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.