Aroxysmal Isorders: Approach To Paroxysmal Disorders

CHAPTER 1
Paroxysmal Disorders
Paroxysmal disorders are characterized by the neurological disease (Silverstein & Jensen, 2007).
sudden onset of neurological dysfunction and Uncontrolled seizures may contribute to further
stereotyped recurrence. In children, such events brain damage. Brain glucose decreases during
often clear completely. Examples of paroxysmal prolonged seizures and excitatory amino acid
disorders include epilepsy, migraine, periodic release interferes with DNA synthesis. There-
paralysis, and paroxysmal movement disorders. fore, seizures identified by electroencephalogra-
phy (EEG) that occur without movement in
newborns paralyzed for respiratory assistance are
APPROACH TO PAROXYSMAL important to identify and treat. The challenge
DISORDERS for the clinician is to differentiate seizure activity
from normal neonatal movements and from
The diagnosing physician rarely witnesses the pathological movements caused by other mecha-
paroxysmal event. It is important to obtain the nisms (Box 1-1).
description of the event from the observer and The long-term prognosis in children with
not second hand. The information easily becomes neonatal seizures is better in term newborns than
distorted if transferred from the observer to the in premature newborns (Ronen et al, 2007).
parent and then to you. Most spells are not sei- However, the etiology of the seizures is the pri-
zures, and epilepsy is not a diagnosis of exclusion. mary determinant of prognosis.
Physicians often misdiagnose syncope as a sei-
zure, as many people stiffen and tremble at the
end of a faint. The critical distinction is that syn-
Seizure Patterns
cope is associated with pallor and preceded by Seizures in newborns, especially in the prema-
dimming of vision, and a feeling of lightheaded- ture, are poorly organized and difficult to distin-
ness or clamminess, whereas seizures rarely are. guish from normal activity. Newborns with
“Spells” seldom remain unexplained when hydranencephaly or atelencephaly are capable of
viewed. Because observation of the spell is criti- generating the full variety of neonatal seizure
cal to diagnosis, ask the family to record the patterns. This supports the notion that seizures
spell. Most families either own or can borrow a may arise from the brainstem as well as the hemi-
camera or a cell phone with video capability. spheres. The absence of myelinated pathways for
Even when a purchase is required, a video is seizure propagation may confine seizures arising
often more cost effective than brain imaging and in the brainstem. For the same reason, seizures
the family has something useful to show for the originating in one hemisphere are less likely to
expenditure. Always ask the following two ques- spread beyond the contiguous cortex or to pro-
tions: Has this happened before? Does anyone duce secondary bilateral synchrony.
else in the family have similar episodes? Often, Box 1-2 lists clinical patterns that have been
no one offers this important information until associated with epileptiform discharges in new-
requested. Episodic symptoms that last only sec- borns. This classification is useful but does not
onds and cause no abnormal signs usually remain do justice to the rich variety of patterns actually
unexplained and do not warrant laboratory
investigation. The differential diagnosis of par-
oxysmal disorders is somewhat different in the BOX 1-1 Movements That Resemble
neonate, infant, child, and adolescent, and pre- Neonatal Seizures
sented best by age groups.
Benign nocturnal myoclonus*
Jitteriness*
PAROXYSMAL DISORDERS Nonconvulsive apnea
OF NEWBORNS Normal movement
Opisthotonos
Pathological myoclonus
Seizures are the main paroxysmal disorder of the
newborn, occurring in 1.8–3.5 % of live births in *Denotes the most common conditions and the ones
the United States, and an important feature of with disease modifying treatments
1
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2 1 Paroxysmal Disorders
motor cortex. In an otherwise alert and responsive

BOX 1-2 Seizure Patterns
full-term newborn, unifocal clonic seizures always
in Newborns
indicate a cerebral infarction or hemorrhage or
Apnea with tonic stiffening of body focal brain dysgenesis. In newborns with states of
Focal clonic movements of one limb or both decreased consciousness, focal clonic seizures
limbs on one side* may indicate a focal infarction superimposed on
Multifocal clonic limb movements* a generalized encephalopathy.
Myoclonic jerking Diagnosis. During the seizure, the EEG may
Paroxysmal laughing show a unilateral focus of high-amplitude sharp
Tonic deviation of the eyes upward or to one waves adjacent to the central fissure. The dis-
side*
Tonic stiffening of the body
charge can spread to involve contiguous areas in
the same hemisphere and can be associated with
*Denotes the most common conditions and the ones unilateral seizures of the limbs and adversive
with disease modifying treatments movements of the head and eyes. The interic-
tal EEG may show focal slowing, sharp waves or
amplitude attenuation.
observed. Nor does the classification account for Newborns with focal clonic seizures should
the 50 % of prolonged epileptiform discharges be immediately evaluated using magnetic reso-
on the EEG without visible clinical changes. nance imaging (MRI) with diffusion-weighted
Generalized tonic-clonic seizures rarely occur. images. Computed tomography (CT) or ultra-
Many newborns suspected of having generalized sound is acceptable for less stable neonates
tonic-clonic seizures are actually jittery (see Jit- unable to make the trip to the MRI suite or tol-
teriness, discussed later in this chapter). New- erate the time needed for this procedure.
borns paralyzed to assist mechanical ventilation
pose an additional problem in seizure identifica- Multifocal Clonic Seizures
tion. In this circumstance, the presence of rhyth-
mic increases in systolic arterial blood pressure, Clinical Features. In multifocal clonic sei-
heart rate, and oxygenation desaturation should zures, migratory jerking movements are noted in
alert physicians to the possibility of seizures. first one limb and then another. Facial muscles
The term subtle seizures encompass several dif- may be involved as well. The migration appears
ferent patterns in which tonic or clonic move- random and does not follow expected patterns of
ments of the limbs are lacking. EEG monitoring epileptic spread. Sometimes, prolonged move-
often fails to show that such movements are ments occur in one limb, suggesting a focal
associated with epileptiform activity. One excep- rather than a multifocal seizure. Detection of
tion is tonic deviation of the eyes, which is usu- the multifocal nature comes later, when nursing
ally a seizure manifestation. One of the most notes appear contradictory concerning the side
common manifestations of seizures in the young or the limb affected. Multifocal clonic seizures
infant is behavioral arrest and unresponsiveness. are a neonatal equivalent of generalized tonic-
Behavioral arrest is only obvious when the child clonic seizures. They are ordinarily associated
is very active, which is not common in a sick neo- with severe, generalized cerebral disturbances
nate and therefore often goes unnoticed. such as hypoxic-ischemic encephalopathy, but
The definitive diagnosis of neonatal seizures may also represent benign neonatal convulsions
often requires EEG monitoring. A split-screen when noted in an otherwise healthy neonate.
16-channel video-EEG is the ideal means for Diagnosis. Standard EEG usually detects
monitoring. An aEEG (amplitude EEG) is also a multifocal epileptiform activity. If not, a 24-hour
useful monitoring technique. Seizures in the monitor is appropriate.
newborn may be widespread and electrographi-
cally detectable even when the newborn is not Myoclonic Seizures
convulsing clinically.
Clinical Features. Brief, nonrhythmic exten-
sion and flexion movements of the arms, the legs,
Focal Clonic Seizures
or all limbs characterize myoclonic seizures.
Clinical Features. Repeated, irregular slow They constitute an uncommon seizure pattern in
clonic movements (1 to 3 jerks/second) affecting the newborn, but their presence suggests severe,
one limb or both limbs on one side are charac- diffuse brain damage.
teristic of focal clonic seizures. Rarely do such Diagnosis. No specific EEG pattern is asso-
movements sustain for long periods, and they ciated with myoclonic seizures in the newborn.
do not “march” as though spreading along the Myoclonic jerks often occur in babies born to
1 Paroxysmal Disorders 3
drug-addicted mothers. Whether these move- invariably associated with a 40 % or greater reduc-
ments are seizures, jitteriness, or myoclonus tion in heart rate. The frequency of these apneic
(discussed later) is uncertain. spells correlates with brainstem myelination.
Even at 40 weeks conceptional age, premature
newborns continue to have a higher incidence of
Tonic Seizures
apnea than do full-term newborns. The incidence
Clinical Features. The characteristic feature of apnea sharply decreases in all infants at 52
of tonic seizures are extension and stiffening weeks conceptional age. Apnea with bradycardia
of the body, usually associated with apnea and is unlikely to be a seizure. Apnea with tachycardia
upward deviation of the eyes. Tonic posturing raises the possibility of seizure and should be eval-
without the other features is rarely a seizure uated with simultaneous EEG recording.
manifestation. Tonic seizures are more common Diagnosis. Apneic spells in an otherwise
in premature than in full-term newborns and normal-appearing newborn is typically a sign
usually indicate structural brain damage rather of brainstem immaturity and not a pathological
than a metabolic disturbance. condition. The sudden onset of apnea and states
Diagnosis. Tonic seizures in premature new- of decreased consciousness, especially in prema-
borns are often a symptom of intraventricular ture newborns, suggests an intracranial hemor-
hemorrhage and an indication for ultrasound rhage with brainstem compression. Immediate
study. Tonic posturing also occurs in newborns ultrasound examination is in order.
with forebrain damage, not as a seizure manifes- Apneic spells are almost never a seizure mani-
tation but as a disinhibition of brainstem reflexes. festation unless associated with tonic deviation
Prolonged disinhibition results in decerebrate pos- of the eyes, tonic stiffening of the body, or char-
turing, an extension of the body and limbs associ- acteristic limb movements. However, prolonged
ated with internal rotation of the arms, dilation apnea without bradycardia, and especially with tachy-
of the pupils, and downward deviation of the cardia, is a seizure until proven otherwise.
eyes. Decerebrate posturing is often a terminal Management. Short episodes of apnea do
sign in premature infants with intraventricular not require intervention. The rare ictal apnea
hemorrhage caused by pressure on the upper requires the use of anticonvulsant agents.
brainstem (see Chapter 4).
Tonic seizures and decerebrate posturing Benign Nocturnal Myoclonus
look similar to opisthotonos, a prolonged arching
of the back not necessarily associated with eye Clinical Features. Sudden jerking movements
movements. The cause of opisthotonos is prob- of the limbs during sleep occur in normal people
ably meningeal irritation. It occurs in kernic- of all ages (see Chapter 14). They appear primar-
terus, infantile Gaucher disease, and some ily during the early stages of sleep as repeated
aminoacidurias. flexion movements of the fingers, wrists, and
elbows. The jerks do not localize consistently,
stop with gentle restraint, and end abruptly with
Seizure-Like Events arousal. When prolonged, the usual misdiagno-
Apnea sis is focal clonic or myoclonic seizures.
Diagnosis. The distinction between noctur-
Clinical Features. An irregular respiratory nal myoclonus and seizures or jitteriness is that
pattern with intermittent pauses of 3 to 6 seconds, benign nocturnal myoclonus occurs solely dur-
often followed by 10 to 15 seconds of hyperpnea, ing sleep, is not activated by a stimulus, and the
is a common occurrence in premature infants. EEG is normal.
The pauses are not associated with significant Management. Treatment is unnecessary, and
alterations in heart rate, blood pressure, body education and reassurance are usually sufficient.
temperature, or skin color. Immaturity of the Rarely a child with violent myoclonus experi-
brainstem respiratory centers causes this respira- ences frequent arousals disruptive to sleep, and
tory pattern, termed periodic breathing. The inci- a small dose of clonazepam may be considered.
dence of periodic breathing correlates directly Videos of children with this benign condition
with the degree of prematurity. Apneic spells are are very reassuring for the family to see and are
more common during active than quiet sleep. available on the internet.
Apneic spells of 10 to 15 seconds are detectable
at some time in almost all premature and some
Jitteriness
full-term newborns. Apneic spells of 10 to 20 sec-
onds are usually associated with a 20 % reduction Clinical Features. Jitteriness or tremulous-
in heart rate. Longer episodes of apnea are almost ness is an excessive response to stimulation.
BOX 1-3 Differential Diagnosis of Neonatal Seizures by Peak Time of Onset

24 Hours 72 Hours to 1 Week
Bacterial meningitis and sepsis* (see Chapter 4) Cerebral dysgenesis (see Chapter 18)
Direct drug effect Cerebral infarction (see Chapter 11)*
Hypoxic-ischemic encephalopathy* Familial neonatal seizures
Intrauterine infection (see Chapter 5) Hypoparathyroidism
Intraventricular hemorrhage at term* (see Chap- Idiopathic cerebral venous thrombosis*
ter 4) Intracerebral hemorrhage (see Chapter 11)
Laceration of tentorium or falx Kernicterus
Pyridoxine dependency* Methylmalonic acidemia
Subarachnoid hemorrhage* Nutritional hypocalcemia*
Propionic acidemia
24 to 72 Hours Tuberous sclerosis
Bacterial meningitis and sepsis* (see Chapter 4) Urea cycle disturbances
Cerebral contusion with subdural hemorrhage
Cerebral dysgenesis* (see Chapter 18) 1 to 4 Weeks
Cerebral infarction* (see Chapter 11) Adrenoleukodystrophy, neonatal (see Chapter 6)
Drug withdrawal Cerebral dysgenesis (see Chapter 18)
Glycine encephalopathy Fructose dysmetabolism
Glycogen synthase deficiency Gaucher disease type 2 (see Chapter 5)
Hypoparathyroidism-hypocalcemia GM1 gangliosidosis type 1 (see Chapter 5)
Idiopathic cerebral venous thrombosis Herpes simplex encephalitis*
Incontinentia pigmenti Idiopathic cerebral venous thrombosis*
Intracerebral hemorrhage (see Chapter 11) Ketotic hyperglycinemias
Intraventricular hemorrhage in premature new- Maple syrup urine disease, neonatal*
borns* (see Chapter 4) Tuberous sclerosis
Pyridoxine dependency* Urea cycle disturbances
Subarachnoid hemorrhage
Tuberous sclerosis
Urea cycle disturbances
*Denotes the most common conditions and the ones with disease modifying treatments
Touch, noise, or motion provokes a low-ampli- Sepsis, meningitis, and subarachnoid hemor-
tude, high-frequency shaking of the limbs and rhage are next in frequency, followed by intra-
jaw. Jitteriness is commonly associated with uterine infection and trauma. Direct drug effects,
a low threshold for the Moro reflex, but it can intraventricular hemorrhage at term, and pyri-
occur in the absence of any apparent stimulation doxine and folinic acid dependency are relatively
and be confused with myoclonic seizures. rare causes of seizures.
Diagnosis. Jitteriness usually occurs in new- The more common causes of seizures during
borns with perinatal asphyxia that may have sei- the period from 24 to 72 hours after birth are
zures as well. EEG monitoring, the absence of intraventricular hemorrhage in premature new-
eye movements or alteration in respiratory pat- borns, subarachnoid hemorrhage, cerebral contu-
tern, and the presence of stimulus activation dis- sion in large full-term newborns, and sepsis and
tinguishes jitteriness from seizures. Newborns of meningitis at all gestational ages. The cause of uni-
addicted mothers and newborns with metabolic focal clonic seizures in full-term newborns is often
disorders are often jittery. cerebral infarction or intracerebral hemorrhage.
Management. Reduced stimulation decreases Head CT is diagnostic. Cerebral dysgenesis causes
jitteriness. However, newborns of addicted moth- seizures at this time and remains an important
ers require sedation to facilitate feeding and to cause of seizures throughout infancy and child-
decrease energy expenditure. hood. All other conditions are relatively rare. New-
borns with metabolic disorders are usually lethargic and
feed poorly before the onset of seizures. Seizures are
Differential Diagnosis of Seizures rarely the first clinical feature. After 72 hours, the
Seizures are a feature of almost all brain disor- initiation of protein and glucose feedings makes
ders in the newborn. The time of onset of the inborn errors of metabolism, especially aminoac-
first seizure indicates the probable cause (Box idurias, a more important consideration. Box 1-4
1-3). Seizures occurring during the first 24 outlines a battery of screening tests for metabolic
hours, and especially in the first 12 hours, are disorders. Transmission of herpes simplex infec-
usually due to hypoxic-ischemic encephalopathy. tion is during delivery and symptoms begin during
BOX 1-4 Screening for Inborn days postpartum. The encephalopathy includes
Errors of Metabolism that lethargy, intermittent apnea, opisthotonos, and
Cause Neonatal Seizures stereotyped movements such as “fencing” and
“bicycling.” Coma and central respiratory failure
Blood Glucose Low may occur by 7to10 days of age. Seizures begin
Fructose 1,6-diphosphatase deficiency in the second week and are associated with the
Glycogen storage disease type 1 development of cerebral edema. Once seizures
Maple syrup urine disease begin, they continue with increasing frequency
and severity. Without therapy, cerebral edema
Blood Calcium Low becomes progressively worse and results in coma
Hypoparathyroidism and death within 1 month.
Maternal hyperparathyroidism Diagnosis. Plasma amino acid concentrations
Blood Ammonia High show increased plasma concentrations of the
three branch-chained amino acids. Measures of
Argininosuccinic acidemia
Carbamylphosphate synthetase deficiency enzyme in lymphocytes or cultured fibroblasts
Citrullinemia serve as a confirmatory test. Heterozygotes have
Methylmalonic acidemia (may be normal) diminished levels of enzyme activity.
Multiple carboxylase deficiency Management. Hemodialysis may be neces-
Ornithine transcarbamylase deficiency sary to correct the life-threatening metabolic
Propionic acidemia (may be normal) acidosis. A trial of thiamine (10–20 mg/kg/day)
improves the condition in a thiamine-responsive
Blood Lactate High
MSUD variant. Stop the intake of all natural pro-
Fructose 1,6-diphosphatase deficiency tein, and correct dehydration, electrolyte imbal-
Glycogen storage disease type 1
ance, and metabolic acidosis. A special diet, low in
Mitochondrial disorders
Multiple carboxylase deficiency branched-chain amino acids, may prevent further
encephalopathy if started immediately by nasogas-
Metabolic Acidosis tric tube. Newborns diagnosed in the first 2 weeks
Fructose 1,6-diphosphatase deficiency and treated rigorously have the best prognosis.
Glycogen storage disease type 1
Maple syrup urine disease Glycine Encephalopathy. A defect in the glycine
Methylmalonic acidemia cleaving system causes glycine encephalopathy
Multiple carboxylase deficiency (nonketotic hyperglycinemia). Inheritance is
Propionic acidemia autosomal recessive (Hamosh, 2009).
Clinical Features. Affected newborns are nor-
mal at birth but become irritable and refuse feed-
the second half of the first week. Conditions that ing anytime from 6 hours to 8 days after delivery.
cause early and late seizures include cerebral dys- The onset of symptoms is usually within 48
genesis, cerebral infarction, intracerebral hemor- hours but delays by a few weeks occur in milder
rhage, and familial neonatal seizures. allelic forms. Hiccupping is an early and continu-
ous feature; some mothers relate that the child
hiccupped in utero as a prominent symptom.
Aminoacidopathies
Progressive lethargy, hypotonia, respiratory dis-
Maple Syrup Urine Disease. An almost complete turbances, and myoclonic seizures follow. Some
absence (less than 2 % of normal) of branched- newborns survive the acute illness, but cognitive
chain ketoacid dehydrogenase (BCKD) causes impairment, epilepsy, and spasticity characterize
the neonatal form of maple syrup urine disease the subsequent course.
(MSUD). BCKD is composed of six subunits, but In the milder forms range, the onset of sei-
the main abnormality in MSUD is deficiency of zures is after the neonatal period. The develop-
the E1 subunit on chromosome 19q13.1–q13.2. mental outcome is better, but does not exceed
Leucine, isoleucine, and valine cannot be decar moderate cognitive impairment.
boxylated, and accumulate in blood, urine, and Diagnosis. During the acute encephalopathy,
tissues (Figure 1-1). Descriptions of later-onset the EEG demonstrates a burst-suppression pat-
forms are in Chapters 5 and 10. Transmission of tern, which evolves into hypsarrhythmia during
the defect is by autosomal recessive inheritance infancy. The MRI may be normal or may show
(Strauss et al, 2009). agenesis or thinning of the corpus callosum.
Clinical Features. Affected newborns appear Delayed myelination and atrophy are later find-
healthy at birth, but lethargy, feeding difficulty, ings. Hyperglycinemia and especially elevated
and hypotonia develop after ingestion of protein. concentrations of glycine in the cerebrospinal
A progressive encephalopathy develops by 2 to 3 fluid (CSF), in the absence of hyperammonemia,
Maple syrup urine

Hypervalinemia disease
FIGURE 1-1 n Branched-chain amino Valine -Keto-isovalerate Isobutyryl-CoA Methacrylyl-CoA

acid metabolism. 1. Transaminase Valine
system; 2. branched-chain α-keto transaminase
acid dehydrogenase; 3. isovaleryl- Isoleucine -Keto--methylvalerate -Methylbutyryl-CoA Tiglyl-CoA
Isoleucine
CoA dehydrogenase; 4. α-methyl Isovaleric
transaminase
branched-chain acyl-CoA dehyd acidemia
rogenase; 5. propionyl-CoA car- Leucine -Keto-isocaproate Isovaleryl-CoA β-Methylcrotonyl-CoA
boxylase (biotin cofactor); 6. Leucine
methylmalonyl-CoA racemase; 7. transaminase Branched-chain Isovaleryl-CoA
methylmalonyl-CoA mutase (ad- keto acid dehydrogenase
enosylcobalamin cofactor). decarboxylase
organic acidemia or valproic acid treatment

BOX 1-5 Causes of Neonatal
establishes the diagnosis.
Hyperammonemia
Management. No therapy has proven to be
effective. Hemodialysis provides only tem- Liver Failure
porary relief of the encephalopathy, and diet Primary Enzyme Defects in Urea
therapy has not proved successful in modifying Synthesis
the course. Diazepam, a competitor for glycine Argininosuccinic acidemia
receptors, in combination with choline, folic Carbamyl phosphate synthetase deficiency
acid, and sodium benzoate, may stop the sei- Citrullinemia
zures. Oral administration of sodium benzoate Ornithine transcarbamylase deficiency
at doses of 250–750 mg/kg/day can reduce the
plasma glycine concentration into the normal Other Disorders of Amino Acid
range. This substantially reduces but does not Metabolism
normalize CSF glycine concentration. Carni- Glycine encephalopathy
tine, 100 mg/kg/day, may increase the glycine Isovaleric acidemia
conjugation with benzoate. Methylmalonic acidemia
Multiple carboxylase deficiency
Propionic acidemia
Urea Cycle Disturbances. Carbamyl phos
phate synthetase (CPS) deficiency, ornithine Transitory Hyperammonemia
transcarbamylase (OTC) deficiency, citrullinemia, of Prematurity
argininosuccinic acidemia, and argininemia
(arginase deficiency) are the disorders caused by
defects in the enzyme systems responsible for CPS and female carriers of OTC deficiency may
urea synthesis. A similar syndrome results from become symptomatic after ingesting a large pro-
deficiency of the cofactor producer N-acetyl tein load.
glutamate synthetase (NAGS). Arginase deficiency Diagnosis. Suspect the diagnosis of a urea
does not cause symptoms in the newborn. OTC cycle disturbance in every newborn with a com-
deficiency is an X-linked trait; transmission of patible clinical syndrome and hyperammonemia
all others is by autosomal recessive inheritance without organic acidemia. Hyperammonemia
(Summar, 2011). The estimated prevalence of all can be life threatening, and diagnosis within
urea cycle disturbances is 1:30 000 live births. 24 hours is essential. Determine the blood ammo-
Clinical Features. The clinical features of nia concentration and the plasma acid–base status.
urea cycle disorders are due to ammonia intoxi- A plasma ammonia concentration of 150 mmol/L
cation (Box 1-5). Progressive lethargy, vomiting, strongly suggests a urea cycle disorder. Quanti-
and hypotonia develop as early as the first day tative plasma amino acid analysis helps differen-
after delivery, even before the initiation of pro- tiate the specific urea cycle disorder. Molecular
tein feeding. Progressive loss of consciousness genetic testing is available for some disorders, but
and seizures follow on subsequent days. Vom- others still require liver biopsy to determine the
iting and lethargy correlate well with plasma level of enzyme activity. The most common cause
ammonia concentrations greater than 200 µg/ of hyperammonemia is difficult phlebotomy with
dL (120 µmol/L). Coma correlates with concen- improper sample processing. Accurate serum
trations greater than 300 µg/dL (180 µmol/L) ammonia testing requires a good phlebotomist,
and seizures with those greater than 500 µg/dL sample placement on ice, and rapid processing.
(300 µmol/L). Death follows quickly in untreated Management. Treatment cannot await spe-
newborns. Newborns with partial deficiency of cific diagnosis in newborns with symptomatic
hyperammonemia due to urea cycle disorders. Bilirubin Encephalopathy

The treatment measures include reduction of
plasma ammonia concentration by limiting nitro- Unconjugated bilirubin is bound to albumin in
gen intake to 1.2–2.0 g/kg/day and using essential the blood. Kernicterus, a yellow discoloration of
amino acids for protein; allowing alternative path- the brain that is especially severe in the basal
way excretion of excess nitrogen with sodium ben- ganglia and hippocampus, occurs when the
zoate and phenylacetic acid; reducing the amount serum unbound or free fraction becomes exces-
of nitrogen in the diet; and reducing catabolism sive. An excessive level of the free fraction in an
by introducing calories supplied by carbohydrates otherwise healthy newborn is approximately
and fat. Arginine concentrations are low in all 20 mg/dL (340 µmol/L). Kernicterus was an
inborn errors of urea synthesis except for arginase important complication of hemolytic disease
deficiency and require supplementation. from maternal–fetal blood group incompatibil-
Even with optimal supervision, episodes of ity, but this condition is now almost unheard of
hyperammonemia may occur and may lead to in most countries. The management of other
coma and death. In such cases, intravenous causes of hyperbilirubinemia in full-term new-
administration of sodium benzoate, sodium borns is not difficult. Critically ill premature
phenylacetate, and arginine, coupled with nitro- infants with respiratory distress syndrome, aci-
gen-free alimentation, are appropriate. If res dosis, and sepsis are the group at greatest risk. In
ponse to drug therapy is poor, then peritoneal such newborns, lower concentrations of biliru-
dialysis or hemodialysis is indicated. bin may be sufficient to cause bilirubin encepha-
lopathy, and even the albumin-bound fraction
may pass the blood–brain barrier.
Benign Familial Neonatal Seizures
Clinical Features. Three distinct clinical
In some families, several members have seizures phases of bilirubin encephalopathy occur in
in the first weeks of life but do not have epilepsy full-term newborns with untreated hemolytic
or other neurological abnormalities later on. disease. Hypotonia, lethargy, and a poor suck-
Two genes, KCNQ2 and KCNQ3, are associated ing reflex occur within 24 hours of delivery.
with the disorder. In each, transmission of the Bilirubin staining of the brain is already evident
trait is autosomal dominant and mutations affect in newborns during this first clinical phase. On
the voltage gated potassium channel. the second or third day, the newborn becomes
Clinical Features. Brief multifocal clonic sei- febrile and shows increasing tone and opistho-
zures develop during the first week, sometimes tonic posturing. Seizures are not a constant fea-
associated with apnea. Delay of onset may be ture but may occur at this time. Characteristic
as long as 4 weeks. With or without treatment, of the third phase is apparent improvement with
the seizures usually stop spontaneously within normalization of tone. This may cause second
the first months of life. Febrile seizures occur in thoughts about the accuracy of the diagnosis, but
up to one-third of affected children; some have the improvement is short-lived. Evidence of neu-
febrile seizures without first having neonatal sei- rological dysfunction begins to appear toward
zures. Epilepsy develops later in life in as many the end of the second month, and the symptoms
as a third of affected newborns. The seizure become progressively worse throughout infancy.
types include nocturnal generalized tonic-clonic In premature newborns, the clinical features
seizures and simple focal orofacial seizures. are subtle and may lack the phases of increased
Diagnosis. Suspect the syndrome when tone and opisthotonos.
seizures develop without apparent cause in a The typical clinical syndrome after the first
healthy newborn. Laboratory tests are normal. year includes extrapyramidal dysfunction, usu-
The EEG often demonstrates multifocal epilep- ally athetosis, which occurs in virtually every
tiform discharges and may be normal interictally. case (see Chapter 14); disturbances of vertical
A family history of neonatal seizures is critical gaze, upward more often than downward, in
to diagnosis but may await discovery until inter- 90 %; high-frequency hearing loss in 60 %; and
viewing the grandparents; parents are frequently mental retardation in 25 %. Survivors often
unaware that they had neonatal seizures. develop a choreoathetoid form of cerebral palsy.
Management. Treat with anticonvulsants. Diagnosis. In newborns with hemolytic dis-
Oxcarbazepine at doses of 20 mg/kg/day for a ease, the basis for a presumed clinical diagnosis
couple of days and titrated to 40 mg/kg/day can is a significant hyperbilirubinemia and a com-
be helpful. The duration of treatment needed is patible evolution of symptoms. However, the
unclear. We often treat infants for about 9 months, diagnosis is difficult to establish in critically ill
after which we discontinue treatment if the child premature newborns, in which the cause of brain
remains seizure-free and the EEG has normalized. damage is more often asphyxia than kernicterus.
Management. Maintaining serum bilirubin questioning of the mother concerning her use
concentrations below the toxic range, either by of prescription and nonprescription drugs is
phototherapy or exchange transfusion, prevents imperative. Blood, urine, and meconium analy-
kernicterus. Once kernicterus has occurred, fur- ses identify specific drugs.
ther damage can be limited, but not reversed, by Management. Symptoms remit spontane-
lowering serum bilirubin concentrations. Diaz- ously in 3 to 5 days, but appreciable mortality
epam and baclofen are often needed for manage- occurs among untreated newborns. Benzodi-
ment of dystonic postures associated with the azepines or chlorpromazine, 3 mg/kg/day, may
cerebral palsy. relieve symptoms and reduce mortality. Con-
sider phenobarbital 8 mg/kg/day for refrac-
tory cases. Secretion of morphine, meperidine,
Drug Withdrawal
opium, and methadone in breast milk is insuf-
Marijuana, alcohol, narcotic analgesics, and ficient to cause or relieve addiction in the new-
hypnotic sedatives are the nonprescribed drugs born. Levetiracetam 40 mg/kg/day is a good
most commonly used during pregnancy. Mari- option for seizures.
juana and alcohol do not cause drug dependence The occurrence of seizures, in itself, does not
in the fetus and are not associated with with- indicate a poor prognosis. The long-term out-
drawal symptoms, although ethanol can cause come relates more closely to the other risk fac-
fetal alcohol syndrome. Hypnotic sedatives, tors associated with substance abuse in the
such as barbiturates, do not ordinarily produce mother.
withdrawal symptoms unless the ingested doses
are very large. Phenobarbital has a sufficiently Hypocalcemia
long half-life in newborns that sudden with-
drawal does not occur. The prototype of nar- The definition of hypocalcemia is a blood calcium
cotic withdrawal in the newborn is with heroin concentration less than 7 mg/dL (1.75 mmol/L).
or methadone, but a similar syndrome occurs The onset of hypocalcemia in the first 72 hours
with codeine and propoxyphene. Cocaine and after delivery is associated with low birth weight,
methamphetamine also cause significant with- asphyxia, maternal diabetes, transitory neonatal
drawal syndromes. hypoparathyroidism, maternal hyperparathyroid-
Clinical Features. Symptoms of opiate with- ism, and the DiGeorge syndrome (DGS). Later-
drawal are more severe and tend to occur earlier onset hypocalcemia occurs in children fed
in full-term (first 24 hours) than in premature improper formulas, in maternal hyperparathy-
(24 to 48 hours) newborns. The initial feature is roidism, and in DGS.
a coarse tremor, present only during the waking Hypoparathyroidism in the newborn may
state, which can shake an entire limb. Irritabil- result from maternal hyperparathyroidism or
ity, a shrill, high-pitched cry, and hyperactivity may be a transitory phenomenon of unknown
follow. The newborn seems hungry but has dif- cause. Hypocalcemia occurs in less than 10 % of
ficulty feeding and vomits afterward. Diarrhea stressed newborns and enhances their vulnera-
and other symptoms of autonomic instability are bility to seizures, but it is rarely the primary
common. cause.
Myoclonic jerking is present in 10–25 % DGS is associated with microdeletions of
of newborns undergoing withdrawal. Whether chromosome 22q11.2 (McDonald-McGinn et al,
these movements are seizures or jitteriness 2005). Disturbance of cervical neural crest migra-
is not clear. Definite seizures occur in fewer tion into the derivatives of the pharyngeal arches
than 5 %. Maternal use of cocaine during preg- and pouches explains the phenotype. Organs
nancy is associated with premature delivery, derived from the third and fourth pharyngeal
growth retardation, and microcephaly. New- pouches (thymus, parathyroid gland, and great
borns exposed to cocaine, in utero or after vessels) are hypoplastic.
delivery through the breast milk, often show Clinical Features. The 22q11.2 syndrome
features of cocaine intoxication including tachy- encompasses several similar phenotypes: DGS,
cardia, tachypnea, hypertension, irritability, velocardiofacial syndrome (VCFS), and Shprint-
and tremulousness. zen syndrome. The acronym CATCH is used
Diagnosis. Suspect and anticipate drug with- to describe the phenotype of cardiac abnormal-
drawal in every newborn whose mother has a ity, T-cell deficit, clefting (multiple minor facial
history of substance abuse. Even when such a anomalies), and hypocalcemia. The identifica-
history is not available, the combination of irri- tion of most children with DGS is in the neonatal
tability, hyperactivity, and autonomic instability period with a major heart defect, hypocalcemia,
should provide a clue to the diagnosis. Careful and immunodeficiency. Diagnosis of children with
VCFS comes later because of cleft palate or cra- BOX 1-6 Causes of Neonatal
niofacial deformities. Hypoglycemia
The initial symptoms of DGS may be due to
congenital heart disease, hypocalcemia, or both. Primary Transitional Hypoglycemia*
Jitteriness and tetany usually begin in the first 48 Complicated labor and delivery
hours after delivery. The peak onset of seizures Intrauterine malnutrition
is on the third day but a 2-week delay may occur. Maternal diabetes
Many affected newborns die of cardiac causes Prematurity
during the first month; survivors fail to thrive
Secondary Transitional Hypoglycemia*
and have frequent infections secondary to the
failure of cell-mediated immunity. Asphyxia
Diagnosis. Newborns with DGS come to Central nervous system disorders
Cold injuries
medical attention because of seizures and heart
Sepsis
disease. Seizures or a prolonged Q-T interval
brings attention to hypocalcemia. Molecular Persistent Hypoglycemia
genetic testing confirms the diagnosis. Aminoacidurias
Management. Management requires a mul- Maple syrup urine disease
tispecialty team including cardiology, immunol- Methylmalonic acidemia
ogy, medical genetics, and neurology. Plastic Propionic acidemia
surgery, dentistry, and child development con- Tyrosinosis
tribute later on. Hypocalcemia generally Congenital hypopituitarism
responds to parathyroid hormone or to oral cal- Defects in carbohydrate metabolism
Fructose 1, 6-diphosphatase deficiency
cium and vitamin D.
Fructos e+ intolerance
Galactosemia
Hypoglycemia Glycogen storage disease type 1
Glycogen synthase deficiency
A transitory, asymptomatic hypoglycemia is Hyperinsulinism
detectable in 10 % of newborns during the first Organic acidurias
hours after delivery and before initiating feed- Glutaric aciduria type 2
ing. Asymptomatic, transient hypoglycemia is 3-Methylglutaryl-CoA lyase deficiency
not associated with neurological impairment
*Denotes the most common conditions and the ones
later in life. Symptomatic hypoglycemia may with disease modifying treatments
result from stress or inborn errors of metabolism
(Box 1-6).
Clinical Features. The time of onset of symp- a low glucose concentration in a newborn with
toms depends upon the underlying disorder. seizures prompts investigation into the cause of
Early onset is generally associated with perina- the hypoglycemia.
tal asphyxia, maternal diabetes or intracranial Management. Intravenous administration of
hemorrhage, and late onset with inborn errors glucose normalizes blood glucose concentra-
of metabolism. Hypoglycemia is rare and mild tions, but the underlying cause must be deter-
among newborns with classic MSUD, ethyl- mined before providing definitive treatment.
malonic aciduria, and isovaleric acidemia and is
invariably severe in those with 3-methylgluta- Hypoxic-Ischemic Encephalopathy
conic aciduria, glutaric aciduria type 2, and dis-
orders of fructose metabolism. Asphyxia at term is usually an intrauterine event,
The syndrome includes any of the following and hypoxia and ischemia occur together; the
symptoms: apnea, cyanosis, tachypnea, jitteri- result is hypoxic-ischemic encephalopathy
ness, high-pitched cry, poor feeding, vomiting, (HIE). Acute total asphyxia often leads to death
apathy, hypotonia, seizures, and coma. Symp- from circulatory collapse. Survivors are born
tomatic hypoglycemia is often associated with comatose. Lower cranial nerve dysfunction and
later neurological impairment. severe neurological handicaps are the rule.
Diagnosis. Neonatal hypoglycemia is defined Partial, prolonged asphyxia is the usual
as a whole blood glucose concentration of less mechanism of HIE in surviving full-term new-
than 20 mg/dL (1 mmol/L) in premature and borns (Miller et al, 2005). The fetal circulation
low-birth-weight newborns, less than 30 mg/dL accommodates to reductions in arterial oxygen
(1.5 mmol/L) in term newborns during the first by maximizing blood flow to the brain, and to a
72 hours, and less than 40 mg/dL (2 mmol/L) lesser extent the heart, at the expense of other
in full-term newborns after 72 hours. Finding organs.
Clinical experience indicates that fetuses may limbs during the succeeding weeks. Neurologi-
be subject to considerable hypoxia without the cal sequelae are expected in newborns with
development of brain damage. The incidence of severe HIE.
cerebral palsy among full-term newborns with a Diagnosis. EEG and MRI are helpful in
5-minute Apgar score of 0 to 3 is only 1 % if the determining the severity and prognosis of HIE.
10-minute score is 4 or higher. Any episode of In mild HIE, the EEG background rhythms are
hypoxia sufficiently severe to cause brain damage normal or lacking in variability. In severe HIE,
also causes derangements in other organs. New- the background is always abnormal and shows
borns with mild HIE always have a history of suppression of background amplitude. The
irregular heart rate and usually pass meconium. degree of suppression correlates well with the
Those with severe HIE may have lactic acidosis, severity of HIE. The worst case is a flat EEG
elevated serum concentrations of hepatic or one with a burst-suppression pattern. A bad
enzymes, enterocolitis, renal failure, and fatal outcome is invariable if the amplitude remains
myocardial damage. suppressed for 2 weeks or a burst-suppression
Clinical Features. Mild HIE is relatively com- pattern is present at any time. Epileptiform
mon. The newborn is lethargic but conscious activity may also be present but is less predictive
immediately after birth. Other characteristic fea- of the outcome than is background suppression.
tures are jitteriness and sympathetic over-activity MRI with diffusion-weighted images are
(tachycardia, dilatation of pupils, and decreased helpful to determine the full extent of injury.
bronchial and salivary secretions). Muscle tone The basal ganglia and thalamus are often affected
is normal at rest, tendon reflexes are normoreac- by HIE.
tive or hyperactive, and ankle clonus is usually Management. The management of HIE
elicited. The Moro reflex is complete, and a sin- in newborns requires immediate attention to
gle stimulus generates repetitive extension and derangements in several organs and correction
flexion movements. Seizures are not an expected of acidosis. Clinical experience indicates that
feature, and their occurrence suggests concur- control of seizures and maintenance of adequate
rent hypoglycemia, the presence of a second ventilation and perfusion increases the chance
condition or a more significant HIE. of a favorable outcome. A treatment approach
Symptoms diminish and disappear during the involves either whole body or selective head
first few days, although some degree of over- cooling (Gluckman et al, 2005).
responsiveness may persist. Newborns with mild A separate section details the treatment of sei-
HIE are believed to recover normal brain func- zures in newborns. The use of intravenous leve-
tion completely. They are not at greater risk for tiracetam is promising (Furwentsches et al,
later epilepsy or learning disabilities. 2010). Seizures often cease spontaneously during
Newborns with severe HIE are stuporous or the second week, and long-term anticonvulsant
comatose immediately after birth, and respira- therapy may not be necessary. The incidence of
tory effort is usually periodic and insufficient to later epilepsy among infants who had neonatal
sustain life. Seizures begin within the first 12 seizures caused by HIE is 30–40 %. Continuing
hours. Hypotonia is severe, and tendon reflexes, antiepileptic therapy after the initial seizures
the Moro reflex, and the tonic neck reflex are have stopped does not influence whether the
absent as well. Sucking and swallowing are child goes on to develop epilepsy as a lifelong
depressed or absent, but the pupillary and oculo- condition.
vestibular reflexes are present. Most of these
newborns have frequent seizures, which may Organic Acid Disorders
appear on EEG without clinical manifestations.
They may progress to status epilepticus. The Characteristic of organic acid disorders is the
response to antiepileptic drugs is usually incom- accumulation of compounds, usually ketones,
plete. Generalized increased intracranial pres- or lactic acid that causes acidosis in biological
sure characterized by coma, bulging of the fluids (Seashore, 2009). Among the dozens of
fontanelles, loss of pupillary and oculovestibular organic acid disorders are abnormalities in
reflexes, and respiratory arrest often develops vitamin metabolism, lipid metabolism, glycol-
between 24 and 72 hours of age. ysis, the citric acid cycle, oxidative metabolism,
The newborn may die at this time or may glutathione metabolism, and 4-aminobutyric
remain stuporous for several weeks. The acid metabolism. The clinical presentations
encephalopathy begins to subside after the third vary considerably and several chapters contain
day, and seizures decrease in frequency and descriptions. Defects in the further metabo-
eventually stop. Jitteriness is common as the lism of branched-chain amino acids are the
child becomes arousable. Tone increases in the organic acid disorders that most often cause
neonatal seizures. Molecular genetic testing is Clinical Features. Affected children appear
clinically available for detection of several of normal at birth. In 80 % of those with complete
these diseases, including MSUD, propionic mutase deficiency, the symptoms appear during
acidemia, methylmalonic acidemia, biotin- the first week after delivery; those with defects
unresponsive 3-methylcrotonyl-CoA carboxyl- in the synthesis of adenosylcobalamin gener-
ase deficiency, isovaleric acidemia, and glutaric ally show symptoms after 1 month. Symptoms
acidemia type 1. include lethargy, failure to thrive, recurrent
vomiting, dehydration, respiratory distress, and
Isovaleric Acidemia. Isovaleric acid is a fatty acid hypotonia after the initiation of protein feeding.
derived from leucine. The enzyme isovaleryl- Leukopenia, thrombocytopenia, and anemia are
CoA dehydrogenase converts isovaleric acid to present in more than one half of patients. Intra-
3-methylcrotonyl-CoA (see Figure 1-1). Genetic cranial hemorrhage may result from a bleeding
transmission is autosomal recessive inheritance. diathesis. The outcome for newborns with com-
The heterozygote state is detectable in cultured plete mutase deficiency is usually poor. Most
fibroblasts. die within 2 months of diagnosis; survivors have
Clinical Features. Two phenotypes are asso- recurrent acidosis, growth retardation, and cog-
ciated with the same enzyme defect. One is an nitive impairment.
acute, overwhelming disorder of the newborn; Diagnosis. Suspect the diagnosis in any
the other is a chronic infantile form. Newborns newborn with metabolic acidosis, especially if
with the acute disorder are normal at birth but associated with ketosis, hyperammonemia, and
within a few days become lethargic, refuse to hyperglycinemia. Demonstrating an increased
feed, and vomit. The clinical syndrome is simi- concentration of methylmalonic acid in the urine
lar to MSUD except that the urine smells like and elevated plasma glycine levels helps confirm
“sweaty feet” instead of maple syrup. Sixty per the diagnosis. The specific enzyme defect can be
cent of affected newborns die within 3 weeks. determined in fibroblasts. Techniques for prena-
The survivors have a clinical syndrome identical tal detection are available.
to the chronic infantile phenotype. Management. Some affected newborns are
Diagnosis. The excretion of isovaleryl-lysine cobalamin responsive and others are not. Man-
in the urine detects isovaleric acidosis. Assays of agement of those with mutase deficiency is simi-
isovaleryl-CoA dehydrogenase activity utilize lar to propionic acidemia. The long-term results
cultured fibroblasts, and molecular testing is are poor. Vitamin B12 supplementation is useful
available. The clinical phenotype correlates not in some defects of adenosylcobalamin synthesis,
with the percentage of residual enzyme activity, and hydroxocobalamin administration is rea-
but with the ability to detoxify isovaleryl-CoA sonable while awaiting the definitive diagno-
with glycine. sis. Maintain treatment with protein restriction
Management. Dietary restriction of protein, (0.5–l.5 g/kg/day) and hydroxocobalamin (1 mg)
especially leucine, decreases the occurrence of weekly. As in propionic acidemia, oral supple-
later psychomotor retardation. l-Carnitine, mentation of l-carnitine reduces ketogenesis in
50 mg/kg/day, is a beneficial supplement to the response to fasting.
diet of some children with isovaleric acidemia. In
acutely ill newborns, oral glycine, 250–500 mg/ Propionic Acidemia. Propionyl-CoA forms as
day, in addition to protein restriction and carni- a catabolite of methionine, threonine, and
tine, lowers mortality. the branched-chain amino acids. Its further
carboxylation to d-methylmalonyl-CoA requires
Methylmalonic Acidemia. d-Methylmalonyl- the enzyme propionyl-CoA carboxylase and the
CoA is racemized to l-methylmalonyl-CoA coenzyme biotin (see Figure 1-1). Isolated
by the enzyme d-methylmalonyl racemase deficiency of propionyl-CoA carboxylase causes
and then isomerized to succinyl-CoA, which propionic acidemia. Transmission of the defect
enters the tricarboxylic acid cycle. The enzyme is autosomal recessive.
d-methylmalonyl-CoA mutase catalyzes the Clinical Features. Most affected children
isomerization. The cobalamin (vitamin B12) appear normal at birth; symptoms may begin as
coenzyme adenosylcobalamin is a required early as the first day after delivery or delayed for
cofactor. Genetic transmission of the several de months or years. In newborns, the symptoms are
fects in this pathway is by autosomal recessive nonspecific: feeding difficulty, lethargy, hypoto-
inheritance. Mutase deficiency is the most common nia, and dehydration. Recurrent attacks of pro-
abnormality. Propionyl-CoA, propionic acid, found metabolic acidosis, often associated with
and methylmalonic acid accumulate and cause hyperammonemia, which respond poorly to
hyperglycinemia and hyperammonemia. buffering is characteristic. Untreated newborns
rapidly become dehydrated, have generalized or through mouth or hand by the mother or other
myoclonic seizures, and become comatose. caregiver.
Hepatomegaly caused by a fatty infiltration Clinical Features. The clinical spectrum of
occurs in approximately one-third of patients. perinatal HSV infection is considerable. Among
Neutropenia, thrombocytopenia, and occasion- symptomatic newborns, one-third has dissemi-
ally pancytopenia may be present. A bleeding nated disease, one-third has localized involve-
diathesis accounts for massive intracranial hem- ment of the brain, and one-third has localized
orrhage in some newborns. Children who sur- involvement of the eyes, skin, or mouth. Whether
vive beyond infancy develop infarctions in the infection is disseminated or localized, approxi-
basal ganglia. mately half of infections involve the central ner-
Diagnosis. Consider propionic acidemia in vous system. The overall mortality rate is over
any newborn with ketoacidosis or with hyperam- 60 %, and 50 % of survivors have permanent
monemia without ketoacidosis. Propionic acide- neurological impairment.
mia is the probable diagnosis when the plasma The onset of symptoms may be as early as the
concentrations of glycine and propionate and the fifth day but is usually in the second week.
urinary concentrations of glycine, methylcitrate, A vesicular rash is present in 30 %, usually on the
and β-hydroxypropionate are increased. While scalp after vertex presentation and on the but-
the urinary concentration of propionate may tocks after breech presentation. Conjunctivitis,
be normal, the plasma concentration is always jaundice, and a bleeding diathesis may be pres-
elevated, without a concurrent increase in the ent. The first symptoms of encephalitis are irri-
concentration of methylmalonate. tability and seizures. Seizures may be focal or
Deficiency of enzyme activity in peripheral generalized and are frequently only partially
blood leukocytes or in skin fibroblasts establishes responsive to therapy. Neurological deteriora-
the diagnosis. Molecular genetic testing is avail- tion is progressive and characterized by coma
able. Detecting methylcitrate, a unique metabo- and quadriparesis.
lite of propionate, in the amniotic fluid and by Diagnosis. Culture specimens are collected
showing deficient enzyme activity in amniotic from cutaneous vesicles, mouth, nasopharynx,
fluid cells provides prenatal diagnosis. rectum, or CSF. Polymerase chain reaction is
Management. The newborn in ketoacidosis the standard for diagnosis herpes encephalitis.
requires dialysis to remove toxic metabolites, The EEG is always abnormal and shows a peri-
parenteral fluids to prevent dehydration, and odic pattern of slow waves or spike discharges.
protein-free nutrition. Restricting protein intake The CSF examination shows a lymphocytic leu-
to 0.5–l.5 g/kg/day decreases the frequency and kocytosis, red blood cells, and an elevated pro-
severity of subsequent attacks. Oral adminis- tein concentration.
tration of l-carnitine reduces the ketogenic Management. The best treatment is preven-
response to fasting and may be useful as a daily tion. Cesarean section should be strongly con-
supplement. Intermittent administration of non- sidered in all women with active genital herpes
absorbed antibiotics reduces the production of infection at term whose membranes are intact or
propionate by gut bacteria. ruptured for less than 4 hours.
Intravenous acyclovir is the drug of choice for
Herpes Simplex Encephalitis all forms of neonatal HSV disease. The dosage is
60 mg/kg per day divided in 3 doses, given intrave-
Herpes simplex virus (HSV) is a large DNA virus nously for 14 days in skin/eye/mouth disease and
separated into two serotypes, HSV-1 and HSV- for 21 days for disseminated disease. All patients
2. HSV-2 is associated with 80 % of genital her- with central nervous system (CNS) HSV involve-
pes and HSV-1 with 20 %. The overall prevalence ment should undergo a repeat lumbar puncture at
of genital herpes is increasing and approximately the end of intravenous acyclovir therapy to deter-
25 % of pregnant woman have serological evi- mine that the CSF is polymerase chain reaction
dence of past HSV-2 infection. Transmission of (PCR) negative and normalized. Therapy contin-
HSV to the newborn can occur in utero, peripar- ues until documenting a negative PCR. Acute
tum, or postnatally. However, 85 % of neonatal renal failure is the most significant adverse effect
cases are HSV-2 infections acquired during the of parenteral acyclovir. Mortality remains 50 % or
time of delivery. The highest risk for perinatal greater in newborns with disseminated disease.
transmission occurs when a mother with no prior
HSV-1 or HSV-2 antibodies acquires either Trauma and Intracranial Hemorrhage
virus in the genital tract within 2 weeks prior
to delivery (first-episode primary infection). Neonatal head trauma occurs most often in
Postnatal transmission can occur with HSV-1 large term newborns of primiparous mothers.
Prolonged labor and difficult extraction is usual Diagnosis. CT is useful to document the
because of fetal malpositioning or fetal-pelvic extent of hemorrhage. Blood is present in the
disproportion. A precipitous delivery may also interhemispheric fissure and the supratentorial
lead to trauma or hemorrhage. Intracranial hem- and infratentorial recesses. EEG may reveal epi-
orrhage may be subarachnoid, subdural, or intra- leptiform activity without background suppres-
ventricular. Discussion of intraventricular sion. This suggests that HIE is not the cause
hemorrhage is in Chapter 4. of the seizures, and that the prognosis is more
favorable. Clotting studies are needed to evalu-
Idiopathic Cerebral Venous Thrombosis. ate the possibility of a bleeding diathesis.
The causes of cerebral venous thrombosis in Management. Seizures usually respond to
newborns are coagulopathies, polycythemia and anticonvulsants. Specific therapy is not avail-
sepsis. Cerebral venous thrombosis, especially able for the hemorrhage, and posthemorrhagic
involving the superior sagittal sinus, also occurs hydrocephalus is uncommon.
without known predisposing factors, probably due
to the trauma even in relatively normal deliveries. Subdural Hemorrhage
Clinical Features. The initial symptom is Clinical Features. Subdural hemorrhage is
focal seizures or lethargy beginning any time usually the consequence of a tear in the tento-
during the first month. Intracranial pressure rium near its junction with the falx. Causes of
remains normal, lethargy slowly resolves, and tear include excessive vertical molding of the
seizures tend to respond to anticonvulsants. The head in vertex presentation, anteroposterior
long-term outcome is uncertain and probably elongation of the head in face and brow presen-
depends upon the extent of hemorrhagic infarc- tations, or prolonged delivery of the aftercom-
tion of the hemisphere. ing head in breech presentation. Blood collects
Diagnosis. CT venogram or MR venogram in the posterior fossa and may produce brain-
are the standard tests for diagnosis. CT veno- stem compression. The initial features are those
gram is a more sensitive and accurate imaging of mild to moderate HIE. Clinical evidence of
modality. brainstem compression begins 12 hours or lon-
Management. Anticoagulation may decrease ger after delivery. Characteristic features include
the risk of thrombus progression, venous con- irregular respiration, an abnormal cry, declining
gestion leading to hemorrhage and stroke, and consciousness, hypotonia, seizures, and a tense
facilitate re-canalization of the venous sinus. fontanelle. Intracerebellar hemorrhage is some-
Response to therapy varies widely, and dosages of times present. Mortality is high, and neurologi-
low molecular weight heparin frequently require cal impairment among survivors is common.
readjustment to maintain therapeutic anti-Xa Diagnosis. MRI, CT or ultrasound visualizes
levels of 0.5–1 U/mL. A starting dose of 1.7 mg/ the subdural hemorrhages.
kg every 12 hours for term infants, or 2.0 mg/kg Management. Small hemorrhages do not
every 12 hours for preterm infants, may be ben- require treatment, but surgical evacuation of
eficial (Yang et al, 2010). Ultimately, therapeu- large collections relieves brainstem compression.
tic decisions must incorporate treatment of the
underlying cause of the thrombosis, if known.
Pyridoxine Dependency
Primary Subarachnoid Hemorrhage Pyridoxine dependency is a rare disorder trans-
Clinical Features. Blood in the subarach- mitted as an autosomal recessive trait (Gospe,
noid space probably originates from tearing of 2012). The genetic locus is unknown but the
the superficial veins by shearing forces during presumed cause is impaired glutamic decarbox-
a prolonged delivery with the head molding. ylase activity.
Mild HIE is often associated with subarachnoid Clinical Features. Newborns experience sei-
hemorrhage (SAH), but the newborn is usually zures soon after birth. The seizures are usually
well when an unexpected seizure occurs on the multifocal clonic at onset and progress rapidly to
first or second day of life. Lumbar puncture, status epilepticus. Although presentations con-
performed because of suspected sepsis, reveals sisting of prolonged seizures and recurrent epi-
blood in the CSF. The physician may suspect a sodes of status epilepticus are typical, recurrent
traumatic lumbar puncture; however, red blood self-limited events including partial seizures,
cell counts in first and last tube typically show generalized seizures, atonic seizures, myoclonic
similar counts in subarachnoid hemorrhage and events, and infantile spasms also occur. The
clearing numbers in traumatic taps. Most new- seizures only respond to pyridoxine. A seizure-
borns with subarachnoid hemorrhages will not free interval up to 3 weeks may occur after
suffer long-term sequelae. pyridoxine discontinuation. Outcome may be
improved and cognitive deficits decreased with Clinical Features. The female-to-male ratio
early diagnosis and treatment. is 20:1. An erythematous and vesicular rash
Atypical features include late-onset seizures resembling epidermolysis bullosa is present on
(up to age 2 years); seizures that initially respond the flexor surfaces of the limbs and lateral aspect
to antiepileptic drugs and then do not; seizures of the trunk at birth or soon thereafter. The
that do not initially respond to pyridoxine but rash persists for the first few months and a ver-
then become controlled; and prolonged seizure- rucous eruption that lasts for weeks or months
free intervals occurring after stopping pyridox- replaces the original rash. Between 6 and 12
ine. Intellectual disability is common. months of age, deposits of pigment appear in
Diagnosis. Suspect the diagnosis in newborns the previous area of rash in bizarre polymorphic
with an affected older sibling, or in newborns with arrangements. The pigmentation later regresses
daily seizures unresponsive to anticonvulsants, and leaves a linear hypopigmentation. Alopecia,
with progressive course and worsening EEGs. hypodontia, abnormal tooth shape, and dystro-
Characteristic of the infantile-onset variety is phic nails may be associated. Some have retinal
intermittent myoclonic seizures, focal clonic sei- vascular abnormalities that predispose to retinal
zures, or generalized tonic-clonic seizures. The detachment in early childhood.
EEG is continuously abnormal because of gen- Neurological disturbances occur in fewer
eralized or multifocal spike discharges and tends than half of the cases. In newborns, the promi-
to evolve into hypsarrhythmia. An intravenous nent feature is the onset of seizures on the sec-
injection of pyridoxine, 100 mg, stops the clini- ond or third day, often confined to one side of
cal seizure activity and often converts the EEG the body. Residual neurological handicaps may
to normal in less than 10 minutes. However, include cognitive impairment, epilepsy, hemipa-
sometimes 500 mg is required. When giving pyr- resis, and hydrocephalus.
idoxine IV, arousals may look like improvement Diagnosis. The clinical findings and biopsy of
in EEG since hypsarrhythmia is a pattern seen the skin rash are diagnostic. The basis for diag-
initially during sleep. Comparing sleep EEG nosis is the clinical findings and the molecular
before and after pyridoxine is needed to confirm testing of the IKBKG gene.
an EEG response. CSF neurotransmitter testing Management. Neonatal seizures caused by
is available to confirm the diagnosis. incontinentia pigmenti usually respond to stan-
Management. A lifelong dietary supplement dard anticonvulsant drugs. The blistering rash
of pyridoxine, 50–100 mg/day, prevents further requires topical medication and oatmeal baths.
seizures. Subsequent psychomotor development Regular ophthalmological examinations are
is best with early treatment, but this does not needed to diagnose and treat retinal detachment.
ensure a normal outcome. The dose needed to
prevent mental retardation may be higher than
that needed to stop seizures.
Treatment of Neonatal Seizures
Animal studies suggest that continuous seizure
activity, even in the normoxemic brain, may
Folinic Acid Dependency
cause brain damage by inhibiting protein synthe-
Folinic acid dependent seizures present similarly sis, breaking down polyribosomes, and via neu-
to pyridoxine dependency. rotransmitter toxicity. In premature newborns,
Clinical Features. Infants develop seizures an additional concern is that the increased cere-
during the first week of life that are not respon- bral blood flow associated with seizures will
sive to anticonvulsants or pyridoxine. increase the risk of intraventricular hemorrhage.
Diagnosis. A characteristic peak on CSF elec- Protein binding of anticonvulsant drugs may be
trophoresis confirms the diagnosis (Torres et al, impaired in premature newborns and the free
1999). fraction concentration may be toxic, whereas the
Management. Treat the disorder with folinic measured protein-bound fraction appears
acid supplementation, 2.5–5 mg twice daily. therapeutic.
The initial steps in managing newborns with
seizures are to maintain vital function, identify
Incontinentia Pigmenti
and correct the underlying cause, i.e., hypocalce-
(Bloch–Sulzberger Syndrome)
mia or sepsis, when possible, and rapidly provide
Incontinentia pigmenti is a rare neurocutaneous a therapeutic blood concentration of an anticon-
syndrome involving the skin, teeth, eyes, and vulsant drug when needed.
CNS. Genetic transmission is X-linked (Xq28) In the past, treatment of neonatal seizures had
with lethality in the hemizygous male (Scheuerle, little support based on evidence. Conventional
2010). treatments with phenobarbital and phenytoin
seem to be equally effective or ineffective exists between the intravenous dose of

(Painter, 1999). Levetiracetam, oxcarbazepine, phenobarbital in milligrams per kilogram of
and lamotrigine have been studied in infants body weight and the blood concentration in
as young as 1 month of age, demonstrating micrograms per milliliter measured 24 hours
safety and efficacy (Piña-Garza et al, 2005, after the load. A 20 µg/mL blood concentration
2008a,b, 2009). is safely achievable with a single intravenous
When treating neonatal seizures we must loading dose of 20 mg/kg injected at a rate of
first answer two questions: (1). Is the treatment 5 mg/min. The usual maintenance dose is 4 mg/
effective? Neonates have a different chloride kg/day. Use additional boluses of 10 mg/kg,
transporter in the first weeks of life, and opening to a total of 40 mg/kg, for those who fail to
the chloride pore by GABA activation may result respond to the initial load. In term newborns
in a hyperexcitable state rather than anticonvul- with intractable seizures from HIE the use of
sant effect. Furthermore, neuromotor dissocia- this drug to achieve a burst suppression pattern
tion has been documented when using is an alternative. The half-life of phenobarbital
phenobarbital in neonates, causing cessation of in newborns varies from 50 to 200 hours.
clinical convulsions while electrographic sei-
zures continue. (2). Are the seizures worse than Phenytoin. Fosphenytoin sodium is safer than
the possible unknown and known negative effect phenytoin for intravenous administration.
of medications in the developing brain, such as Oral doses of phenytoin are poorly absorbed
apoptosis? A few brief focal seizures may be in newborns. The efficacy of phenytoin in
acceptable in the setting of a resolving neonatal newborns is less than impressive and concerns
encephalopathy. exist regarding potential apoptosis. A single
intravenous injection of 20 mg/kg at a rate of
Antiepileptic Drugs 0.5 mg/kg/min safely achieves a therapeutic blood
concentration of 15–20 µg/mL (40–80 µmol/L).
Levetiracetam. The introduction of intravenous The half-life is long during the first week, and
levetiracetam (100 mg/mL) provides a new and the basis for further administration is current
safer option for the treatment of newborns. knowledge of the blood concentration. Most
Because levetiracetam is not liver metabolized, newborns require a maintenance dosage of
but excreted unchanged in the urine, no drug– 5–10 mg/kg/day.
drug interactions exist. Use of the drug requires
maintaining urinary output. We consider it an Duration of Therapy
excellent treatment option and recommend it
as initial therapy. The initial dose is 30–40 mg/ Seizures caused by an acute, self-limited and
kg; the maintenance dose is 40 mg/kg/day in resolved encephalopathy, such as mild HIE, do
the first 6 months of life, and up to 60 mg/kg/ not ordinarily require prolonged maintenance
day between 6 months and 4 years (Piña-Garza, therapy. In most newborns, seizures stop when
2009). The maintenance dose is dependent on the acute encephalopathy is over. Therefore, dis-
renal clearance. Reduce the dosage and dosing continuation of therapy after a period of com-
interval in neonates with hypoxic injury with plete seizure control is reasonable unless signs of
associated lower renal function. permanent cortical injury are confirmed by
EEG, imaging or clinical examination. If sei-
Oxcarbazepine. Oxcarbazepine suspension is a zures recur, reinitiate antiepileptic therapy.
good option in neonates with functioning In contrast to newborns with seizures caused
gastrointestinal tracts and a lower risk for by acute resolved encephalopathy, treat seizures
necrotizing enterocolitis. Doses between 20 and caused by cerebral dysgenesis or symptomatic
40 mg/kg/day for infants less than 6 months, and epilepsies continuously as most of them are life-
up to 60 mg/kg/day divided two or three times time epileptic conditions.
a day, are adequate for older infants and young
children (Piña-Garza, 2005).
Phenobarbital. Intravenous phenobarbital is a

PAROXYSMAL DISORDERS
widely used drug for the treatment of newborns IN CHILDREN LESS THAN
with seizures. However, its efficacy and safety 2 YEARS OLD
is under review. The chloride transporters
in newborns may convert phenobarbital into The pathophysiology of paroxysmal disorders
a proconvulsant or at least a less effective in infants is more variable than in newborns
anticonvulsant. A unitary relationship usually (Box 1-7). Seizures, especially febrile seizures,
BOX 1-7 Paroxysmal Disorders in decreased motor activity with indeterminate

Children Younger than changes in the level of consciousness arise from the
2 Years temporal, temporoparietal, or parieto-occipital
regions, while seizures with motor activity usually
Apnea and Breath-holding arise from the frontal, central, or frontoparietal
Cyanotic* regions.
Pallid
Dystonia Apnea and Syncope
Glutaric aciduria (see Chapter 14) The definition of infant apnea is cessation of
Transient paroxysmal dystonia of infancy breathing for 15 seconds or longer, or for less than
Migraine
15 seconds if accompanied by bradycardia. Prema-
ture newborns with respiratory distress syndrome
Benign paroxysmal vertigo* (see Chapter 10) may continue to have apneic spells as infants, espe-
Cyclic vomiting*
Paroxysmal torticollis* (see Chapter 14)
cially if they are neurologically abnormal.
Seizures*
Apneic Seizures
Febrile seizures
Epilepsy triggered by fever Apnea alone is rarely a seizure manifestation
Infection of the nervous system (Freed & Martinez, 2001). The frequency of
Simple febrile seizure apneic seizures relates inversely to age, more
Nonfebrile seizures often in newborns than infants, and rare in chil-
Generalized tonic-clonic seizures dren. Isolated apnea occurs as a seizure manifes-
Partial seizures
tation in infants and young children but, when
Benign familial infantile seizures
Ictal laughter reviewed on video, identification of other fea-
Myoclonic seizures tures becomes possible. Overall, reflux accounts
Infantile spasms for much more apnea than seizures in most
Benign myoclonic epilepsy infants and young children. Unfortunately,
Severe myoclonic epilepsy among infants with apneic seizures, EEG abnor-
Myoclonic status malities only appear at the time of apnea. There-
Lennox-Gastaut syndrome fore, monitoring is required for diagnosis.
Stereotypies (see Chapter 14)
*Denotes the most common conditions and the ones Breath-Holding Spells
with disease modifying treatments
Breath-holding spells with loss of consciousness
occur in almost 5 % of infants and young chil-
are the main cause of paroxysmal disorders, but dren. The cause is a disturbance in central auto-
apnea and syncope (breath-holding spells) are nomic regulation probably transmitted by
relatively common as well. Often, the basis for autosomal dominant inheritance with incom-
requested neurological consultation in infants plete penetrance. Approximately 20–30 % of
with paroxysmal disorders is the suspicion of sei- parents of affected children have a history of the
zures. The determination of which “spells” are condition. The term breath-holding is a misno-
seizures is often difficult and relies more on mer because breathing always stops in expira-
obtaining a complete description of the spell tion. Both cyanotic and pallid breath-holding
than any diagnostic tests. Ask the parents to pro- occurs; cyanotic spells are three times more
vide a sequential history. If more than one spell common than pallid spells. Most children expe-
occurred, they should first describe the one that rience only one or the other, but 20 % have both.
was best observed or most recent. The following The spells are involuntary responses to adverse
questions should be included: What was the stimuli. In approximately 80 % of affected chil-
child doing before the spell? Did anything pro- dren, the spells begin before 18 months of age,
voke the spell? Did the child’s color change? If and in all cases they start before 3 years of age.
so, when and to what color? Did the eyes move The last episode usually occurs by age 4 years and
in any direction? Did the spell affect one body no later than age 8 years.
part more than other parts?
In addition to obtaining a home video of the Cyanotic Syncope
spell, ambulatory or prolonged split-screen video- Clinical Features. The usual provoking
EEG monitoring is the only way to identify the stimulus for cyanotic spells is anger, pain, frus-
nature of unusual spells. Seizures characterized by tration, or fear. The infant’s sibling takes away a
toy, the child cries, and then stops breathing in dead and begin mouth-to-mouth resuscitation.
expiration. Cyanosis develops rapidly, followed After the initial limpness, the body may stiffen,
quickly by limpness and loss of consciousness. and clonic movements of the arms may occur. As
Crying may not precede cyanotic episodes pro- in cyanotic syncope, these movements represent
voked by pain. a brainstem release phenomenon, not seizure
If the attack lasts for only seconds, the infant activity. The duration of the spell is difficult to
may resume crying on awakening. Most spells, determine because the observer is so frightened
especially the ones referred for neurological that seconds seem like hours. Afterward the child
evaluation, are longer and are associated with often falls asleep and is normal on awakening.
tonic posturing of the body and trembling move- Diagnosis. Pallid syncope is the result of
ments of the hands or arms. The eyes may roll reflex asystole. Pressure on the eyeballs to ini-
upward. These movements are mistaken for sei- tiate a vagal reflex provokes an attack. I do not
zures by even experienced observers, but they recommend provoking an attack as an office pro-
are probably a brainstem release phenomenon. cedure. The history alone is diagnostic.
Concurrent EEG shows flattening of the record, Management. As with cyanotic spells, the
not seizure activity. major goal is to reassure the family that the child
After a short spell, the child rapidly recovers will not die during an attack. The physician must
and seems normal immediately; after a pro- be very convincing.
longed spell, the child first arouses and then goes
to sleep. Once an infant begins having breath- Febrile Seizures
holding spells, the frequency increases for sev-
eral months and then declines, and finally cease. An infant’s first seizure often occurs at the time
Diagnosis. The typical sequence of cyanosis, of fever. Three explanations are possible: (1) an
apnea, and loss of consciousness is critical for infection of the nervous system; (2) an underly-
diagnosis. Cyanotic syncope and epilepsy are ing seizure disorder in which the stress of fever
confused because of lack of attention to the pre- triggers the seizure, although subsequent sei-
cipitating event. It is not sufficient to ask, “Did zures may be afebrile; or (3) a simple febrile sei-
the child hold his breath?” The question conjures zure, a genetic age-limited epilepsy in which
up the image of breath-holding during inspira- seizures occur only with fever. The discussion of
tion. Instead, questioning should be focused on nervous system infection is in Chapters 2 and 4.
precipitating events, absence of breathing, facial Children who have seizures from encephalitis or
color, and family history. The family often has a meningitis do not wake up afterward; they are usu-
history of breath-holding spells or syncope. ally obtunded or comatose. The distinction between
Between attacks, the EEG is normal. During epilepsy and simple febrile seizures is sometimes
an episode, the EEG first shows diffuse slowing difficult and may require time rather than labo-
and then rhythmic slowing followed by back- ratory tests.
ground attenuation during the tonic-clonic, Epilepsy specialists who manage monitoring
tonic, myoclonic or clonic activity. units have noted that a large proportion of adults
Management. Education and reassurance. with intractable seizures secondary to mesial
The family should be educated to leave the temporal sclerosis have prior histories of febrile
child in supine with airway protection until he seizures as children. The reverse is not true.
or she recovers consciousness. Picking up the Among children with febrile seizures, mesial
child, which is the natural act of the mother or temporal sclerosis is a rare event (Tarkka et al,
observer, prolongs the spell. If the spells occur 2003).
in response to discipline or denial of the child’s Clinical Features. Febrile seizures not caused
wishes, I recommend caretakers comfort the by infection or another definable cause occur in
child but remain firm in their decision, as oth- approximately 4 % of children. Only 2 % of chil-
erwise children may learn that crying translates dren whose first seizure is associated with fever
into getting their wish. This may in turn rein- will have nonfebrile seizures (epilepsy) by age 7
force the spells. years. The most important predictor of subse-
quent epilepsy is an abnormal neurological or
Pallid Syncope developmental state. Complex seizures, defined
Clinical Features. The provocation of pallid as prolonged, focal, or multiple, and a family his-
syncope is usually a sudden, unexpected, painful tory of epilepsy slightly increase the probability
event such as a bump on the head. The child rarely of subsequent epilepsy.
cries but instead becomes white and limp and loses A single, brief, generalized seizure occurring
consciousness. These episodes are truly terrifying in association with fever is likely to be a simple
to behold. Parents invariably believe the child is febrile seizure. The seizure need not occur
during the time when fever is rising. “Brief” and 2. Strong family history of epilepsy and recur-
“fever” are difficult to define. Parents do not rent simple or complex febrile seizures.
time seizures. When a child has a seizure, sec- 3. Febrile status epilepticus.
onds seem like minutes. A prolonged seizure is 4. Febrile seizures with a frequency higher
one that is still in progress after the family has than once per quarter.
contacted the doctor or has left the house for the
emergency room. Postictal sleep is not part of
seizure time.
Nonfebrile Seizures
Simple febrile seizures are familial and prob- Disorders that produce nonfebrile seizures in
ably transmitted by autosomal dominant inheri- infancy are not substantially different from those
tance with incomplete penetrance. One-third of that cause nonfebrile seizures in childhood (see
infants who have a first simple febrile seizure will the following section). Major risk factors for the
have a second one at the time of a subsequent development of epilepsy in infancy and child-
febrile illness, and half of these will have a third hood are congenital malformations (especially
febrile seizure. The risk of recurrence increases migrational errors), neonatal seizures and insults,
if the first febrile seizure occurs before 18 months and a family history of epilepsy.
of age or at a body temperature less than 40°C. A complex partial seizure syndrome with
More than three episodes of simple febrile sei- onset during infancy, sometimes in the newborn
zures are unusual and suggest that the child may period, is ictal laughter associated with hypotha-
later have nonfebrile seizures. lamic hamartoma. The attacks are brief, occur
Diagnosis. Any child thought to have an several times each day, and may be characterized
infection of the nervous system should undergo by odd laughter or giggling. The first thought is
a lumbar puncture for examination of the CSF. that the laughter appears normal, but then facial
Approximately one-quarter of children with bac- flushing and pupillary dilatation are noted. With
terial or viral meningitis have seizures. After the time, the child develops drop attacks and gener-
seizure from CNS infection, prolonged obtun- alized seizures. Personality change occurs and
dation is expected. precocious puberty may be an associated
In contrast, infants who have simple febrile condition.
seizures usually look normal after the seizure. A first partial motor seizure before the age of
Lumbar puncture is unnecessary following a 2 years is associated with a recurrence rate of
brief, generalized seizure from which the child 87 %, whereas with a first seizure at a later age
recovers rapidly and completely, especially if the the rate is 51 %. The recurrence rate after a first
fever subsides spontaneously or is otherwise nonfebrile, asymptomatic, generalized seizure is
explained. 60–70 % at all ages. The younger the age at onset
Blood cell counts, measurements of glucose, of nonfebrile seizures of any type correlates with
calcium, electrolytes, urinalysis, EEG, and cra- a higher incidence of symptomatic rather than
nial CT or MRI on a routine basis are not cost idiopathic epilepsy.
effective and discouraged. Individual decisions Approximately 25 % of children who have
for laboratory testing depend upon the clinical recurrent seizures during the first year, exclud-
circumstance. Obtain an EEG on every infant ing neonatal seizures and infantile spasms, are
who is not neurologically normal or who has a developmentally or neurologically abnormal at
family history of epilepsy. Infants with complex the time of the first seizure. The initial EEG
febrile seizures may benefit from an EEG has prognostic significance; normal EEG results
or MRI. are associated with a favorable neurological
Management. Because only one-third of chil- outcome.
dren with an initial febrile seizure have a second Intractable seizures in children less than 2
seizure, treating every affected child is unreason- years of age are often associated with later cogni-
able. Treatment is unnecessary in the low-risk tive impairment. The seizure types with the
group with a single, brief, generalized seizure. greatest probability of cognitive impairment in
No evidence has shown that a second or third descending order are myoclonic, tonic-clonic,
simple febrile seizure, even if prolonged, causes complex partial, and simple partial.
epilepsy or brain damage. I always offer families Transmission of benign familial infantile epi-
the option to have diazepam gel available for lepsy is by autosomal dominant inheritance.
prolonged or acute repetitive seizures. Onset is as early as 3 months. The gene locus, on
I consider the use of anticonvulsant prophy- chromosome 19, is different from the locus for
laxis in the following situations: benign familial neonatal seizures. Motion arrest,
1. Complex febrile seizures in children with decreased responsiveness, staring or blank eyes,
neurological deficits. and mild focal convulsive movements of the
limbs characterize the seizures. Anticonvulsant BOX 1-8 Neurocutaneous Disorders

drugs provide easy control, and seizures usually Causing Seizures in Infancy
stop spontaneously within 2–4 years.
Incontinentia Pigmenti
Myoclonus and Myoclonic Seizures Seizure type
Neonatal seizures
Infantile Spasms. Infantile spasms are age- Generalized tonic-clonic
dependent myoclonic seizures that occur with an Cutaneous manifestations
incidence of 25 per 100 000 live births in the United Erythematous bullae (newborn)
States and Western Europe. An underlying cause Pigmentary whorls (infancy)
can be determined in approximately 75 % of Depigmented areas (childhood)
patients; congenital malformations and perinatal Linear Nevus Sebaceous Syndrome
asphyxia are common causes, and tuberous
Seizure type
sclerosis accounts for 20 % of cases in some series Infantile spasms
(Box 1-8). Despite considerable concern in the Lennox-Gastaut syndrome
past, immunization is not a cause of infantile Generalized tonic-clonic
spasms. Cutaneous manifestation
The combination of infantile spasms, agenesis Linear facial sebaceous nevus
of the corpus callosum (as well as other midline
Neurofibromatosis
cerebral malformations), and retinal malforma-
tions is referred to as Aicardi syndrome (Sutton & Seizure type
Van den Veyver, 2010). Affected children are Generalized tonic-clonic
Partial complex
always females, and genetic transmission of the
Partial simple motor
disorder is as an X-linked dominant trait with Cutaneous manifestations
hemizygous lethality in males. Café au lait spots
Clinical Features. The peak age at onset Axillary freckles
is between 4 and 7 months and onset always Neural tumors
before 1 year of age. The spasm can be a flexor,
extensor or mixed movement. Spasms generally Sturge-Weber Syndrome
occur in clusters during drowsiness, feedings Seizure type
and shortly after the infant awakens from sleep. Epilepsia partialis continuans
A rapid flexor spasm involving the neck, trunk, Partial simple motor
Status epilepticus
and limbs followed by a tonic contraction sus-
Cutaneous manifestation
tained for 2–10 seconds is characteristic. Less Hemifacial hemangioma
severe flexor spasms consist of dropping of the
head and abduction of the arms or by flexion Tuberous Sclerosis
at the waist. Extensor spasms resemble the sec- Seizure type
ond component of the Moro reflex: the head Neonatal seizures
moves backward and the arms suddenly spread. Infantile spasms
Whether flexor or extensor, the movement is Lennox-Gastaut syndrome
usually symmetrical and brief and tends to Generalized tonic-clonic
occur in clusters with similar intervals between Partial simple motor
Partial complex
spasms.
Cutaneous manifestations
When the spasms are secondary to an iden- Abnormal hair pigmentation
tifiable cause (symptomatic), the infant is usu- Adenoma sebaceum
ally abnormal neurologically or developmentally Café au lait spots
at spasms onset. Microcephaly is common in Depigmented areas
this group. Prognosis depends on the cause, Shagreen patch
the interval between the onset of clinical spasm
and hypsarrhythmia, and the rapidity of treat-
ment and control of this abnormal EEG
pattern.
Idiopathic spasms characteristically occur in idiopathic spasms would be neurologically nor-
children who had been developing normally at mal or only mildly cognitively impaired subse-
the onset of spasms and have no history of pre- quently. Some of these children may have had
natal or perinatal disorders. Neurological find- benign myoclonus. With improvement in diag-
ings, including head circumference, are normal. nostic testing, idiopathic infantile spasms are less
It had been thought that 40 % of children with frequent.
Management. A practice parameter for the

TABLE 1-1 E
lectroencephalographic
medical treatment of infantile spasms is avail-
(EEG) Appearance in
able (Mackay et al, 2004). Adrenocorticotropic
Myoclonic Seizures of
hormone (ACTH), the traditional treatment for
Infancy
infantile spasms, is effective for short-term treat-
Seizure Type EEG Appearance ment control of the spasms. ACTH has no effect
on the underlying mechanism of the disease and is
Infantile spasms Hypsarrhythmia
only a short-term symptomatic therapy. The ideal
Slow spike and wave
dosages and treatment duration is not established.
Burst suppression
ACTH gel is usually given as an intramuscular
Benign Normal
myoclonus
injection of 150 U/m2/day with a gradual tapering
Benign myoclonic Spike and wave (3 cps)
at weekly intervals over 6 to 8 weeks. Oral pred-
epilepsy Polyspike and wave (3 cps)
nisone, 2–4 mg/kg/day, with a tapering at weekly
Severe myoclonic Polyspike and wave (>3 cps)
intervals over 6 to 8 weeks is an alternative ther-
epilepsy apy. Even when the response is favorable, one-
Lennox-Gastaut Spike and wave (2–2.5 cps) third of patients have relapses during or after the
syndrome Polyspike and wave (2–2.5 cps) course of treatment with ACTH or prednisone.
Several alternative treatments avoid the
cps, cycles per second. adverse effects of corticosteroids and may have a
longer-lasting effect. Clonazepam, levetiracetam
(Gümüs et al, 2007; Mikati et al, 2008), and
Diagnosis. The delay from spasm onset to zonisamide (Lotze and Wilfong, 2004) are prob-
diagnosis is often considerable. Infantile spasms ably the safest alternatives. Valproate monother-
are so unlike the usual perception of seizures that apy controls spasms in 70 % of infants with doses
even experienced pediatricians may be slow to of 20–60 mg/kg/day, but due to concern for fatal
realize the significance of the movements. Colic hepatotoxicity has limited use in this age group.
is often the first diagnosis because of the sudden This concern is higher in idiopathic cases as an
flexor movements, and is treated several weeks underlying inborn error of metabolism or mito-
before suspecting seizures. chondrial disease may exist and increase the risk
EEG helps differentiate infantile spasms from for liver failure even in the absence of valproate.
benign myoclonus of early infancy (Table 1-1). Topiramate is an effective adjunctive treatment
The EEG is the single most important test for in doses up to 30 mg/kg/day (Glausser, 2000). It
diagnosis. However, EEG findings vary with the is typically well tolerated with few adverse
duration of recording, sleep state, duration of ill- effects; the most significant is a possible meta-
ness and underlying disorder. Hypsarrhythmia is bolic acidosis at high doses due to its carbonic
the usual pattern recorded during the early stages anhydrase activity.
of infantile spasms. A chaotic and continuously Vigabatrin is effective for treating spasms in
abnormal background of very high voltage and children with tuberous sclerosis and perhaps
random slow waves and spike discharges are cortical dysplasia (Parisi et al, 2007). This
characteristic. The spikes vary in location from medication is also helpful in other etiologies.
moment to moment and are generalized but The main concern regarding vigabatrin is the
never repetitive. Typical hypsarrhythmia usually loss of peripheral vision. Its use is justified in
starts during active sleep, progresses to quiet children with West syndrome (IS, develop-
sleep and finally wakefulness as a progressive mental regression and hypsarrhythmia) as
epileptic encephalopathy. During quiet sleep, most of them have cortical visual impairment
greater interhemispheric synchrony occurs and as part of the epileptic encephalopathy and
the background may have a burst-suppression may actually gain functional vision if vigaba-
appearance. trin is effective.
The EEG may normalize briefly upon Monotherapy for infantile spasms often fails,
arousal but, when spasms recur, an abrupt which suggests that early polypharmacy may
attenuation of the background or high-voltage provide better chances of controlling the pro-
slow waves appear. Within a few weeks, greater gressive epileptic encephalopathy. The authors
interhemispheric synchrony replaces the origi- often combine ACTH or prednisone with rapid
nal chaotic pattern of hypsarrhythmia. The titration of topiramate, vigabatrin or valproic
distribution of epileptiform discharges changes acid. Close follow-up with serial EEGs is essen-
from multifocal to generalized, and back- tial for evaluation of treatment efficacy, and to
ground attenuation follows the generalized determine if adding additional anticonvulsants,
discharges. is necessary. “Time is Brain.”
Benign Myoclonus of Infancy encompasses several syndromes in which an

Clinical Features. Many series of patients encephalopathy is associated with continuous
with infantile spasms include a small number with epileptiform activity. The onset of two syndromes,
normal EEG results. Such infants cannot be dis- early infantile epileptic encephalopathy
tinguished from others with infantile spasms by (Ohtahara syndrome) and early myoclonic
clinical features because the age at onset and the encephalopathy (Dulac, 2001), which may be
appearance of the movements are the same. The the same disorder, is in the first 3 months of age.
spasms occur in clusters, frequently at mealtime. Tonic spasms and myoclonic seizures occur in
Clusters increase in intensity and severity over a each. Both are associated with serious underlying
period of weeks or months and then abate spon- metabolic or structural abnormalities. Some cases
taneously. After 3 months, the spasms usually are familial, indicating an underlying genetic
stop altogether, and, although they may recur disorder. Progression to infantile spasms and the
occasionally, no spasms occur after 2 years of age. Lennox-Gastaut syndrome is common as with
Affected infants are normal neurologically and all epilepsies refractory to medical treatment.
developmentally and remain so afterward. The On EEG, a suppression pattern alternating
term benign myoclonus indicates that the spasms are with bursts of diffuse, high-amplitude, spike-
an involuntary movement rather than a seizure. wave complexes is recorded. These seizures are
Diagnosis. A normal EEG during awake refractory or only partially responsive to most
and sleep or while the myoclonus occurs distin- anticonvulsants drugs. The drugs recommended
guishes this group from other types of myoclo- for infantile spasms are used for these infants.
nus in infancy. No other tests are required.
Management. Education and reassurance. Severe Myoclonic Epilepsy of Infancy. Severe
myoclonic epilepsy of infancy (Dravet syndrome)
Benign Myoclonic Epilepsy. Despite the designa is an important but poorly understood syndrome
tion “benign,” the association of infantile myoclonus (Korff & Nordli, 2006). Some patients show a
with an epileptiform EEG rarely yields a favorable mutation in the sodium-channel gene (SCN1A).
outcome. A seemingly healthy infant has a seizure and then
Clinical Features. Benign myoclonic epilepsy undergoes progressive neurological deterioration
is a rare disorder of uncertain cause. One-third that ends in a chronic brain damage syndrome
of patients have family members with epilepsy (Dravet, 1978).
suggesting a genetic etiology. Onset is between Clinical Features. A family history of epilepsy
4 months and 2 years of age. Affected infants are is present in 25 % of cases. The first seizures are
neurologically normal at the onset of seizures frequently febrile, are usually prolonged, and can
and remain so afterward. Brief myoclonic attacks be generalized or focal clonic in type. Febrile
characterize the seizures. These may be restricted and nonfebrile seizures recur, sometimes as sta-
to head nodding or may be so severe as to throw tus epilepticus. Generalized myoclonic seizures
the child to the floor. The head drops to the appear after 1 year of age. At first mild and diffi-
chest, eyes roll upward, the arms move upward cult to recognize as a seizure manifestation, they
and outward, and legs flex. Myoclonic seizures later become frequent and repetitive and disturb
may be single or repetitive, but consciousness is function. Partial complex seizures with second-
not lost. No other seizure types occur in infancy, ary generalization may also occur. Coincident
but generalized tonic-clonic seizures may occur with the onset of myoclonic seizures are the
in adolescence. slowing of development and the gradual appear-
Diagnosis. EEG during a seizure shows gener- ance of ataxia and hyperreflexia.
alized spike-wave or polyspike-wave discharges. Diagnosis. The initial differential diagnosis
Sensory stimuli do not activate seizures. The is febrile seizures. The prolonged and some-
pattern is consistent with primary generalized times focal nature of the febrile seizures raises
epilepsy. suspicion of symptomatic epilepsy. A specific
Management. Valproate produces com- diagnosis is not possible until the appearance of
plete seizure control, but levetiracetam and myoclonic seizures in the second year. Interic-
zonisamide are safer options for initial treat- tal EEG findings are normal at first. Paroxysmal
ment. Developmental outcome generally is good abnormalities appear in the second year. These
with early treatment, but cognitive impairment are characteristically generalized spike-wave
may develop in some children. If left untreated, and polyspike-wave complexes with a frequency
seizures may persist for years. greater than 3 cps. Photic stimulation, drowsi-
ness, and quiet sleep activate the discharges.
Early Epileptic Encephalopathy with Burst Management. Dravet syndrome is quite diffi-
Suppression. The term epileptic encephalopathy cult to treat and typically requires polypharmacy.
Sodium channel drugs such as phenytoin, car- Most children are neurologically abnormal
bamazepine, lamotrigine, and oxcarbazepine before seizure onset. Every seizure type exists in
tend to exacerbate seizures. Medications such LGS, except for typical absences. Atypical
as levetiracetam (Striano et al, 2007), divalproex absence seizures occur in almost every patient
sodium, topiramate, zonisamide and rufinamide and drop attacks (atonic and tonic seizures) are
are good alternatives. essential for the diagnosis. Characteristic of
atonic seizures is a sudden dropping of the head
Biotinidase Deficiency. Genetic transmission or body, at times throwing the child to the
of this relatively rare disorder is as an autosomal ground. Most children with the syndrome func-
recessive trait (Wolf, 2011). The cause is tion in the cognitively impaired range by 5 years
defective biotin absorption or transport and of age.
was previously called late-onset multiple (holo) Diagnosis. An EEG is essential for diagno-
carboxylase deficiency. sis. The waking interictal EEG consists of an
Clinical Features. The initial features in abnormally slow background with characteristic
untreated infants with profound deficiency are 1.5–2.5 Hz slow spike-and-wave interictal dis-
seizures and hypotonia. Later features include charges, often with an anterior predominance.
hypotonia, ataxia, developmental delay, hearing Tonic seizures are associated with 1 cps slow
loss, and cutaneous abnormalities. In childhood, waves followed by generalized rapid discharges
patients may also develop weakness, spastic pare- without postictal depression.
sis, and decreased visual acuity. In addition to EEG, looking for the underly-
Diagnosis. Ketoacidosis, hyperammonemia, ing cause requires a thorough evaluation with
and organic aciduria are present. Showing bio- special attention to skin manifestations that sug-
tinidase deficiency in serum, during newborn gest a neurocutaneous syndrome (see Box 1-8).
screening, establishes the diagnosis. In profound MRI is useful for the diagnosis of brain dysgen-
biotinidase deficiency, mean serum biotinidase esis, postnatal disorders, and neurocutaneous
activity is less than 10 % of normal. In partial syndromes.
biotinidase deficiency, serum biotinidase activity Management. Seizures are difficult to con-
is 10–30 % of normal. trol with drugs, diet, and surgery. Rufinamide,
Management. Early treatment with biotin, valproate, lamotrigine, topiramate, felbamate,
5–20 mg/day, successfully reverses most of the clobazam, and clonazepam are usually the most
symptoms, and may prevent mental retardation. effective drugs. Consider the ketogenic diet and
surgery when drugs fail. Vagal nerve stimulation
Lennox-Gastaut Syndrome. The triad of (VNS) and corpus callosotomy are alternatives for
seizures (atypical absence, atonic, and myoclonic), drop attacks refractory to medications and diet.
1.5–2 Hz spike-wave complexes on EEG, and
cognitive impairment characterize the Lennox-
Gastaut syndrome (LGS). LGS is the description
Migraine
of one stage in the spectrum of a progressive Clinical Features. Migraine attacks are
epileptic encephalopathy. Nobody is born with uncommon in infancy, but, when they occur, the
LGS. LGS is the result of epilepsies refractory to clinical features are often paroxysmal and sug-
medical management, evolving into symptomatic gest the possibility of seizures. Cyclic vomiting
generalized epilepsies with the characteristics is probably the most common manifestation.
described above. The characteristics of the Attacks of vertigo (see Chapter 10) or torticollis
syndrome fade away in many survivors and the (see Chapter 14) may be especially perplexing,
EEG may evolve into a multifocal pattern with and some infants have attacks in which they rock
variable seizure types. I often used the term back and forth and appear uncomfortable.
Lennox-Gastaut spectrum (also LG little s) for Diagnosis. The stereotypical presentation
the stages preceding and following the stage of benign paroxysmal vertigo is recognizable as a
described by Lennox and Gastaut. migraine variant. Other syndromes often remain
Clinical Features. The peak age at onset undiagnosed until the episodes evolve into a typ-
is 3 to 5 years; less than half of the cases begin ical migraine pattern. A history of migraine in
before age 2 years. Approximately 60 % have an one parent, usually the mother, is essential for
identifiable underlying cause. Neurocutaneous diagnosis.
disorders such as tuberous sclerosis, perinatal Management. There is little if any evi-
disturbances, and postnatal brain injuries are dence on migraine prophylaxis or abortive
most common. Twenty percent of children with treatment in this age group. I have used small
the LGS have a history of infantile spasms before doses of amitriptyline (5 mg) in cases requiring
development of the syndrome. prophylaxis with some success and ibuprofen,
acetaminophen, prochlorperazine or prometha- Familial Paroxysmal Choreoathetosis

zine as abortive therapies.
Genetic transmission is as an autosomal domi-
nant trait and the gene maps to chromosome
PAROXYSMAL DISORDERS 16p11.2. The disorder shares some clinical fea-
OF CHILDHOOD tures with benign familial infantile convulsions
and paroxysmal choreoathetosis. All three disor-
Like infants, seizures are the usual first consider- ders map to the same region on chromosome 16,
ation for any paroxysmal disorder. Seizures are suggesting that they may be allelic disorders.
the most common paroxysmal disorder requir- Clinical Features. FPC usually begins in child-
ing medical consultation. Syncope, especially hood. Most cases are sporadic. Sudden move-
presyncope, is considerably more common but ment, startle, or changes in position precipitate
diagnosis and management usually occur at an attack, which last less than a minute. Several
home unless associated symptoms suggest a attacks occur each day. Each attack may include
seizure. dystonia, choreoathetosis, or ballismus (see
Migraine is probably the most common eti- Chapter 14) and may affect one or both sides of
ology of paroxysmal neurological disorders in the body. Some patients have an “aura” described
childhood; its incidence is 10 times greater than as tightness or tingling of the face or limbs.
that of epilepsy. Chapters 2, 3, 10, 11, 14, and Diagnosis. The clinical features distinguish
15 describe migraine syndromes that may sug- the diagnosis.
gest epilepsy. Several links exist between Treatment. Low dosages of carbamazepine
migraine and epilepsy (Minewar, 2007): (1) ion or phenytoin are effective in stopping attacks.
channel disorders cause both; (2) both are Other sodium channel drugs such as lamotrigine
genetic, paroxysmal, and associated with transi- or oxcarbazepine may be beneficial. Lacosamide
tory neurological disturbances; (3) migraine acts on the sodium channel differently, but is
sufferers have an increased incidence of epi- also helpful.
lepsy and epileptics have an increased incidence
of migraine; and (4) they are both disorders Familial Paroxysmal Nonkinesiogenic
associated with a hyperexcitable brain cortex. Dyskinesia
In children who have epilepsy and migraine,
both disorders may have a common aura and Genetic transmission of PNKD is as an autoso-
one may provoke the other. Basilar migraine mal dominant trait (Spacey & Adams, 2011).
(see Chapter 10) and benign occipital epilepsy The MR1 gene on chromosome 2 is
best exemplify the fine line between epilepsy responsible.
and migraine. Characteristic of both are sei- Clinical Features. PNKD usually begins in
zures, headache, and epileptiform activity. childhood or adolescence. Attacks of dystonia,
Children who have both epilepsy and migraine chorea, and athetosis last from 5 minutes to
require treatment for each condition but some several hours. Precipitants are alcohol, caffeine,
drugs (valproate and topiramate) serve as pro- hunger, fatigue, nicotine, and emotional stress.
phylactic agents for both. Preservation of consciousness is a constant dur-
ing attacks and life expectancy is normal.
Diagnosis. Molecular diagnosis is available
Paroxysmal Dyskinesias on a research basis. Ictal and interictal EEGs are
Paroxysmal dyskinesia occurs in several different normal. Consider children with EEG evidence
syndromes. The best delineated are familial par- of epileptiform activity to have epilepsy and not
oxysmal (kinesiogenic) choreoathetosis (FPC), a paroxysmal dyskinesia.
paroxysmal nonkinesiogenic dyskinesia (PNKD), Management. PNKD is difficult to treat, but
supplementary sensorimotor seizures, and par- clonazepam taken daily or at the first sign of an
oxysmal nocturnal dystonia. The clinical distinc- attack may reduce the frequency or severity of
tion between the first two depends upon whether attacks. Gabapentin is effective in some children.
or not movement provokes the dyskinesia. The
second two are more clearly epilepsies and dis- Hyperventilation Syndrome
cussed elsewhere in this chapter. A familial syn-
drome of exercise induced dystonia and migraine Hyperventilation induces alkalosis by altering
does not show linkage to any of the known genes the proportion of blood gases. This is easier to
for paroxysmal dyskinesias (Munchau et al, accomplish in children than in adults.
2000). Channelopathies account for all paroxys- Clinical Features. During times of emotional
mal dyskinesias. upset, the respiratory rate and depth may increase
insidiously, first appearing like sighing and then paralysis. Two to four attacks occur daily,
as obvious hyperventilation. The occurrence of usually in the afternoon. They are embar-
tingling of the fingers disturbs the patient fur- rassing but usually do not cause physical
ther and may induce greater hyperventilation. harm.
Headache is an associated symptom. Allowing 3. Sleep paralysis occurs in the transition
hyperventilation to continue may result in loss between sleep and wakefulness. The
of consciousness. patient is mentally awake but unable
Diagnosis. The observation of hyperventila- to move because of generalized paraly-
tion as a precipitating factor of syncope is essen- sis. Partial paralysis is less common. The
tial to diagnosis. Often patients are unaware attack may end spontaneously or when the
that they were hyperventilating, but probing patient is touched. Two-thirds of patients
questions elicit the history in the absence of a with narcolepsy-cataplexy also experi-
witness. ence sleep paralysis once or twice each
Management. Breathing into a paper bag week. Occasional episodes of sleep paraly-
aborts an attack in progress. sis may occur in people who do not have
narcolepsy-cataplexy.
4. Hypnagogic hallucinations are vivid, usually
Sleep Disorders frightening, visual, and auditory percep-
tions occurring at the transition between
Narcolepsy-Cataplexy
sleep and wakefulness: a sensation of
Narcolepsy-cataplexy is a sleep disorder charac- dreaming while awake. These are an asso-
terized by an abnormally short latency from ciated event by half of the patients with
sleep onset to rapid eye movement (REM) sleep. narcolepsy-cataplexy. Episodes occur less
A person with narcolepsy attains REM sleep in than once a week.
less than 20 minutes instead of the usual 90 min- 5. Disturbed night sleep occurs in 75 % of cases
utes. Characteristic of normal REM sleep are and automatic behavior in 30 %. Automatic
dreaming and severe hypotonia. In narcolepsy- behavior is characterized by repeated per-
cataplexy, these phenomena occur during formance of a function such as speaking or
wakefulness. writing in a meaningless manner or driv-
Human narcolepsy, unlike animal narcolepsy, ing on the wrong side of the road or to a
is not a simple genetic trait (Scammell, 2003). strange place without recalling the episode.
Evidence suggests an immunologically mediated These episodes of automatic behavior may
destruction of hypocretin-containing cells in result from partial sleep episodes.
human narcolepsy. An alternate name for hypo- Diagnosis. Syndrome recognition is by the
cretin is orexin. Most cases of human narcolepsy clinical history. However, the symptoms are
with cataplexy have decreased hypocretin 1 in embarrassing or sound “crazy” and considerable
the CSF (Nishino, 2007) and an 85–95 % reduc- prompting is required before patients divulge a
tion in the number of orexin/hypocretin-con- full history. Narcolepsy can be difficult to dis-
taining neurons. tinguish from other causes of excessive daytime
Clinical Features. Onset may occur at any sleepiness. The multiple sleep latency test is the
time from early childhood to middle adult- standard for diagnosis. Patients with narcolepsy
hood, usually in the second or third decade and enter REM sleep within a few minutes of falling
rarely before age 5 years. The syndrome has five asleep.
components: Management. Symptoms of narcolepsy tend
1. Narcolepsy refers to short sleep attacks. to worsen during the first years and then stabilize
Three or four attacks occur each day, most while cataplexy tends to improve with time. Two
often during monotonous activity, and scheduled 15-minute naps each day can reduce
are difficult to resist. Half of the patients excessive sleepiness. Most patients also require
are easy to arouse from a sleep attack, and pharmacological therapy.
60 % feel refreshed afterward. Narcolepsy Modafinil, a wake-promoting agent distinct
is usually a lifelong condition. from stimulants, has proven efficacy for narco-
2. Cataplexy is a sudden loss of muscle tone lepsy and is the first drug of choice. The adult
induced by laughter, excitement, or startle. dose is 200 mg each morning, and, while not
Almost all patients who have narcolepsy approved for children, reduced dosages, depend-
have cataplexy as well. The patient may ing on the child’s weight, are in common usage.
collapse to the floor and then arise imme- If modafinil fails, methylphenidate or pemoline
diately. Partial paralysis, affecting just the is usually prescribed for narcolepsy but should be
face or hands, is more common than total given with some caution because of potential
abuse. Use small dosages on schooldays or work- are brisk, and the response spreads to other
days and no medicine, if possible, on weekends muscles.
and holidays. When not taking medicine, The stiffness resolves spontaneously during
patients should be encouraged to schedule short infancy, and by 3 years of age most children are
naps. normal; however, episodes of stiffness may recur
Treatment for cataplexy includes selective during adolescence or early adult life in response
serotonin reuptake inhibitors (SSRIs), clomip- to startle, cold exposure, or pregnancy. Through-
ramine, and protriptyline. out life, affected individuals show a pathologi-
cally exaggerated startle response to visual,
Sleep (Night) Terrors and auditory, or tactile stimuli that would not startle
Sleepwalking normal individuals. In some, the startle is associ-
ated with a transitory, generalized stiffness of the
Sleep terrors and sleepwalking are partial body that causes falling without protective
arousals from nonrapid eye movement (non- reflexes, often leading to injury. The stiffening
REM) sleep. A positive family history is response is often confused with the stiff man
common. syndrome (see Chapter 8).
Clinical Features. The onset usually occurs Other findings include periodic limb move-
by 4 years of age and always by age 6 years. Two ments in sleep (PLMS) and hypnagogic (occur-
hours after falling asleep the child awakens in a ring when falling asleep) myoclonus. Intellect is
terrified state, does not recognize people, and is usually normal.
inconsolable. An episode usually lasts for 5–15 Diagnosis. A family history of startle disease
minutes but can last for an hour. During this helps the diagnosis, but often is lacking. In star-
time the child screams incoherently, may run tle disease, unlike startle-provoked epilepsy, the
if not restrained, and then goes back to sleep. EEG is always normal.
Afterward, the child has no memory of the Management. Clonazepam is the most useful
event. agent to reduce the attack frequency. Valproate
Most children with sleep terrors experience or levetiracetam are also useful. Affected infants
an average of one or more episodes each week. get better with time.
Night terrors stop by 8 years of age in one-half
of affected children but continue into adoles- Syncope
cence in one-third.
Diagnosis. Half of the children with night Syncope is loss of consciousness because of a
terrors are also sleepwalkers, and many have a transitory decline in cerebral blood flow. The
family history of either sleepwalking or sleep pathological causes include an irregular cardiac
terrors. The history alone is the basis for diag- rate or rhythm, or alterations of blood volume or
nosis. A sleep laboratory evaluation often shows distribution. However, syncope is a common event in
that children with sleep terrors suffer from otherwise healthy children, especially in the second
sleep-disordered breathing (Guilleminault decade affecting girls more than boys. Diagnostic test-
et al, 2003). ing is rarely necessary.
Management. Correction of the breath- Clinical Features. The mechanism is a vaso-
ing disturbance often ends sleep terrors and vagal reflex by which an emotional experience
sleepwalking. produces peripheral pooling of blood. Other
stimuli that provoke the reflex are overextension
Stiff Infant Syndrome or sudden decompression of viscera, the Valsalva
maneuver, and stretching with the neck hyper-
(Hyperekplexia) extended. Fainting in a hot, crowded church is
Five different genes are associated with the syn- especially common. Usually, the faint occurs as
drome. Both autosomal dominant and autosomal the worshipper rises after prolonged kneeling.
recessive forms exist (De Koning-Tijssen & Healthy children do not faint while lying
Rees, 2009). down and rarely while seated. Fainting from
Clinical Features. The onset is at birth or anything but standing or arising suggests a car-
early infancy. When the onset is at birth, the diac arrhythmia and requires further investiga-
newborn may appear hypotonic during sleep tion. The child may first feel faint (described as
and develop generalized stiffening on awaken- “faint,” “dizzy,” or “light-headed”) or may lose
ing. Apnea and an exaggerated startle response consciousness without warning. The face drains
are associated signs. Hypertonia in the new- of color and the skin is cold and clammy. With
born is unusual. Rigidity diminishes but does loss of consciousness, the child falls to the floor.
not disappear during sleep. Tendon reflexes The body may stiffen and the limbs may tremble.
The latter is not a seizure and the trembling usually last for more than 1 minute and are fol-
movements never appear as clonic movements. lowed by fatigue and psychomotor slowing. The
The stiffening and trembling are especially com- associated EEG patterns and the response to
mon when keeping the child upright, which pro- treatment are quite different, and the basis for
longs the reduced cerebral blood flow. This is appropriate treatment is precise diagnosis before
common in a crowded church where the pew has initiating treatment.
no room to fall and bystanders attempt to bring Absence seizures occur in four epileptic syn-
the child outside “for air.” A short period of con- dromes: childhood absence epilepsy, juvenile
fusion may follow, but recovery is complete absence epilepsy, juvenile myoclonic epilepsy,
within minutes. and epilepsy with grand mal on awakening. All
Diagnosis. The criteria for differentiating four syndromes are genetic disorders transmit-
syncope from seizures are the precipitating fac- ted as autosomal dominant traits. The pheno-
tors and the child’s appearance. Seizures are types have considerable overlap. The most
unlikely to produce pallor and cold, clammy significant difference is the age at onset.
skin. Always inquire about the child’s facial color
in all initial evaluations of seizures. Diagnostic
Absence Epilepsy
tests are not cost effective when syncope occurs
in expected circumstances and the results of Childhood absence epilepsy usually begins
the clinical examination are normal. Recurrent between ages 5 and 8 years of age. As a rule, later
orthostatic syncope requires investigation of onset is more likely to represent juvenile absence
autonomic function, and any suspicion of cardiac epilepsy, with a higher frequency of generalized
abnormality deserves ECG monitoring. Always tonic-clonic seizures, and persistence into adult
ask the child if irregular heart rate or beats life.
occurred at the time of syncope or at other times. Clinical Features. The reported incidence of
Management. Infrequent syncopal episodes epilepsy in families of children with absence var-
of obvious cause do not require treatment. ies from 15% to 40 %. Concurrence in monozy-
Holding deep inspiration at the onset of symp- gotic twins is 75 % for seizures and 85 % for the
toms may abort an attack (Norcliffe-Kauffman characteristic EEG abnormality.
et al, 2008). Good hydration and avoiding sud- Affected children are otherwise healthy. Typ-
den change from prolonged supine into stand- ical attacks last for 5–10 seconds and occur up to
ing position decreases orthostasis and orthostatic 100 times each day. The child stops ongoing
syncope. activity, stares vacantly, sometimes with rhyth-
mic movements of the eyelids, and then resumes
activity. Aura and postictal confusion never
Staring Spells occur. Longer seizures may last for up to 1 min-
Daydreaming is a pleasant escape for people of ute and are indistinguishable by observation
all ages. Children feel the need for escape most alone from complex partial seizures. Associated
acutely when in school and may stare vacantly features may include myoclonus, increased or
out of the window to the place where they would decreased postural tone, picking at clothes, turn-
rather be. Daydreams can be hard to break, and ing of the head, and conjugate movements of the
a child may not respond to verbal commands. eyes. Occasionally, prolonged absence status
Neurologists and pediatricians often recom- causes confusional states in children and adults.
mend EEG studies for daydreamers. Sometimes, These often require emergency department vis-
the EEG shows sleep-activated central spikes or its (see Chapter 2).
another abnormality not related to staring, A small percent age of children with absence
which may lead the physician to prescribe inap- seizures also have generalized tonic-clonic sei-
propriate antiepileptic drug therapy. The best zures. The occurrence of a generalized tonic-
test for unresponsiveness during a staring spell is clonic seizure in an untreated child does not
applying a mild noxious stimulus, such as pres- change the diagnosis or prognosis, but changes
sure on the nail bed. Children with behavioral medication selection for seizure control.
staring will have an immediate response and Diagnosis. The background rhythms in
children with absence or partial seizures will patients with typical absence seizures usually are
have a decreased or no response. normal. The interictal EEG pattern for typical
Staring spells are characteristic of absence absence seizures is a characteristic 3 Hz spike-
epilepsies and complex partial seizures. They are and-wave pattern lasting less than 3 seconds
usually distinguishable because absence is brief that may cause no clinical changes (Figure 1-2).
(5–15 seconds) and the child feels normal imme- Longer paroxysms of 3 cps spike-wave complexes
diately afterward, while complex partial seizures are concurrent with the clinical seizure (ictal
Fp1–F3
F3–C3
C3–P3
P3–O1
Fp2–F4
F4–C4
C4–P4
FIGURE 1-2 n Absence epilepsy. A
P4–O2 generalized burst of 3 cps spike-
wave complexes appears during
hyperventilation.
Complex Partial Seizures

pattern). The amplitude of discharge is greatest
in the frontocentral regions, but variants with Complex partial seizures arise in the cortex, most
occipital predominance may occur. Although the often the temporal lobe, but can originate from
discharge begins with a frequency of 3 cps, it may the frontal, occipital or parietal lobes as well.
slow to 2 cps as it ends. Complex partial seizures (discussed more fully in
Hyperventilation usually activates the dis- a later section) may be symptomatic of an under-
charge. The interictal EEG is usually normal, lying focal disorder.
but brief generalized discharges are often seen. Clinical Features. Impaired consciousness
Although the EEG pattern of discharge is ste- without generalized tonic-clonic activity char-
reotyped, variations on the theme in the form of acterizes complex partial seizures. Some altered
multiple spike and wave discharges and bi-frontal mentation, lack of awareness or amnesia for the
or bi-occipital 3 Hz delta waves are also accept- event are essential features. They either occur
able. During sleep, the discharges often lose their spontaneously or are sleep-activated. Most last 1–2
stereotypy and become polymorphic and change minutes and rarely less than 30 seconds. Less than
in frequency but remain generalized. Once a cor- 30 % of children report an aura. The aura is usu-
relation between clinical and EEG findings is ally a nondescript unpleasant feeling, but may also
made, looking for an underlying disease is unnec- be a stereotyped auditory or visual hallucination
essary. The distinction between absence epilepsy or abdominal discomfort. The first feature of the
and juvenile myoclonic epilepsy (see later discus- seizure can be staring, automatic behavior, tonic
sion on Myoclonic Seizures) is the age at onset extension of one or both arms, or loss of body
and absence of myoclonic seizures. tone. Staring is associated with a change in facial
Management. Ethosuximide is the most expression and followed by automatic behavior.
effective drug with complete seizure control Automatisms are more or less coordinated,
in about 80 %. Lamotrigine and valproate are involuntary motor activity occurring during a
equally effective with each providing complete state of impaired consciousness either in the
relief of seizures in about 60 % of children. course of or after an epileptic seizure and usually
Ethosuximide is preferred because of its lower followed by amnesia. They vary from facial gri-
incidence of serious side effects. Levetiracetam macing and fumbling movements of the fingers
and zonisamide seem to work in a smaller per- to walking, running, and resisting restraint.
centage of patients and topiramate is relatively Automatic behavior in a given patient tends to be
ineffective for absence seizures. If neither drug similar from seizure to seizure.
alone provides seizure control, use them in The seizure usually terminates with a period
combination at reduced dosages or substitute of postictal confusion, disorientation, or leth-
another drug. The EEG becomes normal if argy. Transitory aphasia is sometimes present.
treatment is successful, and repeating the EEG Secondary generalization is likely if the child is
is useful to confirm the seizure-free state. not treated or if treatment is abruptly
Clonazepam is sometimes useful in the treat- withdrawn.
ment of refractory absence. Carbamazepine Partial complex status epilepticus is a rare
may accentuate the seizures and cause absence event characterized by impaired conscious
status. ness, staring alternating with wandering eye
movements, and automatisms of the face and of the corners of the mouth. Absence and general-
hands. Such children may arrive at the emer- ized tonic-clonic seizures may occur. Such chil-
gency department in a confused or delirious dren are prone to develop absence status
state (see Chapter 2). epilepticus.
Diagnosis. The etiology of complex partial Diagnosis. Reproduce the typical features
seizures is heterogeneous, and a cause is often with video/EEG.
not determined. Contrast-enhanced MRI is Treatment. Treatment is similar to the other
an indicated study in all cases. It may reveal a idiopathic generalized epilepsies: ethosuximide,
low-grade glioma or dysplastic tissue, especially lamotrigine, levetiracetam, divalproex sodium.
migrational defects.
Record an EEG in both the waking and
sleeping states. Hyperventilation and photic
Myoclonic Seizures
stimulation are not useful as provocative mea- Myoclonus is a brief, involuntary muscle contrac-
sures. Results of a single EEG may be normal in tion (jerk) that may represent: (1) a seizure mani-
the interictal period, but prolonged EEGs usu- festation, as in juvenile myoclonic epilepsy; (2) a
ally reveal either a spike or a slow wave focus in physiological response to startle or to falling
the epileptogenic area. During the seizure a dis- asleep; (3) an involuntary movement of sleep; or
charge of evolving amplitude, frequency, and (4) an involuntary movement from disinhibition
morphology occurs in the involved area of of the spinal cord (see Table 14-7). Myoclonic sei-
cortex. zures are often difficult to distinguish from myo
Management. All seizure medications with clonus (the movement disorder) on clinical
the exception of ethosuximide have similar effi- grounds alone. Chapter 14 discusses essential myoc-
cacy controlling partial seizures. I often select lonus and other nonseizure causes of myoclonus.
oxcarbazepine, levetiracetam or lamotrigine
based on safety, tolerability and potential side Juvenile Myoclonic Epilepsy
effects. Topiramate and divalproex sodium
are good alternatives for migraine sufferers Juvenile myoclonic epilepsy (JME) is an heredi-
with disability from this co-morbidity. Sur- tary disorder, probably inherited as an autosomal
gery should be offered to good surgical candi- dominant trait (Wheless & Kim, 2002). It accounts
dates with epilepsy refractory to treatment or for up to 10 % of all cases of epilepsy. Many dif-
unacceptable side effects. Consider ketogenic ferent genetic loci produce JME syndromes.
diet and vagal nerve stimulation for all other Clinical Features. JME occurs in both gen-
patients with partial response to treatments (see ders with equal frequency. Seizures in affected
section on Surgical Approaches to Childhood children and their affected relatives may be
Epilepsy). tonic-clonic, myoclonic, or absence. The usual
age at onset of absence seizures is 7–13 years; of
Eyelid Myoclonia With or Without myoclonic jerks, 12–18 years; and of generalized
tonic-clonic seizures, 13–20 years.
Absences (Jeavons Syndrome) The myoclonic seizures are brief and bilat-
Jeavons syndrome is a distinct syndrome. eral, but not always symmetric, flexor jerks of the
Clinical Features. Children present between arms, which may be repetitive. The jerk some-
age 2 and 14 years with eye closure induced times affects the legs, causing the patient to fall.
seizures (eyelid myoclonia), photosensitivity, The highest frequency of myoclonic jerks is in
and EEG paroxysms, which may be associated the morning. Consciousness is not impaired so
with absence. Eyelid myoclonia, a jerky upward the patient is aware of the jerking movement.
deviation of the eyeballs and retropulsion of the Seizures are precipitated by sleep deprivation,
head, is the key feature. The seizures are brief alcohol ingestion, and awakening from sleep.
but occur multiple times per day. In addition Most patients also have generalized tonic-
to eye closure, bright light, not just flickering clonic seizures, and a third experience absence.
light, may precipitate seizures. Jeavons syn- All are otherwise normal neurologically. The
drome appears to be a lifelong condition. The potential for seizures of one type or another con-
eyelid myoclonia is resistant to treatment. The tinues throughout adult life.
absences are responsive to ethosuximide, dival- Diagnosis. Delays in diagnosis are common,
proex sodium, and lamotrigine. often until a generalized tonic-clonic seizure
An apparently separate condition, perioral myo- brings the child to medical attention. Ignoring the
clonia with absences, also occurs in children. myoclonic jerks is commonplace. Suspect JME in
A rhythmic contraction of the orbicularis oris mus- any adolescent driver involved in a motor vehicle acci-
cle causes protrusion of the lips and contractions dent, when the driver has no memory of the event, but
93 secs Hyperventilation (05:01.2) 100 secs

Command Response
Fp1-A1A2
Fp2-A1A2
Fp3-A1A2
Fp4-A1A2
C3-A1A2
C4-A1A2
P3-A1A2
P4-A1A2
O1-A1A2
O2-A1A2
F7-A1A2
F8-A1A2
T7-A1A2
T8-A1A2
P7-A1A2
P8-A1A2
Fz-A1A2
Cz-A1A2
Pz-A1A2
EKG
10:19:56 AM LE, 10 sec/screen, 30µV/mm, 70.0 Hz, 1.000 Hz, Notch off
FIGURE 1-3 n Childhood absence epilepsy: 3.2 Hz generalized spike and slow wave discharge lasting 4.5 seconds
during hyperventilation.
did not sustain a head injury. The interictal EEG in BOX 1-9 Progressive Myoclonus
JME consists of bilateral, symmetrical spike and Epilepsies
polyspike-and-wave discharges of 3.5–6 Hz, usu-
ally maximal in the frontocentral regions (Figure Ceroid lipofuscinosis, juvenile form (see Chap-
1-3). Photic stimulation often provokes a dis- ter 5)
charge. Focal EEG abnormalities may occur. Glucosylceramide lipidosis (Gaucher type 3)
Management. Levetiracetam is excellent (see Chapter 5)
therapy, stopping seizures in almost all cases Lafora disease
(Sharpe et al, 2008). Other effective drugs Myoclonus epilepsy and ragged-red fibers (see
Chapter 5)
include valproate, lamotrigine, and topiramate.
Ramsay-Hunt syndrome (see Chapter 10)
Treatment is lifelong. Sialidoses (see Chapter 5)
Unverricht-Lundborg syndrome
Progressive Myoclonus Epilepsies
The term progressive myoclonus epilepsies is used
to cover several progressive disorders of the ner- disease. Laforin may play a role in the regulation
vous system characterized by: (1) myoclonus; of glycogen metabolism.
(2) seizures that may be tonic-clonic, tonic, or Clinical Features. Onset is between 11 and
myoclonic; (3) progressive mental deterioration; 18 years of age, with the mean at age 14 years.
and (4) cerebellar ataxia, involuntary movements, Tonic-clonic or myoclonic seizures are the ini-
or both. Some of these disorders are due to specific tial feature in 80 % of cases. Hallucinations
lysosomal enzyme deficiencies, whereas others are from occipital seizures are common. Myoclonus
probably mitochondrial disorders (Box 1-9). becomes progressively worse, may be segmental
or massive, and increases with movement. Cog-
Lafora Disease. Lafora disease is a rare nitive impairment begins early and is relentlessly
hereditary disease transmitted by autosomal progressive. Ataxia, spasticity, and involuntary
recessive inheritance (Jansen & Andermann, movements occur late in the course. Death
2011). A mutation in the EPM2A gene, occurs 5 to 6 years after the onset of symptoms.
encoding for laforin, a tyrosine kinase inhibitor, Diagnosis. The EEG is normal at first and
is responsible for 80 % of patients with Lafora later develops nonspecific generalized polyspike
discharges during the waking state. The back- generalized. Neuronal migrational disorders and
ground becomes progressively disorganized and gliomas often cause intractable partial seizures
epileptiform activity more constant. Photosensi- (Porter et al, 2003). MRI is a recommended
tive discharges are a regular feature late in the study for all children with focal clinical seizures,
course. The basis for diagnosis is the detection seizures associated with an unexplained focal
of one of the two known associated mutations. abnormality on EEG, or with a new or progress-
Management. The seizures become refrac- ing neurological deficit.
tory to most anticonvulsant drugs. Zonisamide, Cerebral cysticercosis is an important cause of
levetiracetam and divalproex sodium are the partial seizures in Mexico and Central America
most effective drugs in myoclonic epilepsies. and is now common in the Southwestern United
Divalproex is a good alternative when the diag- States (Carpio & Hauser, 2002) and becoming
nosis is known and mitochondrial disease is not more common in contiguous regions. Ingestion
suspected. Treatment of the underlying disease of poorly cooked pork containing cystic larvae of
is not available. the tapeworm Taenia solium causes the infection.
Any seizure that originates in the cortex may
Unverricht-Lundborg Syndrome. Unverricht- become a generalized tonic-clonic seizure (sec-
Lundborg syndrome is clinically similar to ondary generalization). If the discharge remains
Lafora disease, except that inclusion bodies localized for a few seconds, the patient experi-
are not present. Genetic transmission is by ences a focal seizure or an aura before losing
autosomal recessive inheritance. Most reports consciousness. Often the secondary generaliza-
of the syndrome are from Finland and other tion occurs so rapidly that a tonic-clonic seizure
Baltic countries but distribution is worldwide. is the initial symptom. In such cases, cortical ori-
Mutations in the cystatin B gene cause defective gin of the seizure may be detectable on EEG.
function of a cysteine protease inhibitor However, normal EEG findings are common
(Lehesjoki & Koskiniemi, 2009). during a simple partial seizure and do not exclude
Clinical Features. Onset is usually between the diagnosis.
6 and 15 years of age. The main features are
stimulus-sensitive myoclonus and tonic-clonic
Acquired Epileptiform Aphasia
seizures. As the disease progresses, other neu-
rological symptoms including cognitive impair- Acquired aphasia in children associated with epi-
ment and coordination difficulties appear. leptiform activity on EEG is the Landau-Kleffner
Diagnosis. EEG shows marked photosensi- syndrome. The syndrome appears to be a disorder
tivity. Genetic molecular diagnosis is available. of auditory processing. The cause is unknown
Management. Zonisamide, levetiracetam except for occasional cases associated with tem-
(Crest et al, 2004) and divalproex sodium are poral lobe tumors.
the most effective drugs in myoclonic epilepsies. Clinical Features. Age at onset ranges from
Divalproex is a good alternative when the diag- 2 to 11 years, with 75 % beginning between 3
nosis is known and mitochondrial disease is not and 10 years. The first symptom may be apha-
suspected. Treatment of the underlying disease sia or epilepsy. Auditory verbal agnosia is the
is not available. initial characteristic of aphasia. The child has
difficulty understanding speech and stops talk-
ing. “Deafness” or “autism” develops. Several
Partial Seizures seizure types occur, including generalized tonic-
This section discusses several different seizure clonic, partial, and myoclonic seizures (Camfield
types of focal cortical origin other than complex & Camfield, 2002). Atypical absence is some-
partial seizures. Such seizures may be purely times the initial feature and may be associated
motor or purely sensory or may affect higher with continuous spike and slow waves during
cortical function. The benign childhood partial slow wave sleep. Hyperactivity and personality
epilepsies are a common cause of partial seizures change occur in half of affected children, prob-
in children. Benign centrotemporal (rolandic) ably caused by aphasia. The neurological exami-
epilepsy and benign occipital epilepsy are the nation is otherwise normal.
usual forms. The various benign partial epilepsy Recovery of language is more likely to occur
syndromes begin and cease at similar ages, have if the syndrome begins before 7 years of age.
a similar course, and occur in the members of the Seizures cease generally by age 10 and always
same family. They may be different phenotypic by age 15.
expressions of the same genetic defect. Diagnosis. Acquired epileptiform aphasia,
Partial seizures are also secondary to underly- as the name implies, is different from autism
ing diseases, which can be focal, multifocal, or and hearing loss because the diagnosis requires
that the child have normal language and Clinical Features. Seizures begin in childhood
cognitive development prior to onset of symp- and usually persist into adult life. The seizures
toms and normal hearing. The EEG shows occur in non-REM sleep and sudden awakenings
multifocal cortical spike discharges with a pre- with brief hyperkinetic or tonic manifestations
dilection for the temporal and parietal lobes. are characteristic. Patients frequently remain
Involvement is bilateral in 88 % of cases. conscious and often report auras of shivering,
An intravenous injection of diazepam may tingling, epigastric or thoracic sensations, as well
normalize the EEG and transiently improve as other sensory and psychic phenomena.
speech, but this should not suggest that Clusters of seizures, each lasting less than a
epileptiform activity causes the aphasia. minute, occur in one night. Video-EEG record-
Instead, both features reflect an underlying ings demonstrate partial seizures originating in
cerebral disorder. the frontal lobe. A vocalization, usually a gasp or
Every child with the disorder requires cranial grunt that awakens the child, is common. Other
MRI to exclude the rare possibility of a temporal auras include sensory sensations, psychic phe-
lobe tumor. nomena (fear, malaise, etc.), shivering, and diffi-
Management. Standard anticonvulsants usu- culty breathing. Thrashing or tonic stiffening
ally control the seizures but do not improve with superimposed clonic jerks follows. The eyes
speech. Corticosteroid therapy, especially early are open, and the individual is often aware of
in the course, may normalize the EEG and pro- what is happening; many sit up and try to grab
vide long-lasting remission of aphasia and sei- on to a bed part.
zures. One 5-year-old girl showed improved Diagnosis. The family history is important to
language and control of seizures with levetirace- the diagnosis, but many family members may not
tam monotherapy, 60 mg/kg/day (Kossoff et al, realize that their own attacks are seizures or want
2003a). Immunoglobulins 2 mg/kg over two others to know that they experience such bizarre
consecutive days have also shown efficacy. symptoms. The interictal EEG is usually normal,
and concurrent video-EEG is often required to
Acquired Epileptiform Opercular capture the event, which reveals rapidly general-
Syndrome ized discharges with diffuse distribution. Often,
movement artifact obscures the initial ictal EEG.
This syndrome and autosomal dominant rolandic Children who have seizures when awake and
epilepsy and speech apraxia are probably the same no family history of epilepsy may have supple-
entity. They are probably different from acquired mentary sensorimotor seizures (see later section
epileptiform aphasia but may represent a spec- on Supplementary Sensorimotor Seizures).
trum of the same underlying disease process. Management. Any of the anticonvulsant
Clinical Features. Onset is before age 10 agents except for ethosuximide may be effective.
years. Brief nocturnal seizures occur that mainly Many of these patients get only partial control
affect the face and mouth but may become sec- with monotherapy and multiple combinations
ondarily generalized. Oral dysphasia, inability are tried. I have many patients that ended up
to initiate complex facial movements (blowing with a combination of oxcarbazepine and dival-
out a candle), speech dysphasia, and drooling proex sodium to get their seizures under control.
develop concurrently with seizure onset. Cogni-
tive dysfunction is associated. Genetic transmis-
Childhood Epilepsy With Occipital
sion is by autosomal dominant inheritance with
Paroxysms
anticipation.
Diagnosis. The EEG shows centrotemporal Two genetic occipital epilepsies are separable
discharges or electrical status epilepticus during because of different genetic abnormalities.
slow wave sleep.
Management. The dysphasia does not respond Benign Occipital Epilepsy of Childhood.
to anticonvulsant drugs. Genetic transmission is by autosomal dominant
inheritance. It may be a phenotypic variation
of benign rolandic epilepsy. Both epilepsies are
Autosomal Dominant Nocturnal
commonly associated with migraine.
Frontal Lobe Epilepsy
Clinical Features. Age at onset is usually
Bizarre behavior and motor features during sleep between 4 and 8 years. One-third of patients
are the characteristics of this epilepsy syndrome, have a family history of epilepsy, frequently
often misdiagnosed as a sleep or psychiatric dis- benign rolandic epilepsy. The initial seizure
order. Several different gene loci are identifiable manifestation can consist of (1) nonformed visual
among families. hallucinations, usually flashing lights or spots;
(2) blindness, hemianopia, or complete amau- age. Television and video games induce seizures.
rosis; (3) visual illusions, such as micropsia, The seizures begin with colorful, moving spots in
macropsia, or metamorphopsia; or (4) loss of the peripheral field of vision. With progression
consciousness lasting for up to 12 hours. More of the seizure, tonic head and eye version devel-
than one feature may occur simultaneously. ops with blurred vision, nausea, vomiting, sharp
Unilateral clonic seizures, complex partial sei- pain it the head or orbit, and unresponsiveness.
zures, or secondary generalized tonic-clonic sei- Cognitive status, the neurological examination,
zures follow the visual aura. Afterward, the child and brain imaging are normal. The interictal
may have migraine-like headaches and nausea. EEG shows bilateral synchronous or asynchro-
Attacks occur when the child is awake or asleep, nous occipital spikes and spike-wave complexes.
but the greatest frequency is at the transition Intermittent photic stimulation may induce an
from wakefulness to sleep. Photic stimulation or occipital photoparyoxysmal response and gener-
playing video games may induce seizures. alized discharges. The ictal EEG shows occipital
Diagnosis. Results of the neurological exami- epileptiform activity, which may shift from one
nation, CT, and MRI are normal. The interictal side to the other. This epilepsy requires distinc-
EEG shows unilateral or bilateral independent tion from idiopathic generalized epilepsy with
high-amplitude, occipital spike-wave discharges photosensitivity.
with a frequency of 1.5–2.5 cps. Eye open- Management. Standard anticonvulsant drugs
ing enhances the discharges, light sleep inhib- usually accomplish seizure control.
its them. A similar interictal pattern occurs in
some children with absence epilepsy, suggest-
Benign Childhood Epilepsy with
ing a common genetic disorder among differ-
Centrotemporal Spikes (BECTS)
ent benign genetic epilepsies. During a seizure,
rapid firing of spike discharges occurs in one or Benign rolandic epilepsy is an alternate name for
both occipital lobes. BECTS. Genetic transmission is as an autosomal
Epilepsy associated with ictal vomiting is a variant dominant trait. Forty percent of close relatives
of benign occipital epilepsy (Panayiotopoulos, have a history of febrile seizures or epilepsy.
1999). Seizures occur during sleep and vomiting, Clinical Features. The age at onset is between
eye deviation, speech arrest, or hemiconvulsions 3 and 13 years, with a peak at 7 to 8 years. Sei-
are characteristic. zures usually stop spontaneously by age 13 to 15
Management. Standard anticonvulsant drugs years. This epilepsy is not always benign. In fact,
usually provide complete seizure control. Typi- some children have their seizures only partially
cal seizures never persist beyond 12 years of controlled with polypharmacy. Observations such
age. However, not all children with occipital as “incomplete phenotype penetrance”, the inci-
discharges have a benign epilepsy syndrome. dence of seizures and the response to treatment
Persistent or hard-to-control seizures raise the may be incorrect by the “incomplete observation”
question of a structural abnormality in the occip- in children that may have only mild seizures when
ital lobe, and require MRI examination. everybody is sleeping. Seventy percent of children
have seizures only while asleep, 15 % only when
Panayiotopoulos Syndrome awake, and 15 % both awake and asleep.
Clinical Features. The age at onset of Pan- The typical seizure wakes the child from sleep.
ayiotopoulos syndrome is 3 to 6 years, but the Paresthesias occur on one side of the mouth, fol-
range extends from 1 to 14 years. Seizures usu- lowed by ipsilateral twitching of the face, mouth,
ally occur in sleep and autonomic and behavioral and pharynx, resulting in speech arrest (if domi-
features predominate. These include vomiting, nant hemisphere) or dysarthria (if nondominant
pallor, sweating, irritability, and tonic eye devia- hemisphere) and drooling. Consciousness is
tion. The seizures last for hours in one-third of often preserved. The seizure lasts for 1 or 2 min-
patients. Seizures are infrequent and the overall utes. Daytime seizures do not generalize, but
prognosis is good with remission occurring in 1-2 nocturnal seizures in children younger than 5
years. A third of children have only one seizure. years old often spread to the arm or evolve into a
Diagnosis. The interictal EEG shows runs generalized tonic-clonic seizure. Some children
of high amplitude 2–3 Hz sharp and slow wave with BECTS have cognitive or behavioral prob-
complexes in the posterior quadrants. Many lems, particularly difficulty with sustained atten-
children may have central-temporal or frontal tion, reading, and language processing.
spikes. The ictal EEG in Panayiotopoulos syn- Diagnosis. When evaluating a child for a first
drome is posterior slowing. nocturnal, generalized tonic-clonic seizure, ask
Children with idiopathic photosensitive occip- the parents if the child’s mouth was “twisted.”
ital epilepsy, present between 5 and 17 years of If they answer affirmatively, the child probably
has BECTS. They never report this observation causes include infarction, hemorrhage, tumor,
spontaneously. hyperglycemia, Rasmussen’s encephalitis, and
Results of neurological examination and brain inflammation. Make every effort to stop the sei-
imaging studies are normal. Interictal EEG zures with intravenous antiepileptic drugs (see
shows unilateral or bilateral spike discharges in later section on Treatment of Status Epilepti-
the central or centrotemporal region. The spikes cus). The response to anticonvulsant drugs and
are typically of high voltage and activated by the outcome depend on the underlying cause.
drowsiness and sleep. The frequency of spike
discharge does not correlate with the subsequent
Hemiconvulsions-Hemiplegia
course. Children with both typical clinical sei-
Syndrome (Rasmussen Syndrome)
zures and typical EEG abnormalities, especially
with a positive family history, do not require Rasmussen syndrome is a poorly understood dis-
neuroimaging. However, those with atypical fea- order. While originally described as a form of
tures or hard-to-control seizures warrant MRI to focal, viral encephalitis, an infectious etiology is
exclude a low-grade glioma. not established.
Management. Most anticonvulsant drugs Clinical Features. Focal jerking frequently
are effective. I often prescribe levetiracetam or begins in one body part, usually one side of the
oxcarbazepine in these children. Most children face or one hand, and then spreads to contigu-
eventually stop having seizures whether they are ous parts. Trunk muscles are rarely affected. The
treated or not. However, I am impressed that, in rate and intensity of the seizures vary at first, but
many, the epilepsy is not so benign, and in some con- then become more regular and persist during
tinues into adult life. sleep. By 4 months from first symptom, all have
refractory motor seizures (Granata et al, 2003b).
The seizures defy treatment and progress to
Electrical Status Epilepticus During
affect first both limbs on one side of the body
Slow Wave Sleep (ESES)
and then the limbs on the other side. Progressive
In ESES, sleep induces paroxysmal EEG activ- hemiplegia develops and remains after seizures
ity. The paroxysms may appear continuously or have stopped.
discontinuously during sleep. They are usually Diagnosis. EEG and MRI are initially normal
bilateral, but sometimes strictly unilateral or and then the EEG shows continuous spike dis-
with unilateral predominance. charges originating in one portion of the cortex,
Clinical Features. Age at onset is 3 to 14 with spread to contiguous areas of the cortex and
years. The seizure types during wakefulness are to a mirror focus on the other side. Secondary
atypical absence, myoclonic, or akinetic seizures. generalization may occur. Repeated MRI shows
Children with paroxysmal EEG activity only rapidly progressive hemiatrophy with ex vacuo
during sleep tend not to have clinical seizures. dilation of the ipsilateral ventricle. PET shows
Such children are often undiagnosed for months widespread hypometabolism of the affected hemi-
or years. Neuropsychological impairment and sphere at a time when the spike discharges remain
behavioral disorders are common. Hyperactiv- localized. The CSF is usually normal, although a
ity, learning disabilities and, in some instances, few monocytes may be present.
psychotic regressions may persist even after Management. The treatment of Rasmussen
ESES has ceased. syndrome is especially difficult. Standard anti-
Diagnosis. The most typical paroxysmal epileptic therapy is not effective for stopping sei-
discharges of EEG are spike waves of 1.5 and zures or the progressive hemiplegia. The use of
3.5 Hz, sometimes associated with polyspikes or immunosuppressive therapy is recommended by
polyspikes and waves. some (Granata et al, 2003a) and antiviral therapy
Treatment. Standard anticonvulsant drugs by others. These medical approaches are rarely
are rarely effective. High-dose steroids, ACTH, successful. Early hemispherectomy is the treat-
high-dose benzodiazepines, levetiracetam and ment of choice (Kossoff et al, 2003b).
intravenous immunoglobulin have all reported
some success. Reading Epilepsy
There was a belief that reading epilepsy and
Epilepsia Partialis Continuans
juvenile myoclonic epilepsy were variants
Focal motor seizures that do not stop spontane- because many children with reading epilepsy
ously are termed epilepsia partialis continuans. experience myoclonic jerks of the limbs shortly
This is an ominous symptom and usually indi- after arising in the morning. However, recent
cates an underlying cerebral disorder. Possible studies indicate that reading epilepsy is idiopathic
epilepsy originating from the left temporal lobe BOX 1-10 Diagnostic Considerations
(Archer et al, 2003). for a First Nonfebrile
Clinical Features. Age at onset is usually in Tonic-Clonic Seizure after
the second decade. Myoclonic jerks involving 2 Years of Age
orofacial and jaw muscles develop while read-
ing. Reading time before seizure onset is vari- Acute encephalopathy or encephalitis (see Chap-
able. The initial seizure is usually in the jaw and ter 2)
described as “jaws locking or clicking.” Other Isolated unexplained seizure
initial features are quivering of the lips, choking Partial seizure of any cause with secondary
in the throat, or difficulty speaking. Myoclonic generalization
jerks of the limbs may follow, and some children Primary generalized epilepsy
Progressive disorder of the nervous system (see
experience a generalized tonic-clonic seizure if
Chapter 5)
they continue reading. Generalized tonic-clonic
seizures may also occur at other times.
Diagnosis. The history of myoclonic jerks
during reading and during other processes Management. Monotherapy with oxcarbaze-
requiring higher cognitive function is critical to pine, levetiracetam, lamotrigine or topiramate
the diagnosis. The interictal EEG usually shows are usually satisfactory for seizure control in
generalized discharges and brief spike-wave both types. Other anticonvulsants such as phe-
complexes can be provoked by reading that are nytoin, carbamazepine and valproate have simi-
simultaneous with jaw jerks. lar efficacy. I chose medications based on safety,
Management. Some patients claim to control tolerability, potential side effects and cost.
their seizures without the use of anticonvulsant
drugs by quitting reading at the first sign of Generalized Seizures
orofacial or jaw jerks. This seems an impracti-
cal approach and an impediment to education. Generalized tonic-clonic seizures are the most
Levetiracetam and lamotrigine are good treat- common seizures of childhood. They are dramatic
ment options. and frightening events that invariably demand
medical attention. Seizures that are prolonged or
repeated without recovery are termed status epilep-
Temporal Lobe Epilepsy
ticus. Many children with generalized tonic-clonic
Temporal lobe epilepsy in children may be pri- seizures have a history of febrile seizures during
mary or secondary. Inheritance of primary tem- infancy. Some of these represent a distinct autoso-
poral lobe epilepsy is often as an autosomal mal dominant disorder. Box 1-10 summarizes the
dominant trait. Among children with secondary diagnostic considerations in a child who has had a
temporal lobe epilepsy, 30 % give a history of an generalized tonic-clonic seizure.
antecedent illness or event and 40 % show MRI Clinical Features. The onset may occur any
evidence of a structural abnormality. time after the neonatal period, but the onset of
Clinical Features. Seizure onset in primary primary generalized epilepsy without absence is
temporal lobe epilepsy occurs in adolescence or usually during the second decade. With absence,
later. The seizures consist of simple psychic (déjà the age at onset shifts to the first decade.
vu, cognitive disturbances, illusions and hal- Sudden loss of consciousness is the initial
lucinations) or autonomic (nausea, tachycardia, feature. The child falls to the floor, and the body
sweating) symptoms. Secondary generalization stiffens (tonic phase). Repetitive jerking move-
is unusual. Seizure onset in secondary temporal ments of the limbs follow (clonic phase); these
lobe epilepsy is during the first decade and often movements at first are rapid and rhythmic and
occurs during an acute illness. The seizures are then become slower and more irregular as the sei-
usually complex partial in type, and secondary zure ends. The eyes roll backward in the orbits;
generalization is more common. breathing is rapid and deep, causing saliva to froth
Diagnosis. A single EEG in children with pri- at the lips; and urinary and fecal incontinence may
mary temporal lobe epilepsy is likely to be nor- occur. A postictal sleep follows the seizure from
mal. The frequency of interictal temporal lobe which arousal is difficult. Afterward, the child
spikes is low, and diagnosis requires prolonged appears normal but may have sore limb muscles
video-EEG monitoring. The incidence of focal and a painful tongue, bitten during the seizure.
interictal temporal lobe spikes is 78% in chil- Diagnosis. A first generalized tonic-
dren with secondary temporal lobe epilepsy, but clonic seizure requires laboratory evaluation.
detection may require several standard or pro- Individualize the evaluation. Important deter-
longed EEG studies. mining factors include neurological findings,
family history, and known precipitating factors. in someone with epilepsy or who is familiar
An eyewitness report of focal features at the with the disease. Children or adolescents with
onset of the seizure, or the recollection of an limited coping mechanisms for stress may sub-
aura, indicates a partial seizure with secondary consciously use the complaint of seizure to pro-
generalization. tect themselves from overwhelming situations.
During the seizure, the EEG shows general- It is important to examine cases of epilepsy
ized repetitive spikes in the tonic phase and then “refractory to treatment” for this possibility.
periodic bursts of spikes in the clonic phase. Pseudoseizures occur more often in adoles-
Movement artifact usually obscures the clonic cence than in childhood and more often in
portion. As the seizure ends, the background females than in males (3:1). Common teenage
rhythms are slow and the amplitude attenuates. stressors including school performance, sport
Between seizures, brief generalized spike or performance, social relations, and peer pres-
spike-wave discharges that are polymorphic in sure are more frequently the trigger for psy-
appearance may occur. Discharge frequency some- chogenic symptoms than sexual abuse, which
times increases with drowsiness and light sleep. unfortunately is a common occurrence. People
The presence of focal discharges indicates second- with pseudoseizures may also have true sei-
ary generalization of the tonic-clonic seizure. zures; often, the pseudoseizures begin while
The CSF is normal following a brief tonic- epilepsy is controlled when the patient is over-
clonic seizure due to primary epilepsy. However, whelmed by stressors and has inadequate cop-
prolonged or repeated seizures may cause a leu- ing mechanisms.
kocytosis as many as 80 cells/mm3 with a poly- Clinical Features. Pseudoseizures are often
morphonuclear predominance. The protein misdiagnosed as epilepsy. Thirty to forty
concentration can be mildly elevated, but the percent of adults with “refractory seizures” are
glucose concentration is normal. ultimately diagnosed with pseudoseizures after
Management. Do not start prophylactic anti- undergoing inpatient EEG monitoring. Some
epileptic therapy in an otherwise normal child patients may have both epilepsy and pseudo-
who has had a single unexplained seizure. The seizures. The following may raise suspicion for
recurrence rate is probably less than 50 % after 1 pseudoseizures:
year. Several drugs are equally effective in children 1. Abrupt onset of daily, multiple, “severe”
with recurrent seizures that require treatment. seizures without a preceding neurological
insult.
2. Movements with trashing, jerking, asym-
Epilepsy with Generalized Tonic-Clonic
metric characteristics including, side
Seizures on Awakening
to side head motion, asymmetric up
Epilepsy with generalized tonic-clonic seizures and down arm or leg motions, pelvic
on awakening is a familial syndrome distinct thrusting, etc.
from juvenile myoclonic epilepsy. Onset occurs 3. Non-stereotyped events with multiple
in the second decade, and 90 % of seizures occur variable characteristics.
on awakening, regardless of the time of day. Sei- 4. Provoked rather than unprovoked events
zures also occur with relaxation in the evening. (emotional or other triggers).
Absence and myoclonic seizures may occur. The 5. Periods of unresponsiveness during which
mode of inheritance is unknown. attacks may be precipitated and ended by
Clinical Features. Onset occurs in the second suggestion. Patients usually do not hurt
decade, and 90 % of seizures occur on awaken- themselves nor experience incontinence.
ing, regardless of the time of day. Seizures also However, incontinence or trauma may
occur with relaxation in the evening. Absence occur in pseudoseizures.
and myoclonic seizures may occur. 6. Epileptic patients bite the side of their
Diagnosis. The EEG shows a pattern of idio- tongue or the buccal mucosa. Pseudo-
pathic generalized epilepsies. seizure patients may bite the tip of their
Management. Treatment is similar to that of tongue.
juvenile myoclonic epilepsy with levetiracetam, 7. Epileptics have labored and slow breathing
valproate, lamotrigine, and topiramate (Wheless after a convulsion; pseudoseizures typically
& Kim, 2002). are followed by tachypnea.
Diagnosis. The diagnosis of most pseudosei-
Pseudoseizures zures is by observation alone. A good descrip-
tion or family captured video may be sufficient.
Psychogenic symptoms are common. Pseudo- When doubt remains, video-EEG monitoring is
seizure is often a psychogenic manifestation the best method of diagnosis.
Management. We often use the help of coun- child. It is thought that many otherwise normal chil-
selors for children with pseudoseizures to iden- dren started on antiepileptic medication after a first
tify and address stressors. In addition, SSRIs seizure and then remain seizure free for 2 years should
for children with the comorbidity of anxiety or not have received medication in the first place. The
depression including citalopram 10–20 mg/day, decision to stop therapy, like the decision to start
escitalopram 5–10 mg/day or sertraline 50–100 therapy, requires an individualized approach to
mg/day are often helpful. the child and the cause of the epilepsy. Children
who are neurologically abnormal (remote symp-
Video Game-Induced Seizures tomatic epilepsy) and those with specific epileptic
syndromes that are known to persist into adult life
Children who experience seizures while playing are likely to have recurrences, while some crypto-
video games have a photosensitive seizure disor- genic cases have a low incidence of recurrence
der demonstrable on EEG during intermittent after the first or second seizure. Three-quarters
photic stimulation. Two-thirds have primary of relapses occur during the withdrawal phase and
generalized epilepsy (generalized tonic-clonic, in the 2 years thereafter. Contrary to popular
absence, and juvenile myoclonic epilepsy), and belief, the rapid withdrawal of antiepileptic drugs
the rest have partial epilepsies, usually benign in a person who does not need therapy does not
occipital epilepsy. provoke seizures with the probable exception of
high-dose benzodiazepines. However, all parents
know that seizure medication is never abruptly
MANAGING SEIZURES withdrawn and it is foolish to suggest otherwise.
Attempt to stop antiepileptic therapy 1 year
Antiepileptic Drug Therapy before driving age in children who are seizure
free and neurologically normal without evidence
The goal when treating epilepsy is to make the of having a lifelong epileptic tendency.
child and his or her brain function at the highest
level between seizures as often we are unable to
Principles of Therapy
provide seizure freedom. In other words, achieve
maximum normal function by balancing seizure Start therapy with a single drug. Most children
control against drug toxicity (Hirtz et al, 2003). with epilepsy achieve complete seizure control
with monotherapy when using the correct drug
Indications for Starting Therapy for the seizure type. Even patients whose sei-
zures are never controlled are likely to do better
Initiate therapy in neurologically abnormal chil- on the smallest number of drugs. Polypharmacy
dren (symptomatic epilepsy) after the first sei- poses several problems: (1) drugs compete with
zure; more seizures are expected. After a first each other for protein-binding sites; (2) one drug
unexplained and untreated generalized tonic- can increase the rate and pathway of metabolism
clonic seizure, less than half of otherwise normal of a second drug; (3) drugs have cumulative tox-
children will have a second seizure. It is reason- icity; and (4) compliance is more difficult.
able to delay therapy, if the child is not operating When using more than one drug, change only
a motor vehicle. Always treat juvenile myoclonic one drug at a time. When making several changes
epilepsy and absence epilepsy, not only because simultaneously, it is impossible to determine
of expected seizure recurrence, but also because which drug is responsible for a beneficial or an
uncontrolled absence impairs education and has adverse effect.
higher risks of trauma. Administer anticonvulsant drugs no more
than twice a day, and urge families to buy pill-
Discontinuing Therapy boxes marked with the 7 days of the week. It is
difficult to remember to take medicine when you are
Antiepileptic drug therapy is required in children not in pain to prevent something you do not remem-
who experience seizures during an acute enceph- ber from happening. If you ask people if they ever miss
alopathy, e.g., anoxia, head trauma, encephalitis. their doses the answer is often never, as it is impossible
However, it is reasonable to stop therapy when to remember what you forgot.
the acute encephalopathy is over and seizures
have stopped if no significant residual deficits. Blood Concentrations. The development of
Pooled data on epilepsy in children suggests techniques to measure blood concentrations of
that discontinuing antiepileptic therapy is suc- antiepileptic drugs was an important advance in the
cessful after 2 years of complete control. Pooled treatment of epilepsy. However, reference values of
data is worthless when applied to the individual drug concentrations are guidelines. Some patients
TABLE 1-2 Antiepileptic Drugs for Children

Blood concentra-
Drug Initial dose Target dose tion (mg/mL) Half-life (hours)
Carbamazepine 10 mg/kg/day 20–30 mg/kg/day 4–12 14–27
Clonazepam 0.02 mg/day 0.5–1 mg/day * 20–40
Ethosuximide 10 mg/kg/day 15–40 mg/kg/day 50–100 30–40
Felbamate 15 mg/kg/day 15–45 mg/kg/day 40–80 20–23
Lamotrigine 0.5 mg/kg/day 5–10 mg/kg/day 2–20 25 (monotherapy)
(non-valproate)
Levetiracetam 30 mg/kg/day 60 mg/kg 15–40 5
Oxcarbazepine 10 mg/kg/day 20–40 mg/kg/day 10–40 9
Phenobarbital 3–5 mg/kg/day 5–10 mg/kg/day 15–40 35–73
Phenytoin 5–10 mg/kg/day 5–10 mg/kg/day 10–25 24
Primidone 5 mg/kg/day 10–25 mg/kg/day 8–12 8–22
Topiramate 1-3 mg/kg/day 5–9 mg/kg/day † 18–30
Valproate 20 mg/kg/day 30–60 mg/kg/day 50–100 6–15
Vigabatrin 40–60 mg/kg/day 60–80 mg/kg/day † Days
Zonisamide 1.5 mg/kg/day 6 mg/kg/day † 24
*Not clinically useful.

†Notestablished.
Concomitant therapy with other drugs often influences dosages.
are seizure free with concentrations that are below concurrent use of other anticonvulsants or other
the reference value, and others are unaffected by medications. This is one reason that children with
apparently toxic concentrations. I rely more on epilepsy may have a toxic response to a drug or
patient response than on blood concentration. increased seizures at the time of a febrile illness.
Fortunately, for children, many of the newer drugs, Some anticonvulsants have active metabolites
e.g. lamotrigine, levetiracetam, do not require the with anticonvulsant and toxic properties. With
measurement of blood concentrations. However, the exception of phenobarbital derived from
levels may be helpful in some situations. primidone and monohydroxy derived from
Measuring total drug concentrations, protein- oxcarbazepine these metabolites are not usually
bound and free fractions, is customary even measured. Active metabolites may provide sei-
though the free fraction is responsible for effi- zure control or have toxic effects when the blood
cacy and toxicity. While the ratio of free to bound concentration of the parent compound is low.
fractions is relatively constant, some drugs have a
greater affinity for binding protein than other Adverse Reactions. Some anticonvulsant drugs
drugs and displace them when used together. irritate the gastric mucosa and cause nausea
The free fraction of the displaced drug increases and vomiting. When this occurs, taking smaller
and causes toxicity even though the measured doses at shorter intervals, using enteric-coated
total drug concentration is “therapeutic.” preparations, and administering the drug after
Most antiepileptic drugs follow first-order meals may relieve symptoms.
kinetics, i.e., blood levels increase proportionately Toxic adverse reactions are dose related.
with increases in the oral dose. The main excep- Almost all anticonvulsant drugs cause sedation
tion is phenytoin, whose metabolism changes from when blood concentrations are excessive. Subtle
first-order to zero-order kinetics when the enzyme cognitive and behavioral disturbances, recogniz-
system responsible for its metabolism saturates. able only by the patient or family, often occur at
Then a small increment in oral dose produces low blood concentrations. Never discount the
large increments in blood concentration. patient’s observation of a toxic effect because the
The half-lives of the antiepileptic drugs listed blood concentration is within the “therapeutic
in Table 1-2 are at steady state. Half-lives are gen- range.” As doses are increased, attention span,
erally longer when therapy with a new drug begins. memory, and interpersonal relations may become
Achieving a steady state usually requires five half- seriously impaired. This is especially common
lives. Similarly, five half-lives are required to elim- with barbiturates but can occur with any drug.
inate a drug after discontinuing administration. Idiosyncratic reactions are not dose related. They
Drug half-lives vary from individual to individual may occur as hypersensitivity reactions (usually
and may be shortened or increased by the manifest as rash, fever, and lymphadenopathy) or
because of toxic metabolites. Idiosyncratic reactions its own metabolism, and the initial dose should
are not always predictable, and respecting the be 25 % of the maintenance dose to prevent
patient’s observation is essential. Notwithstanding toxicity. The usual maintenance dosage is 15–
package inserts and threats of litigation, routine labora- 20 mg/kg/day to provide a blood concentration
tory studies of blood counts and organ function in a healthy of 4–12 µg/mL. However, infants often require
child are neither cost effective nor helpful. It is preferable 30 mg/kg/day. The half-life at steady state is
to do studies based on clinical features. 5–27 hours, and children usually require doses
three times a day. Two long-acting preparations
are available for twice a day dosing. Concurrent
Selection of an Antiepileptic Drug
use of cimetidine, erythromycin, grapefruit,
The use of generic drugs is difficult to avoid in fluoxetine, and propoxyphene interferes with
managed health care programs. Unfortunately, carbamazepine metabolism and causes toxicity.
several different manufacturers provide generic Adverse Effects. A depression of peripheral
versions of each drug; the bioavailability and half- leukocytes is expected but is rarely sufficient (abso-
life of these products vary considerably, and lute neutrophil count less than 1000) to warrant
maintaining a predictable blood concentration discontinuation of therapy. Routine white blood
may be difficult. I usually increase the dose of cell counts each time the patient returns for a fol-
patients partially controlled when they have a low-up visit are not cost effective and do not allow
breakthrough seizure and decrease the dose 10 % the prediction of life-threatening events. The
when they experience side effects. A variation of most informative time to repeat the white blood
10 % up and down from one to the next refill cell count is concurrently with a febrile illness.
when changing between brands and multiple Cognitive disturbances may occur within the
generics either way is not trivial. These changes therapeutic range. Sedation, ataxia, and nystag-
may result in loss of seizure control or side effects. mus occur at toxic blood concentrations.
Common reasons for loss of seizure control in
children who were previously seizure free are Clobazam (Onfi®, Lundbeck)
nonadherence and changing from the brand Indications. Seizures within the spectrum of
name to a generic drug, or from one generic to Lennox-Gastaut, which includes all seizure types
another. Patients should be told when their medica- other than typical absence seizures.
tion is being changed from brand to generic, generic to Administration. For patients with less than
brand or generic to different generic. 30 Kg of weight, the initial dosage is 5 mg daily
For the most part, the basis of drug selection is titrating up to 20 mg daily (divided into two
the neurologist’s comfort with using a specific drug, doses) as tolerated. For patients with more than
other health conditions and drug use in the patient, 30 Kg of weight, the initial dosage is 10 mg daily
the available preparations with respect to the child’s titrating up to 40 mg daily (divided into two
age, and the spectrum of antiepileptic activity of the doses) as tolerated.
drug. Levetiracetam, lamotrigine, topiramate, val- Adverse Effects. Sedation.
proate, zonisamide, rufinamide and felbamate are
drugs with a broad spectrum of efficacy against Clonazepam (Klonopin®, Roche)
many different seizure types. The basis of the fol- Indications. Clonazepam treats infantile
lowing comments is personal experience and pub- spasms, myoclonic seizures, absence, and partial
lished reports. Patent extensions granted by the seizures.
FDA, when research in children is completed, has Administration. The initial dosage is
helped tremendously in the acquisition of knowl- 0.025 mg/kg/day in two divided doses. Recom-
edge of the use of anticonvulsants in children. mended increments are 0.025 mg/kg every 3 to
5 days as needed and tolerated. The usual main-
Carbamazepine (Tegretol®, Tegretol-XR®, tenance dosage is 0.1 mg/kg/day in three divided
Novartis; Carbatrol®, Shire Pharmaceuticals). doses. Most children cannot tolerate dosages
In my own practice, oxcarbazepine has replaced of more than 0.15 mg/kg/day. The therapeutic
carbamazepine entirely because of its better side blood concentration is 0.02–0.07 µg/mL, 47 %
effect profile and tolerability. of the drug is protein bound, and the half-life
Indications. Partial seizures, primary or is 20–40 hours. Rectal administration is suitable
secondary generalized tonic-clonic seizures. for maintenance if needed.
Carbamazepine increases the frequency of Adverse Effects. Toxic effects with dos-
absence and myoclonic seizures and is therefore ages within the therapeutic range include seda-
contraindicated. tion, cognitive impairment, hyperactivity, and
Administration. Approximately 85 % of the excessive salivation. Idiosyncratic reactions are
drug is protein bound. Carbamazepine induces unusual.
Ethosuximide (Zarontin®, Pfizer) Administration. The usual titration dose is

Indications. Ethosuximide is the drug of from 10 to 60 mg/kg/day, over two weeks. The
choice for treating absence epilepsy. It is also mechanism of action is similar to pregabalin, but
useful for myoclonic absence. the efficacy is significantly lower.
Administration. The drug is absorbed rapidly, Adverse Effects. The adverse effects are seda-
and peak blood concentrations appear within tion, edema, increased weight.
4 hours. The half-life is 30 hours in children and
up to 60 hours in adults. The initial dosage is Lacosamide (Vimpat®, UCB Pharma)
20 mg/kg/day in three divided doses after meals to Indications. Partial seizures with and without
avoid gastric irritation. Dose increments of 10 mg/ secondary generalization.
kg/day as needed and tolerated to provide seizure Administration. The usual titration dose is
control without adverse effects. Levels between from 2 to 10 mg/kg/day, over two to four weeks.
50 and 120 µg/mL are usually therapeutic. The mechanism of action is on the sodium chan-
Adverse Effects. The common adverse reactions nel but different from the traditional sodium
are nausea and abdominal pain. These symptoms channel anticonvulsants.
occur from gastric irritation within the therapeutic Adverse Effects. The adverse effects are seda-
range and limit the drug’s usefulness. The liquid tion, ataxia, dizziness.
preparation causes more irritation than the cap-
sule. Unfortunately, gel capsules are large and Lamotrigine (Lamictal®, GlaxoSmithKline)
some young children refuse to try this option until Indications. Lamotrigine is useful in absence
older. Always take the medication after eating. epilepsy, atonic seizures, juvenile myoclonic
epilepsy, the Lennox-Gastaut syndrome, partial
Felbamate (Meda Pharmaceuticals) epilepsies, and primary generalized tonic-clonic
Indications. Felbamate has a wide spectrum seizures (Biton et al, 2005). The spectrum of
of antiepileptic activity. Its primary use is for activity is similar to that of valproate.
refractory partial and generalized seizures, the Administration. The initial dose depends on
Lennox-Gastaut syndrome, atypical absence, whether the medication is used as monotherapy
and atonic seizures. (0.3 mg/kg/day), combined with liver enzyme
Administration. Felbamate is rapidly absorbed inducing drugs (0.6 mg/kg/day) or with valpro-
after oral intake. Maximal plasma concentrations ate (0.15 mg/kg/day) for the first 2 weeks, then
occur in 2–6 hours. The initial dosage is 15 mg/kg/ double the dose for 2 weeks and then increase
day in three divided doses. Avoid nighttime doses by the same amount weekly until achieving doses
if the drug causes insomnia. To attain seizure con- of 1–3 mg/kg/day (with valproate), 5–7 mg/kg/
trol, use weekly dosage increments of 15 mg/kg, day in monotherapy, and 5–15 mg/kg/day when
as needed, to a total dose of approximately 45 mg/ added to liver enzyme inducers.
kg/day. Toxicity limits the total dosage. Levels Plasma concentrations between 2 and 20 µg/
between 50 and 100 µg/mL are usually therapeutic. mL are usually helpful in reducing or stopping
Adverse Effects. Initial evidence suggested that seizures.
adverse effects of felbamate were mild and dose Adverse Effects. The main adverse reaction
related (nausea, anorexia, insomnia, weight loss) is rash, which is more likely with titrations faster
except when in combination with other antiepilep- than recommended. Other adverse effects are diz-
tic drugs. The addition of felbamate increases the ziness, ataxia, diplopia, insomnia and headache.
plasma concentrations of phenytoin and valproate
as much as 30 %. The carbamazepine serum con- Levetiracetam (Keppra, UCB Pharma)
centration falls, but the concentration of its active Indications. Levetiracetam has a broad spec-
epoxide metabolite increases almost 50 %. trum of activity and is useful for most seizure
Post marketing experience showed that felb- types (Berkovic et al, 2007). It is especially effec-
amate causes fatal liver damage and aplastic ane- tive in the treatment of juvenile myoclonic epi-
mia in about 1 in 10,000 exposures. Regular lepsy (Sharpe et al, 2007; Noachtar et al, 2008).
monitoring of blood counts and liver function is Its broad spectrum of activity, safety, and lack of
required and may not help decrease these fatali- drug–drug interactions make it an excellent first-
ties. However, this is a valuable drug in refrac- line choice for most epilepsies.
tory epilepsy and has a place when used with Administration. Levetiracetam is available as
caution and informed consent. a tablet, a suspension, and a solution for intrave-
nous administration. The half-life is short, but
Gabapentin (Neurontin®, Pfizer) the duration of efficacy is longer. Twice daily oral
Indications. Partial seizures with and without dosing is required. The initial dose in children is
secondary generalization and neuropathic pain. 20 mg/kg and the target dose is 20–80 mg/kg.
Adverse Effects. Levetiracetam is minimally Phenytoin (Dilantin®, Pfizer US

liver metabolized. Metabolism occurs in the blood Pharmaceuticals)
and excretion in the urine. It does not interfere Indications. Phenytoin treats tonic-clonic
with the metabolism of other drugs and has no and partial seizures.
life threatening side effects. It makes some chil- Administration. Oral absorption is slow and
dren cranky. This was a rare event in the initial unpredictable in newborns, erratic in infants, and
studies on the drug, but the incidence approaches probably not reliable until 3 to 5 years of age.
10 %. The concomitant use of a small dose of Even in adults, considerable individual variabil-
pyridoxine, 50 mg once or twice a day, seems to ity exists. Once absorbed, phenytoin is 70– 95 %
relieve the irritability. The mechanism of action protein bound. A typical maintenance dosage is
is probably an effect on GABA as its cofactor. 7 mg/kg/day in children. The half-life is up to
60 hours in term newborns, up to 140 hours in
Oxcarbazepine (Trileptal®, Novartis) premature infants, 5–14 hours in children, and
Indications. Oxcarbazepine is the active break 10–34 hours in adults. Capsules usually require
down product of carbamazepine. It has the same two divided doses, but tablets are more rapidly
therapeutic profile as carbamazepine but much absorbed and may require three divided doses a
better tolerability and adverse effect profile. day. Administration of three times the mainte-
Administration. Oxcarbazepine is available nance dose achieves rapid oral loading. Fosphe-
as a tablet and as a suspension. Twice daily dos- nytoin sodium has replaced parenteral phenytoin
ing is required. The initial dose is 10 mg/kg and (see discussion of Status Epilepticus).
then incrementally increased, as needed, to a Adverse Effects. The major adverse reactions
total dose of 20–60 mg/kg in two divided doses are hypersensitivity, gum hypertrophy, and hir-
(Glausser et al, 2000; Piña-Garza et al, 2005). sutism. Hypersensitivity reactions usually occur
Adverse Effects. The main adverse effect is within 6 weeks of the initiation of therapy. Rash,
drowsiness, but this is not as severe as with car- fever, and lymphadenopathy are characteristic.
bamazepine. Hyponatremia is a potential prob- Once such a reaction has occurred, discontinue
lem mainly in older populations. the drug. Concurrent use of antihistamines is not
appropriate management. Continued use of the
Phenobarbital drug may produce a Stevens-Johnson syndrome
Indications. Phenobarbital is effective for or a lupus-like disorder.
partial and generalized tonic-clonic seizures. It is The cause of gum hypertrophy is a combina-
especially useful to treat status epilepticus. tion of phenytoin metabolites and plaque on the
Administration. Oral absorption is slow, and teeth. Persons with good oral hygiene are unlikely
once daily dosing is best when given with the eve- to have gum hypertrophy. Discuss the impor-
ning meal than at bedtime if seizures are hypnago- tance of good oral hygiene at the onset of ther-
gic. Since intramuscular absorption requires 1 to 2 apy. Hirsutism is rarely a problem, and then only
hours, the intramuscular route is useless for rapid for girls. Discontinue the drug when it occurs.
loading (see Treatment of Status Epilepticus); Memory impairment, decreased attention span,
50 % of the drug is protein bound, and 50 % is free. and personality change may occur at therapeutic
Initial and maintenance dosages are 3–5 mg/ concentrations, but they occur less often and are
kg/day. The half-life is 50–140 hours in adults, less severe than with phenobarbital.
35–70 hours in children, and 50–200 hours in
term newborns. Because of the very long half-life Pregabalin (Lyrica®, Pfizer)
at all ages, once-a-day doses are usually satisfac- Indications. Partial seizures with and without
tory, achieving steady state blood concentrations secondary generalization and neuropathic pain.
after 2 weeks of therapy. Therapeutic blood con- Administration. The usual titration dose is
centrations are 15–40 µg/mL. from 2 to 10 mg/kg/day, over two weeks. The
Adverse Effects. Hyperactivity is the most com- mechanism of action is similar to gabapentin, but
mon and limiting side effect in children. Adverse the efficacy is significantly higher.
behavioral changes occur in half of children Adverse Effects. The adverse effects are seda-
between ages 2 and 10 years. Cognitive impair- tion, edema, increased weight.
ment is common. Hyperactivity and behavioral
changes are both idiosyncratic and dose-related. Primidone (Mysoline®, Valeant
Stevens-Johnson syndrome is more likely Pharmaceuticals)
when compared with other anticonvulsant Indications. Mysoline treats tonic-clonic and
agents. Drowsiness and cognitive dysfunction, partial seizures.
rather than hyperactivity, are the usual adverse Administration. Primidone metabolizes to at
effects after 10 years of age. Allergic rash is the least two active metabolites, phenobarbital and
main idiosyncratic reaction. phenyl-ethyl-malonamide (PEMA). The half-life
of primidone is 6–12 hours, and that of PEMA absence, myoclonic absence, myoclonus, and
is 20 hours. The usual maintenance dosage is tonic-clonic seizures.
10–25 mg/kg/day, but the initial dosage should Administration. Oral absorption is rapid, and
be 25 % of the maintenance dosage or intolerable the half-life is 6–15 hours. Three times a day
sedation occurs. A therapeutic blood concen- dosing of the liquid achieves constant blood con-
tration of primidone is 8–12 µg/mL. The blood centrations. An enteric-coated capsule (Depak-
concentration of phenobarbital derived from ote and Depakote sprinkles) slows absorption
primidone is generally four times greater, but and allows twice-a-day dosing in children.
this ratio alters with concurrent administration The initial dosage is 20 mg/kg/day. Increments
of other antiepileptic drugs. of 10 mg/kg/day to a dose of 60 mg/kg/day provide
Adverse Effects. The adverse effects are the a blood concentration of 50–100 µg/mL. Blood
same as for phenobarbital, except that the risk of concentrations of 80–120 µg/mL are often
intolerable sedation from the first tablet is greater. required to achieve seizure control. Protein bind-
ing is 95 % at blood concentrations of 50 µg/mL
Rufinamide (Banzel®, Eisai) and 80 % at 100 µg/mL. Therefore doubling the
Indications. Seizures within the spectrum of blood concentration increases the free fraction
Lennox-Gastaut, which includes all seizure types eightfold. Valproate has a strong affinity for plasma
other than typical absence seizures. proteins and displaces other antiepileptic drugs.
Administration. The initial dosage is 15 mg/ Valproate is available for intravenous use. A
Kg/day titrating up to 45 mg/Kg/day (divided dose of 25 mg/kg leads to a serum level of 100 µg/
into two doses) over two weeks. mL. Maintenance should start 1 to 3 hours after
Adverse Effects. Sedation, emesis and GI loading at 20 mg/kg/day divided into two doses.
symptoms. Adverse Effects. Valproate has dose-related and
idiosyncratic hepatotoxicity. Dose-related hepato-
Tiagabine (Gabitril®, Cephalon Inc.) toxicity is harmless and characterized by increased
Indications. Adjunctive therapy for partial- serum concentrations of transaminases. Important
onset and generalized seizures. dose-related effects are a reduction in the plate-
Administration. The initial single-day dose is let count, pancreatitis, and hyperammonemia.
0.2 mg/kg/day. Increase every 2 weeks by 0.2 mg/ Thrombocytopenia may result in serious bleeding
kg until achieving optimal benefit or adverse after trivial injury, while pancreatitis and hepati-
reactions occur. tis are both associated with nausea and vomiting.
Adverse Effects. The most common adverse Hyperammonemia causes cognitive disturbances
effects are somnolence and difficulty concen and nausea. These adverse reactions are revers-
trating. ible by reducing the daily dose. Reduced plasma
carnitine concentrations occur in children taking
Topiramate (Topamax®, Ortho McNeil) valproate, and some believe that carnitine supple-
Indications. Use for partial-onset and gener- mentation helps relieve cognitive impairment.
alized epilepsies, especially the Lennox-Gastaut The major idiosyncratic reaction is fatal liver
syndrome. It is also effective for migraine pro- necrosis attributed to the production of an aber-
phylaxis and a reasonable choice in children with rant and toxic metabolite. The major risk (1:800)
both disorders. is in children younger than 2 years of age who
Administration. The initial dose is 1–2 mg/ are receiving polytherapy. Many such cases may
kg/day, increased incrementally to up to 10– result from the combination of valproate on an
15 mg/kg/day divided into two doses. underlying inborn error of metabolism. Fatal
Adverse Effects. Weight loss may occur at hepatotoxicity is unlikely to occur in children
therapeutic dosages. When used in overweight over 10 years of age treated with valproate alone.
children, this is no longer an “adverse” event. The clinical manifestations of idiosyncratic
Cognitive impairment is common and often hepatotoxicity are similar to those of Reye syn-
detected by relatives rather than the patient. drome (see Chapter 2). They may begin after 1 day
Fatigue and altered mental status occur at toxic of therapy or may not appear for 6 months. No
dosages. Glaucoma is a rare idiosyncratic reac- reliable way exists to monitor patients for idiosyn-
tion. Oligohydrosis is common, and the physi- cratic hepatotoxicity or to predict its occurrence.
cian should advise patients to avoid overheating.
Vigabatrin (Sabril®, Lundbeck)
Valproate (Depakene®, Depakote®, and Indications. Effective treating infantile
Depacon®, Abbott Pharmaceutical) spasms and partial seizures.
Indications. Use mainly for generalized sei- Administration. Vigabatrin is a very-long-
zures. It is especially useful for mixed seizure dis- acting drug and needs only single day dosing,
orders. Included are myoclonic seizures, simple but twice daily dosing is preferable to reduce
adverse effects. The initial dose is 50 mg/kg/ intravenous preparation can be given rectally. The
day, which increases incrementally, as needed, to dose is 0.5 mg/kg for children age 2 to 5 years,
200–250 mg/kg/day. 0.3 mg/kg for children age 6 to 12, and 0.2 mg/kg
Adverse Effects. Peripheral loss of vision is for children >12 years with an upper limit of 20 mg.
the main serious adverse event. The defect is rare If the rectal dose fails to stop the seizures, a second
and consists of circumferential field constriction dose is recommended 10 minutes after the first
with nasal sparing. Behavioral problems, fatigue, dose and hospital emergency services are required.
confusion, and gastrointestinal upset are usually Status epilepticus is a medical emergency requiring
mild and dose related. prompt attention. Initial assessment should be
rapid and includes cardiorespiratory function, a
Zonisamide (Zonegran®, Eisai Inc.) history leading up to the seizure, and a neurologi-
Indications. Like levetiracetam, zonisamide cal examination. Establish a controlled airway
has a broad spectrum of activity. It is effective immediately and ventilate. Next, establish venous
against both primary generalized and partial access. Measures of blood glucose, electrolytes,
onset epilepsies and is one of the most effective and anticonvulsant drug concentrations in children
drugs in myoclonic epilepsies. with known epilepsy are required. Perform other
Administration. Zonisamide is a long-acting tests, i.e., a toxic screen, as indicated. Once blood is
drug and should be given once at bedtime. The withdrawn, start an intravenous infusion of saline
initial dose in children is 2 mg/kg/day. The max- solution for the administration of anticonvulsant
imum dose is around 15 mg/kg/day. drugs and the administration of an intravenous
Adverse Effects. Common adverse effects are bolus of a 50 % glucose solution, 1 mg/kg.
drowsiness and anorexia. Of greater concern is
the possibility of oligohydrosis and hyperther- Drug Treatment
mia. Monitoring for decreased sweating and
hyperthermia is required. The ideal drug for treating status epilepticus is
one that acts rapidly, has a long duration of action,
and does not produce sedation. The use of benzo-
Management of Status Epilepticus diazepines (diazepam and lorazepam) for this pur-
The definition of status epilepticus is a pro- pose is common. However, they are inadequate by
longed single seizure (longer than 30 minutes) or themselves because their duration of action is
repeated seizures without interictal recovery. brief. In addition, children given intravenous ben-
Generalized tonic-clonic status is life threa zodiazepines after a prior load of barbiturate often
tening and the most common emergency in have respiratory depression. The dose of diaze-
pediatric neurology. The prognosis after status pam is 0.2 mg/kg, not to exceed 10 mg at a rate of
epilepticus in newborns is invariably poor (Pisani 1 mg/min. Lorazepam may be preferable to diaz-
et al, 2007). The causes of status epilepticus are: epam because of its longer duration of action. The
(1) a new acute illness such as encephalitis; (2) a usual dosage in children 12 years of age or younger
progressive neurological disease; (3) loss of sei- is 0.1 mg/kg. After age 12 years, it is 0.07 mg/kg.
zure control in a known epileptic; or (4) a febrile Intravenous fosphenytoin is an ideal agent
seizure in an otherwise normal child. The cause because it has a long duration of action, does not
is the main determinate of outcome. Recurrence produce respiratory depression, and does not
of status epilepticus is most likely in children impair consciousness. The initial dose is 20 mg/
who are neurologically abnormal and is rare in kg (calculated as phenytoin equivalents). Admin-
children with febrile seizures. The assessment of istration can be intravenous or intramuscular,
status epilepticus in children is the subject of a but the intravenous route is greatly preferred.
Practice Parameter of the Child Neurology Unlike phenytoin, which requires slow infusions
Society (Rivello et al, 2006). (0.5 mg/kg/min) to avoid cardiac toxicity, fos-
Absence status and complex partial status are phenytoin infusions are rapid and often obviate
often difficult to identify as status epilepticus. the need for prior benzodiazepine therapy.
The child may appear to be in a confusional state. Infants generally require 30 mg/kg.
Fosphenytoin is usually effective unless a
severe, acute encephalopathy is the cause of sta-
Immediate Management
tus. Children who fail to wake up at an expected
Home management of prolonged seizures or clus- time after the clinical signs of status have stopped
ters of seizures in children with known epilepsy is require an EEG to exclude the possibility of
possible using rectal diazepam to prevent or abort electrical status epilepticus.
status epilepticus (O’Dell et al, 2005). A rectal Intravenous levetiracetam, 20–40 mg/kg, is an
diazepam gel is commercially available, or the excellent alternative to fosphenytoin, because it
Photic-9 Hz (00:09.9)
Fp1-A1A2
Fp2-A1A2
Fp3-A1A2
Fp4-A1A2
C3-A1A2
C4-A1A2
P3-A1A2
P4-A1A2
O1-A1A2
O2-A1A2
F7-A1A2
F8-A1A2
T7-A1A2
T8-A1A2
P7-A1A2
P8-A1A2
Fz-A1A2
Cz-A1A2
Pz-A1A2
EKG
10:08:47 AM LE, 10 sec/screen, 20µV/mm, 70.0 Hz, 1.000 Hz, Notch off
FIGURE 1-4 n Juvenile myoclonic epilepsy: 4.7 Hz generalized spike and slow wave discharge lasting 2.5 seconds
during photic stimulation.
does not require hepatic metabolism, has mini-

mal interactions, is not cardiotoxic, and can be
The Ketogenic Diet
infused faster; however, it has not undergone the The Bible mentions fasting and praying as a
testing to be universally accepted in status proto- treatment for epilepsy. The introduction of diet-
cols. Other attractive options before pentobarbi- induced ketosis to mimic fasting dates to 1921,
tal or midazolam induced coma include when barbiturates and bromides were the only
lacosamide and Depacon. available antiepileptic drugs. This method
When all else fails, several alternatives are became less popular with the introduction of
available; my preference is pentobarbital coma. effective pharmacotherapy. However, it remains
Transfer the patient from the emergency depart- an effective method to treat children with sei-
ment to an intensive care unit. Intubation and zures refractory to antiepileptic drugs at nontoxic
mechanically ventilation must be in place. After levels. The diet is most effective in infants and
placing an arterial line, monitor the patient’s young children. A diet that consists of 60 %
blood pressure, cardiac rhythm, body tempera- medium-chain triglycerides, 11 % long-chain
ture, and blood oxygen saturation. saturated fat, 10 % protein, and 19 % carbohy-
With an EEG monitor recording continu- drate is commonly used. The main side effects
ously, infuse 10 mg/kg boluses of pentobarbital are abdominal pain and diarrhea (Nordli, 2002).
until a burst-suppression pattern appears on the The ketogenic diet causes a prompt elevation
EEG (Figure 1-4); a minimum of 30 mg/kg is in plasma ketone bodies that the brain uses as an
generally required. Hypotension is the most seri- energy source. The mechanism of action is not
ous complication and requires treatment with established. The ketogenic diet is most effective
vasopressors. It generally does not occur until for control of myoclonic seizures, infantile
after the administration of 40–60 mg/kg. Barbitu- spasms, atonic/akinetic seizures, and mixed sei-
rates tend to accumulate, and the usual dosage zures of the Lennox-Gastaut syndrome. The
needed to maintain pentobarbital coma is ketogenic diet is not a “natural” treatment for
3 mg/kg/h. Maintaining coma for several days is epilepsy. Side effects are common and altera-
safe. Continuous EEG recording indicates a tions in chemistries are more significant than
burst-suppression pattern. Slow or stop the barbi- with the use of medications; however, it is a good
turate infusion every 24 to 48 hours to see if coma alternative when epilepsy is not controlled or
is still required to prevent seizure discharges. medications are not tolerated.
Vagal Nerve Stimulation intractable epilepsy and hemiplegia. The original

procedure consisted of removing the cortex of
VNS is a treatment for refractory seizures that one hemisphere along with a variable portion of
uses a programmed stimulus from a chest- the underlying basal ganglia. The extent of sur-
implanted generator via coiled electrodes tun- gery depended partly upon the underlying dis-
neled to the left cervical vagus nerve. Current ease. The resulting cavity communicated with the
indications for VNS are for adjunctive treatment third ventricle and developed a subdural mem-
of refractory partial seizures. The main adverse brane lining. The immediate results were good.
effects are voice changes or hoarseness. The keto- Seizures were relieved in about 80 % of children,
genic diet is preferable to VNS in children less and behavior and spasticity improved without
than 12 years of age (Wheless & Maggio, 2002). deterioration of intellectual function or motor
However, VNS is a consideration in children function in the hemiparetic limbs.
with refractory epilepsy. Many patients seem to However, late complications of hemorrhage,
have shorter postictal periods and improved hydrocephalus, and hemosiderosis occurred in up
mood with this therapy. A 30–40 % reduction in to 35 % of children and were sometimes fatal.
seizures is in general a reasonable expectation. The subdural membrane repeatedly tore, bleed-
ing into the ventricular system and staining the
Surgical Approaches to Childhood ependymal lining and the pia arachnoid with iron.
Epilepsy Because of these complications, less radical
alternatives are generally preferred. These alter-
Epilepsy surgery is an excellent option for selected natives are the Montreal-type hemispherectomy
children with intractable epilepsy. Surgery is never and interhemispheric commissurotomy. The
a substitute for good medical therapy, and antiepi- Montreal-type hemispherectomy is a modified
leptic drug therapy often continues after surgery. procedure with removal of most of the damaged
Lesionectomies, hemispherectomy, interhemi- hemisphere but with portions of the frontal and
spheric commissurotomy, and temporal lobectomy occipital lobes left in place, but disconnected
or hippocampectomy are appropriate for different from the other hemisphere and brainstem. The
situations. None of these procedures is new, and all best results are in children with diseases affecting
have gone through phases of greater or lesser popu- only one hemisphere, Sturge-Weber syndrome
larity since their introduction. The use of functional (Kossoff et al, 2002), and Rasmussen encephalitis
MRI, Wada test, single-photon emission computed (Kossoff et al, 2003).
tomography (SPECT), positron emission tomog-
raphy (PET), and magnetoencephalography
Interhemispheric Commissurotomy
(MEG), when indicated, improves the localization
of the epileptogenic foci and the surgical outcomes. Disconnecting the hemispheres from each other
and from the brainstem is an alternative to hemi-
Lesionectomy, Temporal Lobectomy spherectomy in children with intractable epi-
or Hippocampectomy lepsy and hemiplegia. Another use of this
procedure is to decrease the occurrence of sec-
The resection of an epileptogenic lesion may be ondary generalized tonic-clonic seizures from
needed for diagnosis when neoplasms are sus- partial or minor generalized seizures. The effi-
pected. Lesionectomy is often an excellent treat- cacy of commissurotomy and hemispherectomy
ment choice for epilepsies resistant to medical in children with infantile hemiplegia is probably
treatment when the MRI shows an underlying comparable, but efficacy of commissurotomy in
structural abnormality in the focus of seizures. other forms of epilepsy is unknown.
Around 80 % of patients with well-circumscribed Complete and partial commissurotomies are in
unifocal epilepsies associated with lesions may use. Complete commissurotomy entails division
remain seizure free after surgical resections. The of the entire corpus callosum, anterior commis-
hippocampus or the temporal lobe are often the sure, one fornix, and the hippocampal commis-
target of a potential epilepsy surgery. The success sure. Complete commissurotomies may be one-or
rate decreases in cases where the MRI shows no two-stage procedures. Partial commissurotomies
underlying abnormality or the patient has multi- vary from division of the corpus callosum and hip-
ple seizure semiologies and multifocal epilepsies. pocampal commissure to division of only the
anterior portion of the corpus callosum.
Hemispherectomy Two immediate, but transitory, postoperative
complications may follow interhemispheric
The use of hemispherectomy, or more correctly commissurotomy: (1) a syndrome of mutism, left
hemidecortication, is exclusively for children with arm and leg apraxia, and urinary incontinence;
and (2) hemiparesis. They are both more com- Granata T, Gobbi G, Spreaficio, et al. Rasmussen’s encepha-
mon after one-stage, complete commissurotomy litis. Early characteristics allows diagnosis. Neurology
than after two-stage procedures or partial com- 2003b;60:422–5.
Guilleminault C, Palombini L, Pelayo R, et al. Sleepwalking
missurotomy and probably caused by prolonged
and sleep terrors in prepubertal children: What triggers
retraction of one hemisphere during surgery. them? Pediatrics 2003;111:e17–25.
Long-term complications may include stuttering Gümüs H, Kumandas S, Per H. Levetiracetam monotherapy
and poorly coordinated movements of the hands. in newly diagnosed cryptogenic West syndrome. Pediatric
Neurology 2007;37:350–3.
Hamosh A. Glycine encephalopathy. In: GeneClinics: Medical
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Aroxysmal Isorders: Approach To Paroxysmal Disorders

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CHAPTER 1

motor cortex. In an otherwise alert and responsive

BOX 1-3 Differential Diagnosis of Neonatal Seizures by Peak Time of Onset

Maple syrup urine

FIGURE 1-1 n Branched-chain amino Valine -Keto-isovalerate Isobutyryl-CoA Methacrylyl-CoA

organic acidemia or valproic acid treatment

hyperammonemia due to urea cycle disorders. Bilirubin Encephalopathy

seem to be equally effective or ineffective exists between the intravenous dose of

Phenobarbital. Intravenous phenobarbital is a

BOX 1-7 Paroxysmal Disorders in decreased motor activity with indeterminate

limbs characterize the seizures. Anticonvulsant BOX 1-8 Neurocutaneous Disorders

Management. A practice parameter for the

Benign Myoclonus of Infancy encompasses several syndromes in which an

acetaminophen, prochlorperazine or prometha- Familial Paroxysmal Choreoathetosis

Complex Partial Seizures

93 secs Hyperventilation (05:01.2) 100 secs

TABLE 1-2 Antiepileptic Drugs for Children

*Not clinically useful.

Ethosuximide (Zarontin®, Pfizer) Administration. The usual titration dose is

Adverse Effects. Levetiracetam is minimally Phenytoin (Dilantin®, Pfizer US

does not require hepatic metabolism, has mini-

Vagal Nerve Stimulation intractable epilepsy and hemiplegia. The original

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Aroxysmal Isorders: Approach To Paroxysmal Disorders

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Document Information

Original Title

Copyright

Available Formats

Share this document

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Did you find this document useful?

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Aroxysmal Isorders: Approach To Paroxysmal Disorders

Uploaded by

Copyright:

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CHAPTER 1

motor cortex. In an otherwise alert and responsive

BOX 1-3 Differential Diagnosis of Neonatal Seizures by Peak Time of Onset

Maple syrup urine

FIGURE 1-1 n Branched-chain amino Valine -Keto-isovalerate Isobutyryl-CoA Methacrylyl-CoA

organic acidemia or valproic acid treatment

hyperammonemia due to urea cycle disorders. Bilirubin Encephalopathy

seem to be equally effective or ineffective exists between the intravenous dose of

Phenobarbital. Intravenous phenobarbital is a

BOX 1-7 Paroxysmal Disorders in decreased motor activity with indeterminate

limbs characterize the seizures. Anticonvulsant BOX 1-8 Neurocutaneous Disorders

Management. A practice parameter for the

Benign Myoclonus of Infancy encompasses several syndromes in which an

acetaminophen, prochlorperazine or prometha- Familial Paroxysmal Choreoathetosis

Complex Partial Seizures

93 secs Hyperventilation (05:01.2) 100 secs

TABLE 1-2 Antiepileptic Drugs for Children

*Not clinically useful.

Ethosuximide (Zarontin®, Pfizer) Administration. The usual titration dose is

Adverse Effects. Levetiracetam is minimally Phenytoin (Dilantin®, Pfizer US

does not require hepatic metabolism, has mini-

Vagal Nerve Stimulation intractable epilepsy and hemiplegia. The original

You might also like

BOX 1-3 Differential Diagnosis of Neonatal Seizures by Peak Time of Onset

FIGURE 1-1 n Branched-chain amino Valine -Keto-isovalerate Isobutyryl-CoA Methacrylyl-CoA

BOX 1-7 Paroxysmal Disorders in decreased motor activity with indeterminate

limbs characterize the seizures. Anticonvulsant BOX 1-8 Neurocutaneous Disorders

TABLE 1-2 Antiepileptic Drugs for Children