drop attacks. Vagal nerve stimulation (VNS) is often used for intractable epilepsies of various types and for seizures of diffuse or multifocal anatomic origin that do not yield themselves to resective surgery. Focal resection and hemispherectomy result in a high rate (50-80%) of seizure freedom. Corpus callosotomy and VNS result in lower rates (5-10%) of seizure freedom; however, these procedures do result in significant reductions in the frequency and severity of seizures, decrease in medication requirements, and meaningful improvements in the patient’s quality of life in approximately half or more of eligible patients.

Discontinuation of Therapy

Discontinuation of AEDs is usually indicated when children are free of seizures for at least 2 yr. In more-severe syndromes such as temporal lobe epilepsy secondary to mesial temporal sclerosis, Lennox-Gastaut syndrome, or severe myoclonic epilepsy, a prolonged period of seizure freedom on treatment is often warranted before AEDs are withdrawn, if withdrawal is attempted at all. In benign epilepsy syndromes, the duration of therapy can often be as short as 6 mo.

Many factors should be considered before discontinuing medication, including the likelihood of remaining seizure free after drug withdrawal based on the type of epilepsy syndrome and etiology, the risk of injury in case of seizure recurrence (e.g., if the patient drives), and the adverse effects of AED therapy. Most children who have not had a seizure for ≥2 yr and who have a normal EEG when AED withdrawal is initiated remain free of seizures after discontinuing medication, and most relapses occur within the first 6 mo.

Certain risk factors can help the clinician predict the prognosis after AED withdrawal. The most important risk factor for seizure relapse is an abnormal EEG before medication is discontinued. Children who have remote symptomatic epilepsy are less likely to be able to stop AEDs than children who have idiopathic epilepsy. In patients with absences or in those treated with valproate for primary generalized epilepsy, the risk of relapse might still be high despite a normal EEG because valproate can normalize EEGs with generalized spike-wave abnormalities. Thus, in these patients, repeating the EEG during drug withdrawal can help identify recurrence of the EEG abnormality and associated seizure risk before clinical seizures recur. Older age of epilepsy onset, longer duration of epilepsy, presence of multiple seizure types, and need to use >1 AED are all factors associated with a higher risk of seizure relapse after AED withdrawal.

AED therapy should be discontinued gradually, often over a period of 3-6 mo. Abrupt discontinuation can result in withdrawal seizures or status epilepticus. Withdrawal seizures are especially common with phenobarbital and benzodiazepines; therefore, special attention must be given to a prolonged tapering schedule during the withdrawal of these AEDs. Seizures that occur >2 to 3 mo after AEDs are completely discontinued indicate relapse, and resumption of treatment is usually warranted.

The decision to attempt AED withdrawal must be assessed mutually among the clinician, the parents, and the child. Risk factors should be identified and precautionary measures should be anticipated in case of seizure relapse. The patient and family should be counseled fully on what to expect, what precautions to take (including cessation of driving for a period of time), and what to do in case of relapse. A prescription for rectal diazepam to be given at the time of seizures that might occur during and after tapering may be warranted (see Table 586-12 for dosing).

Pathophysiology

The immature brain has many differences from the mature brain that render it more excitable and more likely to develop seizures. Based predominantly on animal studies, these are delay in Na⁺, K⁺-ATPase maturation and increased NMDA and AMPA receptor density. In addition, the specific types of these receptors that are increased are those that are permeable to calcium (GLUR2 AMPA receptors). This contributes to increased excitability and to the long-term consequences associated with seizures, particularly those resulting from perinatal hypoxia. Medications that block AMPA receptors such as topiramate may thus prove useful in this clinical setup.

Another difference is delay in the development of inhibitory GABAergic transmission. In fact, GABA in the immature brain has an excitatory function as the chloride gradient is reversed relative to the mature brain, with higher concentrations of chloride being present intracellularly than extracellularly. Thus, opening of the chloride channels in the immature brain results in depolarizing the cell and not in hyperpolarizing it. This phenomenon appears to be more prominent in male neonates, perhaps explaining their greater predisposition to seizures. The reason for this is that the Cl⁻ transporter, NKCC1, is predominantly expressed in the neonatal period, leading to transport of Cl⁻ into the cell, and to cellular depolarization upon activation of GABA_A receptors. This is important for neuronal development but renders the neonatal brain hyperexcitable. With maturation, expression of NCCK1 decreases and KCC2 increases. KCC2 transports Cl⁻ out of the cell, resulting in reduction of intracellular chloride concentration so that when GABA_A receptors are activated, Cl⁻ influx and hyperpolarization occur. Bumetanide, a diuretic that blocks NKCC1, can prevent excessive GABA depolarization and avert the neuronal hyperexcitability underlying neonatal seizures.

Although it is susceptible to developing seizures, the immature brain appears to be more resistant to the deleterious effects of seizures than the mature brain, as a result of increases in calcium binding proteins that buffer injury-related increases in calcium, increased extracellular space, decreased levels of the second messenger inositol triphosphate, and the immature brain’s ability to tolerate hypoxic conditions by resorting to anaerobic energy metabolism.

Whether seizures are injurious to the immature brain is controversial. Many animal studies indicate that seizures are detrimental to the immature brain. Human studies also suggest harmful effects of seizures as shown by MRI and by the association of worse prognosis in neonates with seizures even when correcting for confounding factors. Even electrographic seizures without clinical correlates have been shown to be associated with worse prognosis. However, it is difficult in most models and in human studies to distinguish effects of seizures, the underlying disease responsible for the seizures, and, in the case of expedient treatment, the AEDs used to stop the seizures. Most physicians currently believe that it is favorable to control clinical as well as electrographic seizures, but not at the expense of causing severe systemic toxicity from AEDs.

Types of Neonatal Seizures

There are 5 main neonatal seizure types: subtle, clonic, tonic, spasms, and myoclonic. Spasms, focal clonic or tonic, and generalized myoclonic seizures are, as a rule, associated with electrographic discharges (epileptic seizures), whereas the subtle, generalized tonic and other myoclonic seizures are usually not associated with discharges and thus are thought to usually represent release phenomena with abnormal movements secondary to brain injury rather than true epileptic seizures. To determine clinically whether such manifestations are seizures or release phenomena is often difficult, but precipitation of such manifestations by stimulation and aborting them by restraint or manipulation would suggest that they are not seizures. Performing such maneuvers at the bedside is often helpful. In addition, continuous bedside EEG monitoring helps make this distinction. Thus, such monitoring is the standard of care in many nurseries.

Etiology

Causes of neonatal seizures are shown in Table 586-14.

Diagnosis

Some cases can be correctly diagnosed by simply taking the prenatal and postnatal history and performing an adequate physical examination. Depending on the case, additional tests or procedures can be performed. EEG is considered the main tool for diagnosis. It can show paroxysmal activity (e.g., sharp waves) in between the seizures and electrographic seizure activity if a seizure is captured. However, some neonatal seizures might not be associated with EEG abnormalities as noted above either because they are “release phenomena” or alternatively because the discharge is deep and is not detected by the scalp EEG. Additionally, electrographic seizures can occur without observed clinical signs (electroclinical dissociation). This is presumed to be due to the immaturity of cortical connections resulting in many cases in no or minimal motor manifestations. Continuously monitoring the EEG at the bedside in the neonatal intensive care unit (NICU) for neonates at risk for neonatal seizures and brain injury has become part of routine clinical practice in many centers, providing real-time measurements of the brain’s electrical activity and identifying seizure activity. Some centers apply EEG monitoring to at-risk babies even before seizures develop; others monitor patients who have manifested or are suspected of having seizures. In addition, there are currently attempts to develop methods for continuous monitoring of cerebral activity with automated detection and background analysis of neonatal seizures, similar to the continuous ECG monitoring in intensive care facilities.

Careful neurologic examination of the infant might uncover the cause of the seizure disorder. Examination of the retina might show the presence of chorioretinitis, suggesting a congenital TORCH infection, in which case titers of mother and infant are indicated. The Aicardi syndrome, which occurs exclusively in infant girls, is associated with coloboma of the iris and retinal lacunae, refractory seizures, and absence of the corpus callosum. Inspection of the skin might show hypopigmented lesions characteristic of tuberous sclerosis or the typical crusted vesicular lesions of incontinentia pigmenti; both neurocutaneous syndromes are associated with generalized myoclonic seizures beginning early in life. An unusual body odor suggests an inborn error of metabolism.

Blood should be obtained for determinations of glucose, calcium, magnesium, electrolytes, and blood urea nitrogen. If hypoglycemia is a possibility, serum glucose testing is indicated so that treatment can be initiated immediately. Hypocalcemia can occur in isolation or in association with hypomagnesemia. A lowered serum calcium level is often associated with birth trauma or a CNS insult in the perinatal period. Additional causes include maternal diabetes, prematurity, DiGeorge syndrome, and high-phosphate feedings. Hypomagnesemia (<1.5 mg/dL) is often associated with hypocalcemia and occurs particularly in infants of malnourished mothers. In this situation, the seizures are resistant to calcium therapy but respond to intramuscular magnesium, 0.2 mL/kg of a 50% solution of MgSO₄. Serum electrolyte measurement can indicate significant hyponatremia (serum sodium <135 mEq/L) or hypernatremia (serum sodium >150 mEq/L) as a cause of the seizure disorder.

A lumbar puncture is indicated in virtually all neonates with seizures, unless the cause is obviously related to a metabolic disorder such as hypoglycemia or hypocalcemia secondary to feeding of high concentrations of phosphate. The latter infants are normally alert interictally and usually respond promptly to appropriate therapy. The CSF findings can indicate a bacterial meningitis or aseptic encephalitis. Prompt diagnosis and appropriate therapy improve the outcome for these infants. Bloody CSF indicates a traumatic tap or a subarachnoid or intraventricular bleed. Immediate centrifugation of the specimen can assist in differentiating the two disorders. A clear supernatant suggests a traumatic tap, and a xanthochromic color suggests a subarachnoid bleed. Mildly jaundiced normal infants can have a yellowish discoloration of the CSF that makes inspection of the supernatant less reliable in the newborn period.

Many inborn errors of metabolism cause generalized convulsions in the newborn period. Because these conditions are often inherited in an autosomal recessive or X-linked recessive fashion, it is imperative that a careful family history be obtained to determine whether siblings or close relatives developed seizures or died at an early age. Serum ammonia determination is useful for screening for the hypoglycemic hyperammonemia syndrome and for suspected urea cycle abnormalities. In addition to having generalized clonic seizures, these latter infants present during the 1st few days of life with increasing lethargy progressing to coma, anorexia and vomiting, and a bulging fontanel. If the blood gases show an anion gap and a metabolic acidosis with hyperammonemia, urine organic acids should be immediately determined to investigate the possibility of methylmalonic or propionic acidemia.

Maple syrup urine disease (MSUD) should be suspected when a metabolic acidosis occurs in association with generalized clonic seizures, vomiting, bulging fontanel, and muscle rigidity during the 1st wk of life. The result of a rapid screening test using 2,4-dinitrophenylhydrazine that identifies keto derivatives in the urine is positive in MSUD.

Additional metabolic causes of neonatal seizures include nonketotic hyperglycinemia, a lethal condition characterized by markedly elevated plasma and CSF glycine levels, persistent generalized seizures, and lethargy rapidly leading to coma; ketotic hyperglycinemia in which seizures are associated with vomiting, fluid and electrolyte disturbances, and a metabolic acidosis; and Leigh disease suggested by elevated levels of serum and CSF lactate or an increased lactate:pyruvate ratio. Biotinidase deficiency should also be considered. A comprehensive description of the diagnosis and management of these metabolic diseases is discussed in Part XI.

Unintentional injection of a local anesthetic into a fetus during labor can produce intense tonic seizures. These infants are often thought to have had a traumatic delivery because they are flaccid at birth, have abnormal brainstem reflexes, and show signs of respiratory depression that sometimes requires ventilation. Examination may show a needle puncture of the skin or a perforation or laceration of the scalp. An elevated serum anesthetic level confirms the diagnosis. The treatment consists of supportive measures and promotion of urine output by administering intravenous fluids with appropriate monitoring to prevent fluid overload.

Benign familial neonatal seizures, an autosomal dominant condition, begins on the 2nd-3rd day of life, with a seizure frequency of 10-20/day. Patients are normal between seizures, which stop in 1-6 mo. Fifth-day fits occur on day 5 of life (4-6 days) in normal-appearing neonates. The seizures are multifocal and are often present for <24 hr. The diagnosis requires exclusion of other causes of seizures. The prognosis is good.

Pyridoxine dependency, a rare disorder, must be considered when generalized clonic seizures begin shortly after birth with signs of fetal distress in utero. These seizures are particularly resistant to conventional anticonvulsants such as phenobarbital or phenytoin. The history may suggest that similar seizures occurred in utero. Some cases of pyridoxine dependency are reported to begin later in infancy or in early childhood. This condition is inherited as an autosomal recessive trait. In affected infants, large amounts of pyridoxine are required to maintain adequate production of GABA. When pyridoxine-dependent seizures are suspected, 100-200 mg of pyridoxine or pyridoxal phosphate should be administered intravenously during the EEG, which should be promptly performed once the diagnosis is considered. The seizures abruptly cease, and the EEG normalizes in the next few hours. Not all cases of pyridoxine dependency respond dramatically to the initial bolus of IV pyridoxine. Therefore, a 6-wk trial of oral pyridoxine (10-20 mg/day) or preferably pyridoxal phosphate (as pyridoxine does not help infants with the related but distinct syndrome of pyridoxal dependency) is recommended for infants in whom a high index of suspicion continues after a negative response to IV pyridoxine. Measurement of serum pipecolic acid (elevated) and CSF pyridoxal-5-phosphate (decreased) might prove to be the more precise method of confirming the diagnosis of pyridoxine dependency. These children require lifelong supplementation of oral pyridoxine 10 mg/day. Generally, the earlier the diagnosis and therapy with pyridoxine, the more favorable the outcome. Untreated children have persistent seizures and are uniformly severely mentally retarded.

Drug-withdrawal seizures can occur in the newborn nursery but can take several weeks to develop because of prolonged excretion of the drug by the neonate. The incriminated drugs include barbiturates, benzodiazepines, heroin, and methadone. The infant may be jittery, irritable, and lethargic and can have myoclonus or frank clonic seizures. The mother might deny the use of drugs; a serum or urine analysis can identify the responsible agent.

Infants with focal seizures, suspected stroke or intracranial hemorrhage, and severe cytoarchitectural abnormalities of the brain (including lissencephaly and schizencephaly) who clinically may appear normal or microcephalic should undergo MRI or CT scan. Indeed, it is appropriate to recommend imaging of all neonates with seizures unexplained by serum glucose, calcium, or electrolyte disorders. Infants with chromosome abnormalities and adrenoleukodystrophy are also at risk for seizures and should be evaluated with investigation of a karyotype and serum long-chain fatty acids, respectively.

Prognosis

Over the last few decades, prognosis of neonatal seizures has become better owing to improvement and advancement of obstetric care and intensive neonatal care. Mortality from neonatal seizures has decreased from 40 to 20%. The correlation between EEG and prognosis is very clear. Although neonatal EEG interpretation is very difficult, EEG was found to be highly associated with the outcome in premature and full-term infants. An abnormal background is a powerful predictor of less-favorable later outcome. In addition, prolonged electrographic seizures (>10 min/hour), multifocal periodic electrographic discharges, and spread of the electrographic seizures to the contralateral hemisphere also correlate with poorer outcome. The underlying etiology of the seizures is the main determinant of outcome. For example, patients with seizures secondary to hypoxic-ischemic encephalopathy have a 50% chance of developing normally, whereas those with seizures due to primary subarachnoid hemorrhage or hypocalcemia have a much better prognosis.

Treatment

A mainstay in the therapy of neonatal seizures is the diagnosis and treatment of the underlying etiology (e.g., hypoglycemia, hypocalcemia, meningitis, drug withdrawal, trauma), whenever one can be identified. There are conflicting approaches regarding the control of neonatal seizures. Proponents of the first approach argue that complete control of clinical as well as all electrographic seizures is needed. Others would only treat clinical seizures. Most centers favor the first approach but not at the expense of systemic toxicity. An important consideration before starting anticonvulsants is deciding if the patient needs to receive intravenous therapy and loading with an initial bolus or can simply be started on maintenance doses of a long-acting drug. Patients often require assisted ventilation after receiving intravenous or oral loading doses of AEDs, and thus precautions for observations and needed interventions are necessary.

Etiology

Etiologies include new-onset epilepsy of any type, drug intoxication (e.g., tricyclic antidepressants) in children and drug and alcohol abuse in adolescents, drug withdrawal or overdose in patients on AEDs, hypoglycemia, electrolyte imbalance (hypocalcemia, hyponatremia, hypomagnesemia), acute head trauma, encephalitis, meningitis, ischemic (arterial or venous) stroke, intracranial hemorrhage, pyridoxine, folinic acid and pyridoxal phosphate dependency, inborn errors of metabolism (Chapter 586.2) such as nonketotic hyperglycinemia in neonates and mitochondrial encephalopathy with lactic acidosis (MELAS) in children and adolescents, hypoxic-ischemic injury (e.g., after cardiac arrest), systemic conditions (such as hypertensive encephalopathy, renal or hepatic encephalopathy), brain tumors, and any other disorders that can cause epilepsy (such as brain malformations, neurodegenerative disorders, different types of progressive myoclonic epilepsy, storage diseases).

A rare condition called hemiconvulsion, hemiplegia, epilepsy (HHE) syndrome consists of prolonged febrile status epilepticus presumably due to focal acute encephalitis with resultant atrophy in the involved hemisphere, contralateral hemiplegia, and chronic epilepsy and needs to be suspected early on to attempt to control the seizures as early as possible. A somewhat similar condition in older children presenting as fever-induced refractory epileptic encephalopathy (FIRES) has been reported. Rasmussen encephalitis often causes epilepsia partialis continua (Chapter 586.3) and sometimes convulsive status epilepticus. Several types of infections are more likely to cause encephalitis with status epilepticus such as herpes simplex (complex partial and convulsive status), Bartonella (particularly nonconvulsive status), Epstein-Barr virus, and mycoplasma (postinfections encephalomyelitis with any type of status epilepticus). Postinfectious encephalitis and acute disseminated encephalomyelitis are common causes of status epilepticus including refractory status epilepticus.

Mechanisms

The mechanisms leading to the establishment of sustained seizure activity seen in status epilepticus appear to involve failure of desensitization of AMPA glutamate receptors, thus persistence of increased excitability, and reduction of GABA-mediated inhibition due to intracellular internalization of GABA_A receptors. This might explain the clinical observations that status epilepticus is often less likely to stop in the next specific period of time the longer the seizure has lasted and why benzodiazepines appear to be decreasingly effective the longer seizure activity lasts. During status epilepticus there is increased cerebral metabolic rate and a compensatory increase in cerebral blood flow that, after about half an hour, is not able to keep up with the increases in cerebral metabolic rate. This leads to a transition from adequate to inadequate cerebral oxygen tensions and, together with other factors, contributes to neuronal injury resulting from status epilepticus. Status epilepticus can cause both neuronal necrosis and apoptosis. The mechanisms of apoptosis are thought to be related to increases in intracellular calcium and pro-apoptotic factors such as ceramide, Bax, and apoptosis-inducing factor.

Therapy

Status epilepticus is a medical emergency that requires initial and continuous attention to securing airway breathing, and circulation (with continuous monitoring of vital signs including ECG) and determination and management of the underlying etiology (e.g., hypoglycemia). Laboratory studies including glucose and sodium, calcium, or other electrolytes, are abnormal in about 6% and are generally ordered as routine practice. Blood and spinal fluid cultures, toxic screens, and tests for inborn errors of metabolism are often needed, and AED levels need to be determined in known epileptic children already taking these drugs. EEG is often helpful in ruling out pseudo–status epilepticus (psychological conversion reaction mimicking status epilepticus) and in identifying the type of status epilepticus (generalized versus focal), which can guide further testing for the underlying etiology and further therapy. EEG can also help distinguish between postictal depression and later stages of status epilepticus in which the clinical manifestations are subtle (e.g., minimal myoclonic jerks) or absent (electroclinical dissociation) and can help in monitoring the therapy, particularly in patients who are paralyzed and intubated. Neuroimaging needs to be considered after the child has been stabilized, especially if it is indicated by the clinical manifestations or asymmetric or focal nature of the EEG abnormalities or if the seizure etiology is unknown. The EEG manifestations of status epilepticus show several stages that consist of initial distinct electrographic seizures (stage I) followed by waxing and waning electrographic seizures (stage II), continuous electrographic seizures (stage III; many patients start with this directly), continuous ictal discharges punctuated by flat periods (stage IV) and periodic epileptiform discharges on flat background (stage V). The last 2 stages are often associated with subtle clinical manifestations.

The initial therapy usually involves intravenous lorazepam, which is at least as effective as intravenous diazepam but has fewer side effects (Table 586-15). In infants, a trial of pyridoxine is often warranted. If intravenous access is not available, buccal midazolam or intranasal lorazepam are 2 effective options. With all options, respiratory depression is a potential side effect for which the patient should be monitored and managed as needed. Nasal midazolam and rectal diazepam have also been used, but there is less evidence to support their use in status epilepticus as compared to the other options.

Table 586-15 DOSES OF COMMONLY USED ANTIEPILEPTIC DRUGS IN STATUS EPILEPTICUS

After the initial benzodiazepine, the next medication is usually fosphenytoin, and the loading dose is usually 15-20 PE/kg. A level is usually taken 2 hr later to ensure achievement of a therapeutic concentration. Depending on the level maintenance dose, it can be started right away or, more commonly, in 6 hr. With phenytoin and phenobarbital, each 1 mg/kg (1 PE/kg for fosphenytoin) increases the serum concentration by about 1 µg/mL; for valproate, each 1 mg/kg increases the serum concentration by approximately 4 µg/mL. Precautions about the rate of infusion of fosphenytoin and phenytoin (not >0.5-1 mg/kg/min) and the other medications need to be followed because side effects often depend on infusion rate.

The subsequent medication is often phenobarbital. The dose used in neonates is usually 20 mg/kg loading dose, but in infants and children often the dose is 5-10 mg/kg (to avoid respiratory depression), with the dose repeated if there is not an adequate response. There is some evidence to support the use of intravenous valproate as a third-line medication. The place of intravenous levetiracetam awaits further study.

After the second or third medication is given, and sometimes before that, the patient might need to be intubated. All patients with status, even the ones who respond, need to be admitted to the ICU for completion of therapy and monitoring. For refractory status epilepticus, an intravenous bolus of midazolam, propofol, pentobarbital, or thiopental is usually initially used with maintenance of a corresponding continuous intravenous drip. This is done in the ICU. Subsequent boluses and adjustment of the rate of the infusion are usually made depending on clinical and EEG response. Because most of these patients need to be intubated and paralyzed, the EEG becomes the method of choice by which to follow them. The goal is to stop electrographic seizure activity before reducing the therapy. Usually this implies achievement of complete flattening of the EEG. Some consider that achieving a burst suppression pattern may be enough, and the periods of flattening in such a case need to be >5 sec. However, this is an area that is in need of further study.

Patients on these therapies require careful attention to blood pressure and to systemic complications, and some develop multiorgan failure. It is not unusual for patients put into pentobarbital coma to have to be on multiple pressors to maintain their blood pressure during therapy.

The choice among options to treat refractory status epilepticus often depends on the experience of the specific center. Midazolam probably has fewer side effects but is less effective, and barbiturate coma is more effective but carries a higher risk of side effects. On propofol, some patients develop a propofol infusion syndrome with lactic acidosis, hemodynamic instability, and rhabdomyolysis with higher infusion rates (>67 µg/kg/min). Thus electrolytes, creatine phosphokinase, and organ function studies need to be monitored. Often, barbiturate coma and similar therapies are maintained for 1 or more days before it is possible to gradually taper the therapy, usually over a few days. However, in some cases, including cases of new onset refractory status epilepticus (NORSE), such therapies need to be maintained for several weeks or even months. Even though the prognosis in NORSE cases is often poor and many patients do not survive, meaningful recovery despite a prolonged course is still possible. Occasionally, inhalational anesthetics are useful. Probably isoflorane is preferable because halothane can increase intracranial pressure and enflurane can induce seizures.

For nonconvulsive status epilepticus and epilepsia partialis continua, therapy needs to be tailored according to the clinical manifestations and often consists of trials of sequential oral or sometimes parenteral AEDs without resorting to barbiturate coma or overmedication that could result in respiratory compromise. The approach to complex partial status epilepticus is sometimes similar to the approach to convulsive status epilepticus and sometimes intermediate between the approach for epilepsia partialis and that for convulsive status, depending on severity. Long-term consequences after complex partial status epilepticus have been reported, but the complications might also be less severe than those after convulsive status epilepticus. Prolonged nonconvulsive complex partial status epilepticus can last for as much as 4-12 wk, with patients manifesting psychotic symptoms and confusional states. These cases can be resistant to therapy. Despite that, patients still can have a full recovery. Some of these cases appear to improve with the use of steroids or intravenous gamma globulin, which are used if an autoimmune, parainfectious etiology is suspected. Potential therapies under study for convulsive status epilepticus include induction of acidosis (e.g., by hypercapnia), which reduces neuronal excitability and hypothermia. A ketogenic diet has been advocated by some for selected cases of status epilepticus, such as children suffering from FIRES.