Seizures and other paroxysmal disorders in infants and children

Seizures and Other Paroxysmal Disorders in Infants and Children Part 1

M A N U E L R. GOMEZ D O N A L D W. KLASS

ETYMOLOGICALLY, epilepsy means "seized upon" (from the Greek epi = upon + l~psis = seizure, lambdnein = seize or take). As the word's origin indicates, during an epileptic attack or seizure the patient is seized or surprised. Whether the seizure consists of overt movement, subjective symptoms or sudden arrest of movement, the episode is brief and there usually is an abrupt onset and termination. The clinical manifestations and electrographic accompaniments can be widely diverse. The older concepts of epilepsy based'6n clinical descriptions have been much enriched by the contributions of electroencephalography. At present, the electroencephalogram is an indispensable adjunct in the diagnostic evaluation of any patient suspected of having seizures, and it also serves as a tool for investigation of seizure mechanisms. Recent classifications of seizures are based on the combined data from clinical and electrographic sources. For practical purposes, we will deal here with seizures in the chronologic order in which they occur during childhood. We also will consider other spells that need to be differentiated from seizures. We will follow as much as possible the classification recently proposed by the International League Against Epilepsy. x The following arbitrary divisions will be used: I. Seizures in neonates, infants and young children. A. Neonatal seizures. B. Infantile spasms. C. Febrile seizures.

II. Nonconvulsive paroxysmal disorders in infants and children. A. Cyanotic and pallid syncopal attacks. B. Benign paroxysmal vertigo. C. Migraine. III. Convulsive disorders in children.

I. SEIZURES IN NEONATES, INFANTS AND YOUNG CHILDREN A. NEONATAL SEIZURES Seizures occur during the first month of life in about 0.8% of all children,z Neonatal seizures are not usually associated with fever, in contrast to what occurs in the second and third years of life. The pattern of neonatal seizures varies, even in the same infant, and considerable experience is required to identify their epileptic nature. Seizures occurring in premature infants may be especially difficult to recognize, since the manifestations differ greatly from the stereotyped motor events of seizures in older children or adults; many resemble random movements or normal startl e responses. One type is generalized from the onset with aninitial tonic phase: all muscles stiffen, the eyes roll upward (sursumvergence) and the infant is unresponsive. Tonic spasm may constitute the only manifestation of the seizure or may be accompanied by apnea and cyanosis. Other generalized seizures consist of abrupt clonie jerks of voluntary muscles (myoclonia), particularly involving the limbs. Focal motor (partial) seizures are less frequent than generalized attacks in neonates.3 The focal onset, whether clinically observed or electrographically detected, often is inconsistent and may change location with different attacks (erratic seizures). Included in this group are the focal clonic and focal tonic seizures affecting one extremity or muscle group. More frequently, seizures involve more than one extremity of the same side (unilateral tonic or clonie). Some neonatal seizures are difficult to classify. Some are manifested by only brief periods of apnea with cyanosis or more subtle changes in rate or depth of respiration, some by minor changes in tone of one or more extremities and some by irregular clonic movements of the face, mouth and tongue (clonie, tonic, tremor-like or coordinated into sucking or swallowing, to mention but a few examples). Thus, the criteria for establishing seizures as primarily generalized at onset cannot always be applied to those in neonates because of the erratic nature of,the behavioral patterns. 4.5 Rhythmic clonic movements may involve all four limbs at any one time but may affect only one or two limbs at other times. Rose and Lombroso 6 referred to such attacks as "generalized fragmentary" because they resemble a part of the fully developed grand mal seizure. Although predomi4

nantly one part, or "system," of the brain may seem to be involvcd at a particular time, caution should be cxcrciscd before concluding that a neonatal seizure including one side of the body is caused by a single anatomic lesion. Even partial seizures in a neonate must be highly consistent before association with a localized structural lesion can be considercd likely. Two-thirds of neonatal seizures have the onset during the first week of the patient's life, and about half of these occur in the first 48 hours. G As a rule, the earlier the onset of seizures the worse is the prognosis insofar as mortality and neurologic sequelae are concerned. Etiologic Classification

The causes of neonatal seizures are listed in groups in Table 1. Despite all efforts, the etiology of neonatal scizurcs remains unknown in approximately one-fourth of all patients. More than 5 0 % of the patients with neonatal seizures of unknown cause will recover and will have no scquelae. It sometimes is very difficult, if not impossible, to know the prognosis when the ctiology of seizures has not been discovered. T A B L E I.---CAUSES OF NEONATAL SEIZURES

Congenital disorders and mal/ormations

Metabolic and electrolyte disorders

Hypoglycemia Hypocalcemia Hypomagnesemia Pyridoxine dependency Hypernatremia Hyponatremia

Cerebral: Tuberous sclerosis Microgyria and micropolygyria Porencephaly Hydrocephaly and hydranencephaly Agenesis or hypoplasia of lobes, corpus, etc. Holoprosencephaly Heterotopia Megalencephaly Angioma Sturge-Weber angiomatosis Cardiac: Cyanotic congenital heart disease

Toxic disorders

Uremia Bilirubin encephalopathy Drug withdrawal

Narcotics Sedatives Infections

Bacterial meningitis Acute viral meningoencephalitis Congenital toxoplasmosis Congenital rubella Congenital syphilis

Inherited disorders of tnetabolism

Aminoacidurias Leukodystrophies and lipidosis

Trattma at birth

Intracranial hemorrhage: Subarachnoid Subdural Intracerebral lntraventricular Hypoxic or asphyxic encephalopathy Inadvertent injection of local anesthetic

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METABOLIC:AND ELECTROLYTEDISORDERs.--Hypoglycemia.----Itis conventionally accepted that blood glucose values less than 30 mg./100 ml. in the newly born infant of full si~:e (more than 2,500 Gm.) and less than 20 mg./100 ml. in the low-birth-weight infant (less than 2,500 Gm.) indicate hypoglycemia. In additionto convulsions, symptoms of neonatal hypoglycemia can include apnea, irritability or apathy, drowsiness, reluctance to feed, hypotonia, cyanosis and weak or high-pitched cry. However, these symptoms are not pathognomonic of hypoglycemia, and they are not present in all infants with this disorder as defined by the blood glucose values. Griffiths 7 measured blood glucose in 1,000 infants admitted to a special-care unit because of birth weight less than 2,000 Gm. or because of illness and concluded that the symptoms attributable to hypoglycemia were no more frequent in infants with blood glucose values less than 20 mg./100 ml. than in those with normal values. Furthermore, many infants with low blood glucose values were found, at autopsy, to have had an acceptable cause of death other than hypoglycemia. Nevertheless, because it frequently is associated with seizures in the first few days of life and because of the danger that it may cause a serious encephalopathy with permanent sequelae, the possibility of hypoglycemia in the newborn should not be overlooked. A causal relationship between hypoglycemia and seizures is suggested by prompt relief of symptoms after intravenous injection of glucose. For this purpose, 5-10 ml. of a 20-30% solution of glucose in water is administered intravenously after a blood specimen has been taken for determination of the glucose value. If the symptoms disappear, intravenous infusion of 15-20% glucose solution should be continued. When a diagnosis of hypoglycemic convulsions in a neonate has been established, the cause of the hypoglycemia should be sought. Transient hypoglycemia can occur in an infant born of a diabetic mother. Hypoglycemia also may be due to a metabolic disorder-such as hepatorenal glycogenosis (glucose-6-phosphatase deficiency), galactosemia, fructose intolerance or failure to release epinephrine-or to increased secretion of insulin, as in infants with leucine-induced hypoglycemia, or, more rarely, an insulin-secreting adenoma of the pancreas. Glycogen depletion may be the result of glycogen synthetase deficiency, congenital hepatitis, intrauterine anoxia, starvation or hypothermia. Hypoglycemia also can occur in infants delivered by cesarean section, in infants having adrenogenital syndrome, adrenal hemorrhage, or other causes of adrenal insufficiency, and in infants with hypopituitarism or hypothyroidism. Often, however, the cause is not known. Hypocalcemia.--When the serum concentration of ionic calcium falls below 3 mg./100 ml., tetany (peripheral muscle spasms) or true convulsions (generalized, unilateral or focal) occur. Since determina-

tion of ionized calcium concentration is difficult, the total serum calcium concentration usually is measured; in this case, 7.0 mg./100 ml. should be considered the lower limit of normal. Because it can be measured more rapidly, the serum phosphate content has been used to obtain an indirect clue when hypocalcemia is suspected. Low serum calcium may result from maternal hyperparathyroidism, hypoparathyroidism of the infant or renal insufficiency or as a complication of hypernatremia or hypokalemia. It sometimes complicates the effects of maternal diabetes, pre-eclamptic toxemia and difficult labor or delivery. Rose and Lombroso6 found hypocalcemia to be the most common of the known causes of neonatal seizures and that convulsions resulting from hypocalcemia occurred most frequently between the fourth and seventh days of life but also during the sccond week of life. Hypocalcemia should be corrected by slow intravenous infusion of calcium gluconate (2-6 ml. of a 2.5-5% solution). For patients who have convulsions in association with hypocalcemia, the prognosis is excellent if there are no other complicating factors. Hypomagnesemia.--If convulsions or tetany is not alleviated by the intravenous administration of calcium gluconate, the possibility of hypomagnesemia should be considered. Hypomagnesemia may result from primary hypoparathyroidism, from maternal hyperparathyroidism causing secondary hypoparathyroidism, from impaired absorption of magnesium through the intestinal wall, from excessive serum phosphate concentration or from renal disease. The serum magnesium concentration is less than 1.2 mg./100 ml. and may be as low as 0.5 mg./100 ml. An intravenous injection of a 2-5% solution of magnesium sulfate to a total dose of 20-50 mg./kg, may relieve the symptoms of tetany or convulsions. However, cessation of symptoms after such an injection does not conclusively establish a diagnosis of hypomagnesemia, since this treatment may also relieve the symptoms caused by hypocalcemia. Pyridoxble dependency.----This disorder affects the central nervous system exclusively and is characterized by seizures during intake and excretion of pyridoxine in amounts usually considered to be normal and with normal tryptophan metabolism; seizures are eliminated when larger doses of pyridoxine are administered. Pyridoxal phosphate acts as the coenzyme of glutamic decarboxylase for removal of the alpha carboxyl group from glutamic acid to form y-aminobutyric acid (GABA), a reaction that is unique to the central nervous system. Pyridoxine antagonists such as methoxypyridoxine can produce seizures, probably by decreasing the levels of GABA, although otherwise normal humans or animals may exhibit seizures if pyridoxine is deficient in their diet. The metabolic defect responsible for pyridoxine dependency, however, is not known. Pyridoxine-dependent patients who have become seizure-free with small 7

daily supplements of pyridoxine may have seizures again within 24-36 hours after the extra amounts of this vitamin are discontinued. Rapid diminution of abnormalities in the electroencephalogram after intravenous or intramuscular administration of pyridoxine and the clinical effectiveness of sustained oral therapy support the contention that mechanisms for absorption and metabolism of pyridoxine are not disturbed. Administration of 50 mg. of pyridoxine hydrochloride intravenously will stop seizures in neonates who have this disorder. Monitoring the electroencephalogram dui'ing this diagnostic procedure provides additional objective documentation of the results. Pyridoxine deficiency also may cause seizures, as exemplified by an outbreak of convulsions in infants, some years ago, after they had been fed an artificial formula deficient in pyridoxine. This cause of seizures is now rare. Hypernatremia.---Hypernatremia in infancy may be associated with seizures. The disorder follows excessive water loss, decreased water intake or excessive salt intake. The principal manifestations include irritability, lethargy, diminished muscle stretch reflexes, stupor or coma and generalized muscular rigidity. In a survey of 339 infants with acute gastroenteritis,s 63% of those clinically dehydrated had hypernatremia (serum sodium more than 150 mEq./L.), 32% were normonatremic and 5% were hyponatremic (serum sodium less than 130 mEq./L.). Neurologic damage associated with seizures is the most serious effect of hypernatremia. The usual onset of convulsions is in the first 48 hours after admission to the hospital and initiation of treatment with intravenous fluids. The mechanism responsible for seizures, therefore, may not be the hypernatremia per se but the rapid dilution of the hypertonic extracellular fluid and resultant shift of water into the hypertonic cells. Ironside et al. 8 claimed that rehydrating affected infants by administering fluids orally rather than intravenously decreased the incidence of seizures to 6% in their patients as compared to 30% in other series. They attributed the lower incidence of convulsions to the less rapid changes in intracellular osmolality. Therefore, the primary treatment--correction of the electrolyte imbalance--should be accomplished slowly. Anticonvulsant drugs, calcium gluconate or magnesium sulfate also may be necessary adjuncts. Hyponatremia.--Excessive intake of water orally, by enema, or parenterally, decreased intake of sodium (intravenously administered hypotonie fluids) or loss of sodium due to diarrhea or water retention may cause hyponatremia. Manifestations include convulsions, drowsinrss, irritability and stupor or coma. Primary treatment consists of correcting the electrolyte imbalance by administering saline intravenously. If necessary, anticonvulsant medication may be used also.

Toxic DlSORDERS.--Uremia.--Bilateral renal agenesis, renal dysplasia or acquired renal disease may result in neonatal uremia associated with convulsions. Symptomatic therapy for the seizures will be of little value unless the uremia can be corrected. Rapid hemodialysis therapy itself may be complicated by the dialysis disequilibrium syndrome, in which seizures are a component. Bilirubin encephalopathy.--Kernicterus due to hemolytic disease of the newborn is associated with convulsions in the more severely affected infants. Jaundice, irritability, hypotonia and hyporeflexia or rigidity and opisthotonos, high-pitched cry and hyperpyrexia also may occur; these symptoms usually precede the seizures. Prevention of hyperbilirubinemia is of utmost importance but will not be considered here. DRUo WITHDRAWAL.--Vqqlenthe mother is physically dependent on morphine, heroin, opium, barbiturates or other addicting drugs during pregnancy, the newborn infant, if not treated, may experience a withdrawal reaction. Such infants are restless, indefatigable, irritable, flushed, tremulous and hyperpyrexic. They have a sharp, prolonged, high-pitched cry and, because of their hyperactivity, the skin of their heels, knees, chin or nose often is eroded. They suck vigorously as if very hungry, but attempts to feed are ineffectual. They often yawn, sneeze, become dyspneic or apneic, regurgitate or vomit and convulse. If addiction has been mild, the symptoms subside within 3-6 days but when the condition is severe and untreated there is a steady progression to death from dehydration and circulatory collapse. In severe narcotic withdrawal, the mortality is 90% for untreated infants. The syndrome often goes unrecognized, since the symptoms resemble those from diverse diseases such as hypoglycemia, hypocalcemia, acute meningitis or encephalitis, generalized sepsis, adrenal insufficiency or neonatal thyrotoxicosis. --" Treatment of narcotic withdrawal consists of administering a small amount of the narcotic to which the mother has been addicted. For example, an opiate may be given in the form of paregoric, starting with 5 drops every 4 hours and gradually increasing to 20 drops every 4 hours until the infant becomes calm, his temperature becomes normal and he eats and sleeps well. After 1-3 weeks of treatment, the paregoric is gradually withdrawn over a period of several weeks. Barbiturates or diazepam may be used along with the paregoric. iNFECTIONS.--Bacterial meningitis.--Acute purulent meningitis in infants may be heralded by a focal or a generalized convulsion in the absence of fever or signs of meningeal reaction. A bulging or tense anterior fontanelle or a high-pitched cry may be the only clinical finding to suggest the ~disease. Even if such manifestations are absent, the diagnosis can be made by early examination of the cerebrospinal fluid. In the neonate, acute purulent meningitis often is caused by gramnegative bacilli, Listeria monocytogenes or pneumococci. Escherichia 9

cull is by far the most common agent. Infections acquired after operations involving the nervous system, however, can be caused by species of Staphylococcus, Pseudomonas, Aerobacter or Alcaligenes. The physician must be alert to the possibility of these infections and ready to institute immediate treatment with an antibiotic appropriate to the type of organism. Acute viral meningoencephalitis.---A number of infections can be transmitted from mother to infant before or during delivery. Transplacental transmission of virus has been demonstrated for rubella, cytomegalovirus disease, rubeola, mumps, Western equine and Eastern equine encephalitis, acute anterior poliomyelitis, Coxsackie B infections, herpes simplex, chickenpox, smallpox, vaccinia, hepatitis and influenza. Dermal inoculation is another mode of transmission as the infant passes through the birth canal. Herpes simplex infection can be acquired this way and frequently is accompanied by seizures. If the infant survives, severe sequelae include mental retardation and microcephaly. Eastern or Western equine encephalitis also may be the cause of protracted seizures and similar serious consequences. Congenital toxoplasmosis. Toxoplasmosis in the neonate may be manifested by seizures, central chorioretinitis, hydrocephaly or microcephaly. At a later stage, mental retardation and intracranial calcification also occur. Congenital syphilis.--This disease has become prevalent again in the past 15 years, due to an increased incidence of maternal infection among teen-agers. Seizures can be the most significant manifestation of congenital syphilis. Other manifestations are microcephaly, hypotonia, respiratory distress, coryza, petechiae and thrombocytopenia. Penicillin is the preferred treatment for the disease, with anticonvulsants for the control of seizures. TRAUMA AT BIRTH.----Seizures associated with intracranial bleeding, asphyxia neonatorum or both usually appear in the first or second day; within the period of infancy, they rarely occur later than the first week after birth. CraigS studied a group of 374 infants who convulsed within the first 10 days of life and found "acquired noninfectious intracranial pathology" at autopsy in 97 of 158 infants who died. Autopsy findings included subdural, subarachnoid, intraventricular and intracerebral hemorrhage. Only one-fourth of the infants who survived hypoxia or intracranial hemorrhage during birth were subject to neonatal seizures. The long-term prognosis after nonfatal asphyxia or other acquired noninfectious intracranial diseases was worse for infants who also had seizures than for those without associated seizures. The sequence of events leading to convulsions often is difficult to determine when an infant has suffered asphyxia at birth and intracranial bleeding later or vice versa. Sometimes pregnancy, labor and delivery have been normal according to all available information but 10

the infant suddenly develops generalized or focal seizures. In one report, 6 9 infants who exhibited focal seizures on the second day after birth w e r e presumed to have "primary subarachnoid hemorrhage"; the cerebrospinal fluid initially was bloody, was xanthochromic after centrifugation and contained more than 250 mg. of protein per 100 ml. The prognosis was good. Seizures associated with cerebral trauma incurred during a complicated delivery have a much worse prognosis. External signs of trauma include scalp or facial bruises or a cephalohematoma. Respiration may be depressed, the cry may be weak or absent and there may be signs of circulatory collapse. Roentgenograms may disclose a fracture of the skull. The electroencephalogram often demonstrates a focal origin of the seizures. A bul~ng anterior fontanelle may arouse suspicion of a subdural hemorrhage, a lesion that can be diagnosed by subdural puncture. Hypoxia resulting from prolonged labor or delivery, from pelvic, placental or umbilical cord abnormalities or from other causes sometimes is associated with seizures in the first or second day of life. If the infant survives, severe mental and motor deficits are likely, although the full extent of the damage may not be recognized until many years later. An unusual cause of neonatal convulsions is injection of anesthetic into the fetal head through the anterior fontanelle by a misdirected needle or catheter, a complication of maternal caudal anesthesia. This syndrome was reported by Sinclairet al. 9 in 4 infants who exhibited apnea, bradycardia and convulsions shortly after birth. In each instance, the mother had not obtained the desired anesthetic effect, and each infant had a visible puncture mark in the scalp. Two infants who received exchange transfusion survived and had no sequelae. High levels of the anesthetic were demonstra(ed in brain and liver of the 2 who died. CONGENITAL DISORDERS AND MALFORMATIONS.--Cerebral.--Malformations of the central nervous system are the next most frequent cause of neonatal seizures after birth trauma and neonatal infections and, at least in one series, after hypocalcemia. 6 Any type of developmental anomaly of the brain may be associated with seizures in the neonatal period. Tuberous sclerosis is recognized by the characteristic achromic patches found on the infant's skin, either by direct inspection or with the aid of an ultraviolet lamp ("white-ash" sign) or by retinal phakomas of the ocular fundi. Seizures of the massive myoclonic type, infantile spasms or other types of seizures often are the earliest manifestation of tuberous sclerosis. Microgyria, polymicrogyria, pachygyria, lissencephaly, heterotopic islands of nerve cells and agenesis or hypoplasia of cerebral lobes sometimes are discovered at autopsy. Agenesis of the corpus callosum may be demonstrated by pneumography. Porencephaly sometimes |1

may be diagnosed by simple transillumination of the head with a flashlight; at other times, pneumography is necessary. Megalencephaly, hydrocephaly and hydranencephaly causing enlargement of the head are differentiated from one another by the same technics. Holoprosencephaly and other defects of prosencephalic cleavage are recognized when there are medial facial defects varying from a proboscislike nose (cebocephaly) to a pointed forehead and hypotelorism (trigonocephaly). Congenital intracranial angiomatous malformations, either venous, arterial or arteriovenous, may be present many years before seizures of focal origin appear. Focal motor seizures with secondary generalization may occur in infants but seldom in neonates. Sturge-Weber trigeminal angiomatosis should be suspected as the cause of seizures when a facial nevus flammeus is present in the distribution of the ophthalmic division of the trigeminal nerve. The electroencephalographic abnormalities associated with congenital cerebral malformations and acquired lesions are numerous and varied. In general, the changes result from disturbance of viable neurons and depend on concurrent spatial, temporal and biodynamic factors. '~ No specific changes exist for each type of lesion. At this point, merely one illustration (Fig. 1 ) will serve to exemplify the severe and complex changes that can occur. As pointed out by DeMyer and White, 1' one of the more characteristic electroencephalograms occurs with the frontal-everted type of holoprosencephaly. Cardiac.--In infants with congenital heart disease, episodes of apnea with cyanosis may be mistaken for seizures and vice versa. In patients with cyanotic congenital heart disease, however, intracranial venous thrombosis may result in seizures. INHERITED DISORDERS OF ..METABOLISM.------In addition to the inherited disorders causing hypoglycemia and pyridoxine dependency mentioned above, other inborn errors of metabolism involving amino acids and lipids may be associated with convulsions. Aminoacidurias.--Feeding difficulties and shrillness of cry at the end of the first week of life constitute the initial manifestations of maple syrup urhle disease. These symptoms are followed by convulsions, hypotonia alternating with hypertonia, respiratory disturbances and loss of Moro and muscle stretch reflexes. The untreated patient becomes" comatose and dies shortly after the first week of life. The disease can be suspected by the characteristic odor of the urine and sweat, which has been described as sweet, caramel-like or like maple syrup. The ketoacid excretion in the urine may be detected with the reagent .2,4-dinitrophenylhydrazine. A precise diagnosis is made by quantitative determination of the plasma amino acids. Treatment consists of a synthetic diet of amino acids excluding methionine, leucine, isoleucine and valine. Glycinosis or hyperglycemia.---With this inborn error of amino acid 12

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metabolism, seizures occur during the first or second postnatal day and are followed by hypotonia, drowsiness, loss of Moro reflex, respiratory arrest and death after 1 week. The disorder resembles maple syrup urine disease except for the characteristic odor. The urine gives a positive test for ketones. The plasma glycine level is 15-20 times higher than in normal infants, but other amino acid blood values as well as serum calcium and glucose are normal. Phenylketonuria.--Seizures also occur in this condition but usually not in neonatal life.

The Electroencephalogram Adequate recordings may be difficult to obtain from neonates and especially under the environmental conditions necessary for premature infants. Good results depend on the services of a technologist with special experience in handling these patients. Furthermore, interpretation of the tracings is more difficult than for other age groups and requires the expert judgment of a well-trained and experienced

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electroencephalographer. The normal electrographic patterns in the first month of life are vastly different from those that develop in the course of normal maturation (Table 2). Because some of these patterns have features that would be considered abnormal if recorded from an older child, the risks of faulty interpretation are high. As one example, apparently "epileptiform" multifocal sharp waves in the recordings of normal premature neonates during sleep frequently are not associated with subsequent seizures or permanent neurologic deficit. Another example is the "trac6 alternant" pattern, a normal pattern during sleep in neonates, which resembles but should not be mistaken for the highly abnormal "burst-suppression" pattern associated with severe and diffuse cerebral dysfunction at older ages. Interictal epileptiform abnormalities differ from those found in older children or adults, since they can be generated only after a critiFro. 3.--Transient EEG abnormalities with neonatal seizures of unknown cause. Bilateral independent sharp-wave foci in upper tracings at age 11 days are no longer present in lower tracings recorded from the same infant at age 3 months. Age: I I days, tonic seizure~.; Otda~

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cal level of cerebral maturation has been reached. Thus, well-formed and widely synchronized spike-wave discharges are rarely recorded during the first year of life. The ictal patterns in the EEG during infancy are as unique as the clinical seizure manifestations described above. Moreover, the temporal and anatomic relationships between the clinical and electrographic ictal events frequently are complex, unusual and apparently discordant, in contrast to the precise relationships that develop later. A focal seizure discharge in the EEG may migrate slowly from one region to another in one hemisphere or back and forth from one hemisphere to another over long periods. During this slowly migrating, or "errant," discharge there may be no behavioral change, or motor manifestations of the seizure may appear to be originating from the contralateral cerebral hemisphere (Fig. 2). The EEG can be most helpful if it is obtained during the seizure. Recordings made between attacks, however, frequently may be useful for diagnosis when the nature of the clinical expression is in doubt. The EEG reflects the electrical manifestations of cerebral dysfunction but the EEG patterns do not indicate a specific disease or a specific type of lesion. In our experience with neonatal seizures, the most frequent causes have been electrolyte or metabolic disturbances and congenital malformations of the brain. Transient focal abnormalities in the EEG (Figs. 3 and 4) often occur with systemic disorders affecting the brain diffusely or from unknown causes, and the abnormalities may not signify a permanent structural lesion. F o r this reason, recordings made subsequently are important for assessing the ultimate cerebral deficit or dysfunction that may persist. Treatment

Treatment of neonatal seizures should be directed primarily to the underlying cause whenever possible and should be instituted as quickly as possible if the cause is a metabolic disturbance, such as hypoglycemia, that may result in permanent cerebral damage. Symptomatic treatment for the seizures is less urgent. When the seizures are infrequent, there is enough time to follow an organized plan for determining the etiology of the seizures before an anticonvulsant drug is administered. If the seizures are prolonged, repetitive and severe or associated with apnea and cyanosis, however, it is important to proceed rapidly to stop them. The following steps may be taken as a general guide for etiologic diagnosis and therapy of neonatal seizures, but modifications will be necessary to suit the individual circumstances. 1. Obtain the history and examine the patient expeditiously while arrangements are made for an EEG. 2. Obtain a blood sample for blood glucose, serum calcium and mag18

nesium and, if indicated, serum sodium determinations. Obtain a sample of cerebrospinal fluid for microscopic examination of cell content, for analysis of glucose and protein content and for culture. 3. Administer 5 ml. of 25% glucose in water intravenously. If seizures and other symptoms continue, hypoglycemia is not the cause. 4. Administer calcium gluconate (2.5% solution) intravenously very slowly, while monitoring the EEG when possible. If seizures or tetany continues, hypocalcemia is excluded as the cause. 5. Slowly administer magnesium sulfate (2% solution), 20-50 mg./kg., intravenously. If seizures or tetany disappears, hypomagnesemia can be provisionally proposed as the cause until the serum magnesium value is known. 6. Administer 50 mg. of pyridoxine hydrochloride intravenously, if possible while the EEG is being recorded. If there is no clinical or EEG change, the infant does not have pyridoxine dependency. 7. If seizures continue despite the measures described above, begin symptomatic treatment with diazepam, 0.5-2.5 mg. slowly administered intravenously. Adequate provisions should be at hand for assisted respiration if needed. 8. If seizures still continue, sodium phenobarbital, 7-10 mg./kg., should be given intravenously very slowly until the attacks stop. 9. After the seizures have been stopped, phenobarbital is given intramuscularly at regular intervals to prevent further convulsions. A dose of 15 mg. given every 4-6 hours usually is sufficient. Excessive somnolence indicates the need for decreasing the dose. 10. Continued proper care is important to prevent aspiration, to maintain an open airway and to avoid dehydration or overhydration. 11. Prophylactic treatment with anticonvulsants given orally should be instituted as soon as the infant is able to take feedings. Phenobarbital is the anticonvulsant of choice in the majority of situations. Diazepam or nitrazepam may be tried if the patient has myoclonic seizures not controlled by phenobarbital.

Prognosis About 14% of neonates with seizures die within 18 months. ~ Of the survivors, 7 . 5 - 8 % will have physical handicaps, mental handicaps or both by the age of 3 yearsP The most c o m m o n sequelae, in order of frequency, are mental retardation, spastic paralysis and continued seizures. Status epilepticus in infants has a very serious prognosis. Aicardi and Chevrie lz have shown that the patient's age at the time of status epilepticus has prognostic significance: younger infants have a greater incidence of neurologic sequelae. B. INFANTILE SPASMS According to current common usage, the term "infantile spasm" is applied to a type of seizure peculiar to infancy and early childhood. This type of seizure should be clearly distinguished from the noncon19

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Onset ger~rotized MlOCIOnlCS~ureS Oge 2mos - about 8per day No change in EEG alter pyridoxine injection Has muffJple ocheomic porches PEG ( 1 2 - 2 4 - 6 9 ) evidence of tuberous sclerosis

FIG. 5.--EEG with pattern of hypsarhythmia from 7-month-old boy with tuberous sclerosis.

vulsive muscular contractions of tetany or tetanospasm. The first published description we know of was by W. J. West in 1841. H e wrote a letter to Lancet 13 describing the seizures of his son, which Sir Charles Clarke had previously recognized and proposed to call "salaam convulsions." Today, these seizures are known in the American pediatric literature as infantile spasms, although many other names are used: lightning attacks, flexion spasms, massive myoclonie seizures, jackknife seizures and minor motor seizures. These names are not synonymous from a descriptive standpoint, however, nor are the conditions necessarily identical in physiopathogenesis or prognosis. Because identical implications have not been definitely established, two groups will be distinguished here: (1) true infantile spasms and (2) global or massive myoclonic seizures. True infantile spasms are characterized by tonic flexion or extension of the head or trunk as the upper extremities abduct and fling forward and the lower extremities flex at the hips and knees. They last longer than typical myoclonie jerks, usually more than 1 second. They occur repetitively in clusters of about 2 - 1 0 0 at irregular intervals of about 2 - 1 0 seconds. The spasm is bilateral and generally symmetric. During the attack, the E E G shows a sudden generalized decrement of activity, often associated with low-amplitude fast rhythms. Between 20

attacks, the EEG usually contains severe abnormalities almost continuously and consisting of randomly distributed high-amplitude slow waves, diffuse sporadic multifocal spike activity and brief generalized spike-wave complexes. This highly abnormal pattern is called hypsarhythmia (Fig. 5). Infantile spasms associated with hypsarhythmia constitute a characteristic syndrome that may be caused by different diseases. The seizures are the first symptom during the first year of life, commonly between the fourth and seventh months. Most patients with this clinical-electrographic syndrome fail to progress normally or have complete arrest of psychomotor development. The hypsarhythmia pattern is almost always altered by age 5 or 6 years. Global o r massive myoclonic seizures affect the entire body and are characterized by sudden flexion of the head, trunk and extremities, lasting a fraction of a second. Sometimes they are precipitated by sensory stimulation such as sound or touch and have a tendency to occur repetitively but at irregular intervals. The EEG usually demonstrates generalized bisynchronous spike-wave or polyspike-wave complexes of high amplitude associated with the movements. Massive myoclonic seizures often occur with infantile spasms and hypsarhythmia in the same infant, indicating severe encephalopathy with poor prognosis; however, the massive myoclonic attacks may occur separately or with other kinds of seizures and interictal EEG patterns. In published reports, the terms "infantile spasms" and "massive myoclonic seizures" have been used interchangeably; or both types of attacks, and also atonic and akinetic seizures, have beengrouped toTABLE 3.--DISORDERSWITHINFANTILESPASMSANDHYPSARHYTHMIA Metabolic disorders

Phenylketonuria Maple syrup urine disease Hyperornithemia Pyridoxinedependency Leucine-sensitivehypoglycemia Gangliosidosis (GM2) or Tay-Sachsinfantilefamilialamauroticidiocy Congenital anomalies Tuberous sclerosis Microgyria Down's syndrome(mongolism) Trigeminal angiomatosis(Sturge-Webersyndrome) Agenesisof part of brain Acquired encephalopatMes Hypoxic Ischemic Traumatic (for example, subdural hematoma) Hypoglycemic Infectious (for example,viral encephalitis) Pertussis immunization 21

gether under the more general term "minor motor seizures." However, too broad a categorization may blur distinctions among several subgroups with possibly different causes, different responses to therapy and different prognostic implications. For this reason, we prefer to distinguish, descriptively at least, the clinical and electrographic features of these attacks. Etiology In 1883, Fdrd 14 correctly pointed out that infantile spasm, which he called "tic de salaam," is just a symptom, as are all other seizure types. He classified infantile spasms as "symptomatic" or "idiopathic" (really meaning cryptogenic). At present, the etiology can be established as presumptively determined for only about half of the patients with this clinical-electrographic syndrome of infantile spasms and hypsarhythmia. Table 3 lists disorders found with the syndrome. As more patients with the syndrome are studied carefully and followed longer, the proportion with known etiology is becoming larger. Tuberous sclerosis sccms to be the most common cause and is found in as many as 20% of these patients. Trealment When the cause is known, the treatment should be directed to eliminate it if at all possible. For instance, in the case of phenylketonuria it may be possible to eliminate the infantile spasms by decreasing the amount of phenylalanine in the diet. However, in the majority of the patients the treatment will be strictly symptomatic. Since the introduction of the use of A C T H in the treatment of infantile spasms by Sorel and Dusaucy-Bauloye, 1~ many series of patients with infantile spasms haveebeen reported. Unfortunately, there has been poor selection due to inadequate discrimination of the seizure type in some of the reports, making the results difficult if not impossible to interpret. It was pointed out in the original paper 1~ that patients treated within 1 week after the onset of infantile spasms no longer had seizures and continued to have normal mental and physical development. In each series there were few patients treated with A C T H within a week after the onset of the infantile spasms. Although the seizures frequently can be brought under control, with the EEG showing disappearance of the electrodecremental seizures and the interictal hypsarhythmia, only a small percentage of patients will have normal intelligence. Recently, Jeavons, Harper and Bower ~6 reported their follow-up study of children who had had infantile spasms and were followed for a period of at least 4 years. Of the 98 patients, 18 died, mostly before the age of 4 years. Of the 80 survivors, only 9 still had spasms but nearly two-thirds had other types of seizures and only one-third were 22

seizure-free at the time of the follow-up. The EEG was normal in 50% of 68 children examined at follow-up; only 3 still showed hypsarhythmia and the remainder showed other bilateral or focal abnormalities. Of the 98 patients, only 13 were regarded as being of normal intelligence; 6 were mildly retarded, 20 were moderately retarded and 41 were severely retarded. Of the 14 patients who were attending regular schools (all were between 7 and 13 years of age), 2 had hemiparesis and 1 had some unspecified neurologic abnormality ("minimal brain damage"). Of these 14, 4 had been treated with ACTH, 3 with dexamethasone and 4 with chlortetracycline; 2 had received no treatment. Jeavons and collaborators 16 concluded that steroids and ACTH have no significant effect on intelligence but, because this treatment has a beneficial although temporary effect on the infantile spasms and the hypsarhythmia, they recommend it. A previous study by Snyder17 indicated that 29% of patients treated with steroids have an IQ of 90 or more, compared with only 10% of the untreated patients. On the basis of our present knowledge, we give ACTH intramuscularly or steroids orally to treat an infant who, having progressed normally during the first 3 or 4 months of life, develops infantile spasms following pertussis immunization or for no known reason. An EEG should be obtained before treatment and again about 1 week after initiation of treatment. The treatment should be continued for 6 weeks and then gradually tapered off; the EEG should be repeated. If seizures of another type occur, the patient should be treated with phenobarbital or some other anticonvulsant. Nitrazepam (Mogadon) is an extremely effective anticonvulsant in infantile spasms and myoclonic seizures. Unfortunately, this drug is not commercially available in the Unite_d States. Phenobarbital, metharbital and diazepam are the anticonvulsants one could choose instead.

Prognosis The etiology of the syndrome appears to be significant in regard to prognosis. In Jeavons and co-workers' series, 16 there were 13 patients who had had infantile spasms attributed to immunization reaction and, of these, 5 were attending schools for normal children. Similarly, of the 28 in t h e cryptogenic group, 9 were attending schools for normal children. The etiologic groups also included infants who had suffered perinatal damage or had congenital malformations, tuberous sclerosis, metabolic disorders, etc. All of these patients had died or were mentally retarded. What may be the effect of frequent generalized epileptic seizures and, in particular, infantile spasms on the development of the central nervous system? Without knowing the etiology of their seizures or the pre-epileptic condition of the patient's brain, one can only speculate 23

about the possible disturbance of the many complex maturational processes occurring at the time. Lacking definitive evidence, it seems reasonable to attempt to control seizures at this early stage of development as quickly and as completely as possible. Hopefully, future research will determine whether or not single or repeated transient insults to the brain from seizures in infancy are related to mental or other neurologic deficit in later childhood. C. FEBRILE SEIZURES About 2% of all children under 5 years of age have seizures when their body temperature increases in the course of an acute illness, z The usual age at onset of these seizures associated with fever is between 18 months and 2 years. Approximately 97% of children who have onset of convulsions, during a febrile episode, before age 5 years are free of seizures in later life. z Although there is no good basis for making a clinical entity of seizures precipitated by fever, for convenience, the term "febrile seizures" is widely used at present. However, one must be careful in evaluating the relationship between fever and convulsions before accepting fever as the sole precipitating cause. One must keep in mind that generalized convulsions of the tonic-clonic type may cause hyperthermia, that acute illnesses affecting the central nervous system (such as purulent meningitis and viral encephalitis) may be manifested by fever and pyrexia before other symptoms appear and that hypernatremic dehydration may be the cause of both seizures and fever (hypernatremic encephalopathy).

Incidence In a prospective studyz of 18,500 unselected children followed from birth in Oakland, California, 2% had one or more "febrile convulsions" by age 5 years. In a retrospective studyTM in the smaller community of Rochester, Minnesota, the annual incidence rate based on the earliest recognized febrile convulsion was 4 per 1,000 children under 5 years of age. In both studies, the peak incidence occurred in the second year of life. In Rochester, almost 1% of children experienced a convulsion with fever during the second year of life. Recurrent seizures with fever occurred in one-third of the children in Oakland and in almost half of those in Rochester.

Etiology A genetic factor has been proposed by several investigators. In a longitudinal prospective study ~9 of children with "febrile convulsions," approximately 10% of the siblings also had seizures. The studies published in the past 40 years by many authors show incidences of sei24

zures of all types varying between 1.5% and 9 5 % among members of the family of children who had febrile seizures, z~ A more recent study 2a demonstrated that the risk of febrile convulsions is 25.3% for any sort of seizure and 17.9% for febrile seizures in siblings of children with febrile convulsions. The patient's sex has been discussed in the past and apparently overemphasized. The great preponderance of males in some groups of patients reported more than 20 years ago 2z is not supported by more recent studies. In the Oakland study, z 53.3% were boys and 46.7% were girls. The difference is not significant when compared with the sex distribution of the cohort. In the Rochester study, TM males also outnumbered females but, again, the difference was not statistically significant. The birth weight in relation to gestational age is not an important factor in febrile seizures although it is in nonfebrile seizures. 2 The incidence of congenital anomalies of the nervous system is the same in children with febrile seizures as in children without febrile seizures. 2 Children who have seizures without fever, however, have 10 times more congenital anomalies of the nervous system than do children without seizures or children with febrile seizures. The nature of the acute febrile illness precipitating the seizures has no relationship to the development of seizures, with two exceptions: roseola infantum and acute gastroenteritis due to salmonellosis. Bamberger and Matthes z3 of Heidelberg reviewed data from 634 children with seizures precipitated by fever and found the following infections: upper respiratory infection, including "flu," 63.6%; acute gastrointestinal infection, 7.3%; bronchopneumonia, 6.3%; otitis, 3.5% ; pyuria, 2.5% ; postvaccination, 4.1% ; measles, 4.9% ; roseola, 1.4% ; scarlatina, 0.2% ; other, 6.2%. re Roseola infantum (or exanthem subitum) has been incriminated as a cause of the fever precipitating convulsions in 6% of one group of children, z4 2 7 % of another z5 and in nearly 50% of a third group. 26 Other exanthematous diseases may be associated with high fever and convulsions, but one must exercise caution before using the label "febrile seizures" under such conditions because neurologic complications, including convulsions, may appear even before eruption of the rash. The large number of rubeola patients in some series of "febrile seizures" should be looked at with skepticism. The same could be said of Seizures following a febrile reaction after immunization against pertussis or smallpox. The high prevalence of these causes of "febrile seizures" in some series raises doubt about the criteria used for selection. Young patients with acute salmonella infections frequently convulse with high fever. In one report, z7 as many as 42% of patients with this type of illness convulsed when the temperature reached 104.2 F, and 11% convulsed when the temperature was only 100.6 F. 95

Diagnosis Convulsions associated with fever usually are generalized clonic or tonic-clonic. Occasionally they are unilateral, at least at their onset. If they leave the child with hemiparesis, the possibility of a focal brain lesion prior to the seizure or resulting from the illness should be considered. The duration of a febrile seizure may be 1 or 2 minutes, but repeated seizures may occur for several minutes to as long as 1 hour. Long-lasting febrile seizures may produce transient or permanent effects on the cerebral cortex, particularly those areas most susceptible to hypoxic damage. Patients with acquired pathologic changes in the cerebrum as a result of protracted seizures would be excluded from the category of "benign febrile seizures." Attempts have been made to delineate a set of criteria for a distinct group of children with "benign febrile seizures." A decision for inclusion in this group often is difficult at the time of the first convulsion and may be established only retrospectively. A diagnosis of "febrile seizure" should not be made unless the increased temperature has been well documented and an extracranial cause of the fever has been identified. The patient should have complete physical and neurologic examinations. If the cause of the fever cannot be identified, and particularly when the patient has not had a previous febrile seizure, lumbar puncture should be performed even when meningismus, tense anterior fontanelle or other signs of meningitis are absent. If fever previously precipitated convulsions in the patient, the physician still needs to search for the source of infection, but under such circumstances a decision to perform a lumbar puncture is more difficult to make. One should remember that much central nervous system damage can result from purulent meningitis if the disease is not recognized and proper treatment is not instituted promptly. Sometimes a lumbar puncture is necessary even for those patients with recognized extracranial infection, zs since this does not preclude the possibility of an associated meningeal infection. Electroenccphalography is useful for diagnosis and also helps to establish the prognosis. A few general principles will be mentioned for proper utilization of the EEG. First, the recording after a grand mal seizure from any cause will likely contain an excess of generalized slow (delta) waves, and this abnormality may persist for as long as several days. Second, the transient postictal abnormality is indistinguishable from the changes produced by meningoencephalitis. Therefore, the E E G need not be considered an urgent procedure unless baseline documentation is being sought for verification of the convulsive nature of an attack. Recordings from children with uncomplicated "febrile seizures" typically revert to normal within about 1 week. Within that period, the E E G may be useful in the following 26

two main circumstances: (1) to search for focal delta abnormality if brain abscess is suspected or (2) to search for generalized fast (beta) abnormality if drug toxicity is in question. As a third general principle, the EEG performed after the acute illness should be obtained both while the patient is awake and while asleep to search for persisting abnormalities. Abnormalities found at that time, depending on type and topography, may indicate an underlying cerebral lesion antedating the seizure or an aftermath of the acute illness having lasting or subsequent clinical sequelae. For example, paroxysmal epileptiform abnormalities denote the likelihood of recurring seizures without fever. Finally, periodic follow-up EEGs are of immense value for prognosis. If abnormalities have been found, they may later subside or recede. If no abnormalities have been present early, they still may appear after a latent period of several months to several years. Prognosis Recent studies, both prospective2 and retrospective, 19 indicate that 3% of children with febrile seizures later have nonfebrile seizures. This is considerably higher than the prevalence rate for all types of epilepsy, estimatedz9 at 3.7 per 1,000 in the United States population. Treatment A controversy has existed for many years about the need for and efficacy of long-term anticonvulsant therapy to prevent further attacks in the child who has had one febrile seizure. If one accepts the conclusion that febrile seizures are always benign and that they will be outgrown by the time the patient reaches the age of 5 or 6 years, there seems to be little need to attemlS~ prevention of repeated attacks. If these seizures are benign, why risk intoxication with a potentially harmful drug and why undergo the trouble of administering a medication three or four times daily? On the other hand, one also can argue that convulsions are injurious and should be prevented if possible. The convulsing child is exposed to transient respiratory arrest and cerebral hypoxia at a time when fever and increased metabolic rate enhance oxygen requirements. Few would argue against attempting an immediate arrest of status epilepticus by intravenous administration of anticonvulsant medication despite the greater risk of this form of therapy as compared with oral medication. The controversy is about the necessity of prophylactic measures with daily oral administration of medicaments, limited to that age range when the patient is most likely to have febrile seizures. Another argument against an attempt to prevent febrile seizures with daily medication is the concept that anticonvulsants are ineffec27

tual when seizures are precipitated by fever. This concept has not been verified, and present data are inadequate to settle the controversy conclusively. Among the data needed are measurements of blood barbiturate levels at the time of the febrile seizures, or shortly thereafter, in patients who convulsed despite alleged oral administration of phenobarbital. One expression of the feeling of many is that, since the question cannot be answered, "in the present state of knowledge, or lack of it, it appears that treatment is a desirable preventive effort."~0 We recommend continuous rather than intermittent treatment with anticonvulsant medication because (1) fever often comes on too quickly and unexpectedly to allow sufficient time for an anticonvulsant medication given orally to reach the necessary tissue level to prevent a seizure, (2) intermittent administration of an anticonvulsant in effective doses for short periods may favor precipitation of seizures at the time of sudden withdrawal and (3) the intermittent method often fails to be effective, and the failure may lead to unwarranted parental guilt for not having given the medicine on time. This method also may engender the overzealous type of mother who has a neurotic anxiety about the child's temperature. For children under 2 years of age, we recommend daily administration of phenobarbital, given orally in doses of 15 mg. three times each day. The tablets maY be crushed and mixed with food or chewed if the child is incapable of swallowing the unbroken tablets. The dosage may be increased t o 15 mg. four times daily if necessary. Children more than 2 years of age need to take 30 mg. of phenobarbital three or four times daily, although one might start with a smaller dose. The medication should be given until the patient has been seizure-free for at least 2.years. There are several exceptions'to this recommended treatment. When a child becomes hyperactive to the extent that he is intolerable to all other members of his family, it may be better to take the risk of an occasional febrile seizure. Development of an allergic skin rash attended by lymphadenopathy, fever or exanthem requires immediate discontinuation of the drug. Other untoward reactions should be weighed in relation to the febrile seizures. Anticonvulsants more toxic than phenobarbital are not recommended unless the febrile seizures are severe, prolonged or numerous. The risk of inducing serious untoward reactions probably outweighs the advantage of preventing febrile seizures in most instances. Intermittent administration of hydantoins definitely is of no value because too long a time is needed to produce an adequate tissue level of anticonvulsant. In addition to prophylactic administration of phenobarbital, if a fever develops, the patient should be treated with antipyretics and sponged with tepid water or water and alcohol. 28

II. NONCONVULSIVE PAROXYSMAL DISORDERS IN INFANTS AND CHILDREN A. CYANOTIC AND PALLID SYNCOPAL ATTACKS Breath-holding spells (or cyanotic syncopal attacks) and pallid syncopal attacks (or fainting) are paroxysmal disorders frequently brought to the attention of the physician. Differentiation of these spells from true seizures or from other disorders usually is possible by means of the clinical history alone. However, sometimes an inadequate description of the events is given by alarmed and anxious parents, and the attacks may present a diagnostic challenge to the physician. In a group of 150 children with syneopal attacks 30 studied at the Mayo Clinic, 30 children previously had been diagnosed as having seizures. A popular misconception is that breath-holding followed by cyanosis and loss of consciousness usually is a voluntary action of the child to attract attention. This idea has been generally discredited but still gets occasional support from those who claim that the spells are an indication of a "disturbed parent-child relationship. ''3~

Clhlical Description Cyanotic syncopal attacks.---This name is applied to the classic breath-holding spells. Other synonyms are "transient hypoxic crisis type I ''3z and "cyanotic infantile syncope. ''33 The onset is before the age of 18 months in 86% of patients and in the first month of life in about 5%.s~ In our experience, they rarely begin after the age of 3 years. They are provoked by pain, fear or anger. After initial crying, apnea in expiration occurs, usually lasting less than 1 minute. When the period of apnea is long, the child becomes cyanotic and then loses consciousness and becomes limp. After the limp phase, particularly if it is prolonged, opisthotonos or clonic movements of the limbs sometimes occur, simulating a generalized convulsion. There may be incontinence of urine or feces. Before the spell ends there may be another brief limp phase. After a short spell, the child may be somnolent or pale and sweaty or he may be entirely normal. After a prolonged spell, the child may sleep for as long as 4 hours. The frequency of attacks is variable. In general, they are spaced weeks or months apart at first, increase to a peak of one or several attacks per week during the second year of life and then decrease in frequency thereafter. Most often they cease before age 7 or 8 years. Pallid syncopa! attacks.--These attacks often are confused with breath-holding spells and sometimes are mistaken for seizures. They also have been named "transient hypoxic crisis type 11"32 and "pallid infantile syncope. ''33 Pallid syncopal attacks almost always are in29

duced by an unexpected painful stimulus, frequently a blow to the head. Without any cry, the child becomes limp, pale and apneic and loses consciousness. Apnea occurs in expiration as in the cyanotic spells. Expressions such as "the life went Out of him" or "the blood rushed out of his head" have been used to describe and interpret the patient's appearance. Occasionally, an opisthotonic phase follows the limp phase, and clonic movements of the limbs also may be observed at this stage. The age at onset of pallid syncopal attacks is between 6 and 24 months. They increase in frequency during the period when thc child becomes more active and more prone to suffer falls, head trauma and other injuries--that is, around the second birthday. The spells then gradually subside and disappear in almost all cases by age 6 years. In our experience, they start at a somewhat later age and they vanish somewhat earlier than do the cyanotic syncopal attacks. Both kinds, however, may occur in the same patient. A mixed type of syncopal attack, the clinical featurcs of which are a combination of those of the cyanotic and the pallid attacks, is recognized also. It is difficult, if not impossible, to classify it with either of the others.

Etiology A family history of similar spells can be elicited for about one-third of childrcn with the cyanotic type and for about 20% of those with the pallid type of syncopal attacks. Familial predisposition, therefore, seems to play a role. Several hypotheses have been offered for the pathophysiologic mechanisms involved in producing these attacks and for the different clinical manifestations. Polygraphic observations during spontaneous and induced spells indicate that cerebral hypoxia occurs with all types but that vagal, respiratory orecardiac influences may predominate during a single episode. All who have studied these attacks agree that no evidence exists for a convulsive origin and that these attacks do not represent epileptic seizures. Associated anemia may be a contributing factor to the production of cerebral hypoxia.34 Behavior problems, including temper tantrums, hyperkincsia and stubbornness and noted in about 30% of the patients, represent an association of uncertain significance.

Diagnosis The distinction from true seizures can be made easily if the description is adequate or if an attack is observed. Between attacks, neurologic function, mental activity and EEG are typically normal. The EEG recorded during an attack contains no epileptiform abnormality. Early stages are accompanied by generalized delta activity. At the height of the attack, generalized flattening occurs, and another stage with delta activity is usual before complete recovery. Particu30

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larly with the pallid type, the EEG demonstrates early bradycardia progressing to asystole, which may last several seconds; cardiac function is normal between attacks. Ocular compression has been advocated to induce attacks, 3~ with EEG and ECG monitoring (Fig. 6). Other than achieving documentation, the diagnostic value of this procedure is limited. Hypoxic attacks in patients with congenital heart disease also tend to occur in the first 2 years of life. Frequently they are precipitated by crying but also are precipitated by feeding and defecation. They tend to occur in the morning, soon after awakening. They are seen most frequently in patients with tetralogy of Fallot but also occur with tricuspid atrcsia, pulmonary atresia and transposition of the great arteries associated with pulmonary stenosis. The cardiac 31

TABLE

4 . - - A G E AT TERMINATION OF BREATtI-HOLDING SPELLS

AGE (YR.)

CYANOTIC

PALLID

O T I I E R NOT G I V E N

TOTAL

,
2

0

0

0

2

l

5

4

2

1

12

2 3 4 5 6 7

12 13 7 5 4 5

5 8 4 5 0 1

6 2 6 3 0 0

1 3 0 2 0 0

24 26 17 15 4 6

=>8

TOTAL

0

0

0

0

0

53

27

19

7

106

findings permit differentiation of these hypoxic attacks from the more common attacks without cardiac defects.

Prognosis Both cyanotic and pallid syncopal attacks terminate by the seventh or, very exceptionally, the eighth year of life (Table 4). The incidence of neurologic or psychiatric disorders after the spells have ceased is not greater than in the average population.

Treatment Anticonvulsant treatment of either cyanotic or pallid attacks is not indicated. The ineffectiveness and potential hazards of anticonvulsant drugs make a proper diagnosis necessary. Although no specific pharmacologic treatment has been discovered, vagal blocking agents such as atropine may be tried in extreme situations when the patient is subject to numerous or prolonge~d attacks. Frequently the physician's efforts need to be directed toward reassuring and counseling the patient's parents. B. BENIGN PAROXYSMAL VERTIGO Attacks of benign paroxysmal vertigo, often mistaken for seizures, are episodes of pallor, nausea, vertigo and loss of balance lasting 10 seconds to 10 minutes. 36 The onset of this disorder is between ages 1 and 3 years, with the peak incidence between 18 months and 2 years. The patients are bright and healthy prior to the onset of attacks and they continue to be normal between attacks. They develop a fear of the attacks. The results of physical and neurologic examinations and the E E G are normal. Although the audiogram is normal, caloric tests are indicative of a vestibular dysfunction in a great majority of the patients. In a study ~; of 17 patients whose onset of attacks was between 14 32

months and 3 years of age and who were examined when they were between 21,4 and 5 years of age, caloric tests gave abnormal responses either unilaterally or bilaterally in 12. The differential diagnosis of benign paroxysmal vertigo must consider vertiginous seizures and other forms of epilepsy. Ataxia may raise the question of a posterior fossa tumor, but the transient nature of the paroxysmal attacks of vertigo should point to the correct diagnosis. Attacks of vertigo in Meniere's syndrome could present a difficult diagnostic problem. Vertigo is precipitated by motion and there is diminution of hearing acuity in the affected side in Meniere's syndrome; this is a rare disorder in early childhood. The etiology of benign paroxysmal vertigo is not known. No association has been found between upper respiratory or ear infection and this disorder. Cerebrospinal fluid has been studied in a few instances and found to be normal. At least one case has been reported in which attacks of benign paroxysmal vertigo later became typical migrainous attacks. 3s It has been suggested that benign paroxysmal vertigo may be an early manifestation of migraine rather than a form of vestibular neuronitis. 38 Treatment with antivertigo medication on a continuous basis has been said to decrease the intensity and frequency of attacks in those children who have them often. This claim has not been confirmed with an adequate therapeutic trial. The drowsiness that may be produced by the antivertigo drugs is less desirable than the attacks in most situations. C. MIGRAINE Migrainous attacks are not unusual in childhood. Most children with migraine are of school age, but migraine has been recognized retrospectively in children as young as" age 15 months. At an early age, the attacks are either poorly described or not typically migrainous. In a study of 9,000 Swedish children, the incidence of migraine increased from 1% at age 6 years to 5% at age 11 years. 39 Of the migrainous children, 42% had one or more attacks each month, which were severe enough to interfere with the usual activity of the child. Migraine may present as unexplained episodes of nausea and vomiting or with abdominal pain. Cases of paroxysmal episodes of the abdominal pain with or without associated headache, nausea and vomiting sometimes may be difficult diagnostic problems. The name "abdominal epilepsy" has been improperly used as a diagnosis for patients who in reality have "abdominal migraine." Migrainous headaches usually are unilateral, changing from one side to the other; they are throbbing in nature and are associated with anorexia, photophobia, nausea and sometimes vomiting. The patient is relieved of his headache after vomiting, after sleeping for several 33

hours or both. Migrainous attacks sometimes come in clusters and are precipitated by excessive tension or excitement. It is not uncommon that migraine attacks become more frequent and severe when school starts or around times like Christmas or prior to a vacation trip. An alarming symptom of migraine is transient loss of consciousness. The name "basilar migraine ''40 has been given to the variant in which the migrainous headache is associated with cerebellar ataxia, diplopia and ophthalmoplegia, vertigo and tinnitus. In some of these cascs, the diagnosis of migraine is not readily entertained during the first attack. The patient is thought to have an acute encephalitis or some lesion causing increased intracranial pressure. Many unnecessary tests are done on these patients, including neuroroentgenologie studies with contrast material and even trephination for ventriculography. Knowing that a patient suspected to have migraine has one or more immediate relatives with typical migraine facilitates the diagnosis, but one must remember that headaches are common in all sectors of the population and that secondhand information is not always reliable enough to establish a history of migraine in the family. The association Of sensory or motor disturbances, hemianopsia, hemiancsthesia or hemiplegia on the side opposite the headache may raise the question of a seizure disorder with postictal sensory or motor loss. When the headache is persistently on the same side and motor or sensory deficit accompanies the attack, one should keep in mind the possibility of a focal seizure disorder secondary to a vascular malformation. The association of focal seizures and migraine secondary to a vascular malformation is indeed exceptional. 4x The patient with migraine is neurologically normal between attacks but the E E G shows nonspecific and usually nonfocal abnormalities more frequently than in the control population, the percentage varying from about 13% 4z to about 3 0 % . 13 Few recordings have been obtained during migrainous episodes. In our experience, an E E G begun shortly after onset of symptoms may be normal, may show transient asymmetry of background rhythms or may contain varying degrees of lateralized or generalized abnormalities. When present, the abnormalities are not epileptiform. After severe migrainous attacks in children, localized delta abnormality may persist ! or more weeks without evidence of permanent neurologic impairment. In general, the more prolonged and severe the attack and the more pronounced the associated neurologic deficit (such as hemiparesis, dysphasia, paresthcsia or hemianopsia) the more prominent and longer-lasting are the abnormalities in the E E G (Fig. 7). Differential diagnosis includes focal seizures with associated or postictal headache and headache associated with intracranial lesions such as vascular anomalies or tumors. Frequently the diagnosis can be established by the clinical history and physical examination with 34

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,

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the aid of roentgenograms, EEG and echoencephalograms, without resorting to contrast roentgenographic studies. Sequential EEGs are particularly important for documenting a resolving disturbance with migraine or a progressive disturbance with other lesions. Abdominal pain as part of mxgraine needs to be differentiated from the abdominal pain of autonomic or vegetative seizures. Some cases of abdominal migraine have been mistaken for acute appendicitis. The prognosis is good for longevity and neurologic function if migraine is recognized. As part of the treatment, reassurance to both parents and child that the attacks of migraine are benign is perhaps the most helpful form of therapy. Prophylactic treatment with phenobarbital in small doses (30-60 mg. twice daily) for several months is the simplest initial therapy before resorting to drugs with higher 35

risk of u n t o w a r d reaction, such as methysergide and e r g o t a m i n e preparations. F r e q u e n t l y , the p a t t e r n a n d time course will be similar to those established in older m e m b e r s of the patient's family.

Part I I will be published as the M a y issue.

REFERENCES 1. Gastaut, H. (Chairman): Clinical and electroencephalographical classification of epileptic seizures, Epilepsia 11 : 102, 1970. 2. Van den Berg, B. J., and Yerushalmy, J.: Studies on convulsive disorders in young children. I. Incidence of febrile and noufebrile convulsions by age and other factors, Pediat. Res. 3:298, 1969. 3. Tibbles, J. A. R., and Prichard, J. S.: The prognostic value of the electroencephalogram in neonatal convulsions, Pediatrics 35:778, 1965. 4. Ajmone Marsan, C.: A newly proposed classification of epileptic seizures: Neurophysiological basis, Epilepsia 6:275, 1965. 5. Craig, W. S.: Convulsive movements occurring in the first 10 days of life, Arch. Dis. Childhood 35:336, 1960. 6. Rose, A. L., and Lombroso, C. T.: A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up, Pediatrics 45:404, 1970. 7. Griffiths, A. D.: Association of hypoglycaemia with symptoms in the newborn, Arch. Dis. Childhood 43:688, 1968. 8. Ironside, A. G., Tuxford, A. F., and Heyworth, B.: A survey of infantile gastroenteritis, Brit. M. J. 3:20, 1970. 9. Sinclair, J. C., Fox, H. A., Lentz, J. F., Fuld, G. L., and Murphy, J.: Intoxication of the fetus by a local anesthetic: A newly recognized complication of maternal caudal anesthesia, New England J. Med. 273:1173, 1965. 10. Klass, D. W.: Value of the EEG'to the clinician, Neurol. Neurocir. Psiquiat. (Mex.) 11:197, 1970. 11. DeMyer, W., and White, P. T.: EEG in holoprosencephaly (arhinencephaly), Arch. Neurol. 11:507, 1964. 12. Aicardi, J., and Chevrie, J. J.: Convulsive status epilepticus in infants and children: A study of 239 cases, Epilepsia 11 : 187, 1970. 13. West, W. J.: On a peculiar form of infantile convulsions (letter to the editor), Lancet 1:724, 1841. 14. F6r6, C.: Le tic de salaam: Les salutations neuropathiques, Prog. Med. 11:970, 1883. 15. Sorel, L., and Dusaucy-Bauloye, A.: Apropos de 21 cas d'hypsarhythmia de Gibbs: Son traitement spectaculaire par I'ACTH, Acta neurol, et psychiat, belg. 58:130, 1958. 16. Jeavons, P. M., Harper, J. R., and Bower, B. D.: Long-term prognosis in infantile spasms: A follow-up report on 112 cases, Developmental Med. & ChildNeurol. 12:413, 1970. 17. Snyder, C. H.: Infantile spasms: Favorable response to steroid therapy, J.A.M.A. 201:198, 1967. 18. Hauser, W. A., Kudand, L. T., Gomez, M. R., and Elveback, L. R.: Prognosis of patients with febrile convulsions in Rochester, Minnesota, 19451967, Tr. Am. Neurol. A. 95:257, 1970. 36

19. Robb, P.: Epilepsy: A:Review of Basic and Clinical Research (NINDB Monograph 1) (Washington, D. C.: Government Printing Office, 1965). 20. Millichap, J. G.: Febrile Convulsions (New York: The Macmillan Company, 1968). 21. Ounsted, C., Lindsay, J., and Norman, R.: Biological factors in temporal lobe epilepsy, Clin. Dev. Med., no. 22, 1966, 135 pp. 22. Lennox, M. A.: Febrile convulsions in childhood: A clinical and electroencephaJographic study, Am. J. Dis. Child. 78:868, 1949. 23. Bamberger, P. H., and Matthes, A.: AnIiille im Kindesalter (Basel: S. Karger AG, 1959). 24. Greenthal, R. M.: Roseola infantum (exanthem subitum), Wisconsin M. J. 40:25, 1941. 25. M/511er, K. L.: Exanthema subitum and febrile convulsions, Acta paediat. 45:534, 1956. 26. Broberger, O.: Exanthema subitum och feberkramper, Nord. med. 59:523, 1958. 27. Kowlessar, M., and Forbes, G. B.: The febrile convulsion in shigellosis, New England J. Med. 258:520, 1958. 28. Samson, J. H., Apthorp, J., and Finley, A.: Febrile seizures and purulent meningitis, J.A.M.A. 210:1918, 1969. 29. Kurland, L. T.: The incidence and prevalence of convulsive disorders in a 9small urban community, Epilepsia 1: 143, 1959. 30. Hammill, J. F., and Carter, S.: Febrile convulsions, New England J. Med. 274:563, 1966. 31. Laxdal, T., Gomez, M. R., and Reiher, J.: Cyanotic and pallid syncopal attacks in children (breath-holding spells), Developmental Med. & Child Neurol. I 1:755, 1969. 32. Maulsby, R., and Kellaway, P.: Transient Hypoxic Crises in Children, in Kellaway, P., and Petersen, I. (eds.), Neurological and Electroencephalographic Correlative Studies in lnIancy (New York: Grune & Stratton, Inc., 1964). 33. Lombroso, C. T., and Lerman, P.: Breathholding spells (cyanotic and pallid infantile syncope), Pediatrics 39:563, 1967. 34. Holowach, J., and Thurston, D. L.: Breath-holding spells and anemia, New England J. Med. 268:21, 1963. 35. Gastaut, H., and Gastaut, Y.: Electroeri~ephalographic and clinical study of anoxic convulsions in children: Their location within the group of infantile convulsions and their differentiation from epilepsy, Electroencephalog. & Clin. Neurophysiol. 10:607, 1958. 36. Basser, L. S.: Benign paroxysmal vertigo of childhood (a variety of vestibular neuronitis), Brain 87:141, 1964. 37. Koenigsberger, M. R., Chutorian, A. M., Gold, A. P., and Schvey, M. S.: Benign paroxysmal vertigo of childhood (abstract), Neurology 18:301, 1968. 38. Fenichel, G. M.: Migraine as a cause of benign paroxysmal vertigo of childhood, J. Pediat. 71:114, 1967. 39. Bille, B.: Cited by Lance, J. W., Incidence of migraine, frequency of attacks and morbidity, Hemicrania 2:4, 1970. 40. Bickerstaff, E. R.: Basilar artery migraine, Lancet 1:15, 1961. 41. Lees, F.: The migrainous symptoms of cerebral angiomata, J. Neurol., Neurosurg. & Psychiat. n.s.25:45, 1962. 42. Ulett, G. A., Evans, D., and O'Leary, J. L.: Survey of EEG findings in 1,000 patients with chief complaint of headache, Electroencephalog. & Clin. Neurophysiol. 4:463, 1952. 43. Selby, G., and Lance, J. W.: Observations in 500 cases of migraine and allied vascular headache, J. Neurol., Neurosurg. & Psychiat. 23:23, 1960. 37

THE NEXT ISSUE

Part II will be published in May, completing the discussion of Seizures and Other Paroxysmal Disorders in Infants and Children with a review of the diagnosis and treatment of convulsive disorders.

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