Clinical Features

Repeated, irregular slow clonic movements (1 to 3 jerks/second) affecting one limb or both limbs on one side are characteristic of focal clonic seizures. Rarely do such movements sustain for long periods, and they do not “march” as though spreading along the motor cortex. In an otherwise alert and responsive full-term newborn, unifocal clonic seizures always indicate a cerebral infarction or hemorrhage or focal brain dysgenesis . In newborns with states of decreased consciousness, focal clonic seizures may indicate a focal infarction superimposed on a generalized encephalopathy.

Diagnosis

During the seizure, the EEG may show a unilateral focus of high-amplitude sharp waves adjacent to the central fissure. The discharge can spread to involve contiguous areas in the same hemisphere and can be associated with unilateral seizures of the limbs and adversive movements of the head and eyes. The interictal EEG may show focal slowing, sharp waves or amplitude attenuation.

Newborns with focal clonic seizures should be immediately evaluated using magnetic resonance imaging (MRI) with diffusion-weighted images. Computed tomography (CT) or ultrasound is acceptable for less stable neonates unable to make the trip to the MRI suite or tolerate the time needed for this procedure.

Clinical Features

In multifocal clonic seizures, migratory jerking movements are noted in first one limb and then another. Facial muscles may be involved as well. The migration appears random and does not follow expected patterns of epileptic spread. Sometimes, prolonged movements occur in one limb, suggesting a focal rather than a multifocal seizure. Detection of the multifocal nature comes later, when nursing notes appear contradictory concerning the side or the limb affected. Multifocal clonic seizures are a neonatal equivalent of generalized tonic-clonic seizures. They are ordinarily associated with severe, generalized cerebral disturbances such as hypoxic-ischemic encephalopathy, but may also represent benign neonatal convulsions when noted in an otherwise healthy neonate.

Diagnosis

Standard EEG usually detects multifocal epileptiform activity. If not, a 24-hour monitor is appropriate.

Clinical Features

Brief, nonrhythmic extension and flexion movements of the arms, the legs, or all limbs characterize myoclonic seizures. They constitute an uncommon seizure pattern in the newborn, but their presence suggests severe, diffuse brain damage.

Diagnosis

No specific EEG pattern is associated with myoclonic seizures in the newborn. Myoclonic jerks often occur in babies born to drug-addicted mothers. Whether these movements are seizures, jitteriness, or myoclonus (discussed later) is uncertain.

Clinical Features

The characteristic feature of tonic seizures are extension and stiffening of the body, usually associated with apnea and upward deviation of the eyes. Tonic posturing without the other features is rarely a seizure manifestation. Tonic seizures are more common in premature than in full-term newborns and usually indicate structural brain damage rather than a metabolic disturbance.

Diagnosis

Tonic seizures in premature newborns are often a symptom of intraventricular hemorrhage and an indication for ultrasound study. Tonic posturing also occurs in newborns with forebrain damage, not as a seizure manifestation but as a disinhibition of brainstem reflexes. Prolonged disinhibition results in decerebrate posturing, an extension of the body and limbs associated with internal rotation of the arms, dilation of the pupils, and downward deviation of the eyes. Decerebrate posturing is often a terminal sign in premature infants with intraventricular hemorrhage caused by pressure on the upper brainstem (see Chapter 4 ).

Tonic seizures and decerebrate posturing look similar to opisthotonos, a prolonged arching of the back not necessarily associated with eye movements. The cause of opisthotonos is probably meningeal irritation. It occurs in kernicterus, infantile Gaucher disease, and some aminoacidurias.

Clinical Features

An irregular respiratory pattern with intermittent pauses of 3 to 6 seconds, often followed by 10 to 15 seconds of hyperpnea, is a common occurrence in premature infants. The pauses are not associated with significant alterations in heart rate, blood pressure, body temperature, or skin color. Immaturity of the brainstem respiratory centers causes this respiratory pattern, termed periodic breathing . The incidence of periodic breathing correlates directly with the degree of prematurity. Apneic spells are more common during active than quiet sleep.

Apneic spells of 10 to 15 seconds are detectable at some time in almost all premature and some full-term newborns. Apneic spells of 10 to 20 seconds are usually associated with a 20 % reduction in heart rate. Longer episodes of apnea are almost invariably associated with a 40 % or greater reduction in heart rate. The frequency of these apneic spells correlates with brainstem myelination. Even at 40 weeks conceptional age, premature newborns continue to have a higher incidence of apnea than do full-term newborns. The incidence of apnea sharply decreases in all infants at 52 weeks conceptional age. Apnea with bradycardia is unlikely to be a seizure. Apnea with tachycardia raises the possibility of seizure and should be evaluated with simultaneous EEG recording.

Diagnosis

Apneic spells in an otherwise normal-appearing newborn is typically a sign of brainstem immaturity and not a pathological condition. The sudden onset of apnea and states of decreased consciousness, especially in premature newborns, suggests an intracranial hemorrhage with brainstem compression. Immediate ultrasound examination is in order.

Apneic spells are almost never a seizure manifestation unless associated with tonic deviation of the eyes, tonic stiffening of the body, or characteristic limb movements. However, prolonged apnea without bradycardia, and especially with tachycardia, is a seizure until proven otherwise.

Management

Short episodes of apnea do not require intervention. The rare ictal apnea requires the use of anticonvulsant agents.

Clinical Features

Sudden jerking movements of the limbs during sleep occur in normal people of all ages (see Chapter 14 ). They appear primarily during the early stages of sleep as repeated flexion movements of the fingers, wrists, and elbows. The jerks do not localize consistently, stop with gentle restraint, and end abruptly with arousal. When prolonged, the usual misdiagnosis is focal clonic or myoclonic seizures.

Diagnosis

The distinction between nocturnal myoclonus and seizures or jitteriness is that benign nocturnal myoclonus occurs solely during sleep, is not activated by a stimulus, and the EEG is normal.

Management

Treatment is unnecessary, and education and reassurance are usually sufficient. Rarely a child with violent myoclonus experiences frequent arousals disruptive to sleep, and a small dose of clonazepam may be considered. Videos of children with this benign condition are very reassuring for the family to see and are available on the internet.

Clinical Features

Jitteriness or tremulousness is an excessive response to stimulation. Touch, noise, or motion provokes a low-amplitude, high-frequency shaking of the limbs and jaw. Jitteriness is commonly associated with a low threshold for the Moro reflex, but it can occur in the absence of any apparent stimulation and be confused with myoclonic seizures.

Diagnosis

Jitteriness usually occurs in newborns with perinatal asphyxia that may have seizures as well. EEG monitoring, the absence of eye movements or alteration in respiratory pattern, and the presence of stimulus activation distinguishes jitteriness from seizures. Newborns of addicted mothers and newborns with metabolic disorders are often jittery.

Management

Reduced stimulation decreases jitteriness. However, newborns of addicted mothers require sedation to facilitate feeding and to decrease energy expenditure.

Clinical Features

Affected newborns appear healthy at birth, but lethargy, feeding difficulty, and hypotonia develop after ingestion of protein. A progressive encephalopathy develops by 2 to 3 days postpartum. The encephalopathy includes lethargy, intermittent apnea, opisthotonos, and stereotyped movements such as “fencing” and “bicycling.” Coma and central respiratory failure may occur by 7to10 days of age. Seizures begin in the second week and are associated with the development of cerebral edema. Once seizures begin, they continue with increasing frequency and severity. Without therapy, cerebral edema becomes progressively worse and results in coma and death within 1 month.

Diagnosis

Plasma amino acid concentrations show increased plasma concentrations of the three branch-chained amino acids. Measures of enzyme in lymphocytes or cultured fibroblasts serve as a confirmatory test. Heterozygotes have diminished levels of enzyme activity.

Management

Hemodialysis may be necessary to correct the life-threatening metabolic acidosis. A trial of thiamine (10–20 mg/kg/day) improves the condition in a thiamine-responsive MSUD variant . Stop the intake of all natural protein, and correct dehydration, electrolyte imbalance, and metabolic acidosis. A special diet, low in branched-chain amino acids, may prevent further encephalopathy if started immediately by nasogastric tube. Newborns diagnosed in the first 2 weeks and treated rigorously have the best prognosis.

Clinical Features

Affected newborns are normal at birth but become irritable and refuse feeding anytime from 6 hours to 8 days after delivery. The onset of symptoms is usually within 48 hours but delays by a few weeks occur in milder allelic forms. Hiccupping is an early and continuous feature; some mothers relate that the child hiccupped in utero as a prominent symptom. Progressive lethargy, hypotonia, respiratory disturbances, and myoclonic seizures follow. Some newborns survive the acute illness, but cognitive impairment, epilepsy, and spasticity characterize the subsequent course.

In the milder forms range, the onset of seizures is after the neonatal period. The developmental outcome is better, but does not exceed moderate cognitive impairment.

Diagnosis

During the acute encephalopathy, the EEG demonstrates a burst-suppression pattern, which evolves into hypsarrhythmia during infancy. The MRI may be normal or may show agenesis or thinning of the corpus callosum. Delayed myelination and atrophy are later findings. Hyperglycinemia and especially elevated concentrations of glycine in the cerebrospinal fluid (CSF), in the absence of hyperammonemia, organic acidemia or valproic acid treatment establishes the diagnosis.

Management

No therapy has proven to be effective. Hemodialysis provides only temporary relief of the encephalopathy, and diet therapy has not proved successful in modifying the course. Diazepam, a competitor for glycine receptors, in combination with choline, folic acid, and sodium benzoate, may stop the seizures. Oral administration of sodium benzoate at doses of 250–750 mg/kg/day can reduce the plasma glycine concentration into the normal range. This substantially reduces but does not normalize CSF glycine concentration. Carnitine, 100 mg/kg/day, may increase the glycine conjugation with benzoate.

Clinical Features

The clinical features of urea cycle disorders are due to ammonia intoxication ( Box 1-5 ). Progressive lethargy, vomiting, and hypotonia develop as early as the first day after delivery, even before the initiation of protein feeding. Progressive loss of consciousness and seizures follow on subsequent days. Vomiting and lethargy correlate well with plasma ammonia concentrations greater than 200 µg/dL (120 µmol/L). Coma correlates with concentrations greater than 300 µg/dL (180 µmol/L) and seizures with those greater than 500 µg/dL (300 µmol/L). Death follows quickly in untreated newborns. Newborns with partial deficiency of CPS and female carriers of OTC deficiency may become symptomatic after ingesting a large protein load.

Diagnosis

Suspect the diagnosis of a urea cycle disturbance in every newborn with a compatible clinical syndrome and hyperammonemia without organic acidemia. Hyperammonemia can be life threatening, and diagnosis within 24 hours is essential. Determine the blood ammonia concentration and the plasma acid–base status. A plasma ammonia concentration of 150 mmol/L strongly suggests a urea cycle disorder. Quantitative plasma amino acid analysis helps differentiate the specific urea cycle disorder. Molecular genetic testing is available for some disorders, but others still require liver biopsy to determine the level of enzyme activity. The most common cause of hyperammonemia is difficult phlebotomy with improper sample processing. Accurate serum ammonia testing requires a good phlebotomist, sample placement on ice, and rapid processing.

Management

Treatment cannot await specific diagnosis in newborns with symptomatic hyperammonemia due to urea cycle disorders. The treatment measures include reduction of plasma ammonia concentration by limiting nitrogen intake to 1.2–2.0 g/kg/day and using essential amino acids for protein; allowing alternative pathway excretion of excess nitrogen with sodium benzoate and phenylacetic acid; reducing the amount of nitrogen in the diet; and reducing catabolism by introducing calories supplied by carbohydrates and fat. Arginine concentrations are low in all inborn errors of urea synthesis except for arginase deficiency and require supplementation.

Even with optimal supervision, episodes of hyperammonemia may occur and may lead to coma and death. In such cases, intravenous administration of sodium benzoate, sodium phenylacetate, and arginine, coupled with nitrogen-free alimentation, are appropriate. If response to drug therapy is poor, then peritoneal dialysis or hemodialysis is indicated.

Clinical Features

Brief multifocal clonic seizures develop during the first week, sometimes associated with apnea. Delay of onset may be as long as 4 weeks. With or without treatment, the seizures usually stop spontaneously within the first months of life. Febrile seizures occur in up to one-third of affected children; some have febrile seizures without first having neonatal seizures. Epilepsy develops later in life in as many as a third of affected newborns. The seizure types include nocturnal generalized tonic-clonic seizures and simple focal orofacial seizures.

Diagnosis

Suspect the syndrome when seizures develop without apparent cause in a healthy newborn. Laboratory tests are normal. The EEG often demonstrates multifocal epileptiform discharges and may be normal interictally. A family history of neonatal seizures is critical to diagnosis but may await discovery until interviewing the grandparents; parents are frequently unaware that they had neonatal seizures.

Management

Treat with anticonvulsants. Oxcarbazepine at doses of 20 mg/kg/day for a couple of days and titrated to 40 mg/kg/day can be helpful. The duration of treatment needed is unclear. We often treat infants for about 9 months, after which we discontinue treatment if the child remains seizure-free and the EEG has normalized.

Clinical Features

Three distinct clinical phases of bilirubin encephalopathy occur in full-term newborns with untreated hemolytic disease. Hypotonia, lethargy, and a poor sucking reflex occur within 24 hours of delivery. Bilirubin staining of the brain is already evident in newborns during this first clinical phase. On the second or third day, the newborn becomes febrile and shows increasing tone and opisthotonic posturing. Seizures are not a constant feature but may occur at this time. Characteristic of the third phase is apparent improvement with normalization of tone. This may cause second thoughts about the accuracy of the diagnosis, but the improvement is short-lived. Evidence of neurological dysfunction begins to appear toward the end of the second month, and the symptoms become progressively worse throughout infancy.

In premature newborns, the clinical features are subtle and may lack the phases of increased tone and opisthotonos.

The typical clinical syndrome after the first year includes extrapyramidal dysfunction, usually athetosis, which occurs in virtually every case (see Chapter 14 ); disturbances of vertical gaze, upward more often than downward, in 90 %; high-frequency hearing loss in 60 %; and mental retardation in 25 %. Survivors often develop a choreoathetoid form of cerebral palsy.

Diagnosis

In newborns with hemolytic disease, the basis for a presumed clinical diagnosis is a significant hyperbilirubinemia and a compatible evolution of symptoms. However, the diagnosis is difficult to establish in critically ill premature newborns, in which the cause of brain damage is more often asphyxia than kernicterus.

Management

Maintaining serum bilirubin concentrations below the toxic range, either by phototherapy or exchange transfusion, prevents kernicterus. Once kernicterus has occurred, further damage can be limited, but not reversed, by lowering serum bilirubin concentrations. Diazepam and baclofen are often needed for management of dystonic postures associated with the cerebral palsy.

Clinical Features

Symptoms of opiate withdrawal are more severe and tend to occur earlier in full-term (first 24 hours) than in premature (24 to 48 hours) newborns. The initial feature is a coarse tremor, present only during the waking state, which can shake an entire limb. Irritability, a shrill, high-pitched cry, and hyperactivity follow. The newborn seems hungry but has difficulty feeding and vomits afterward. Diarrhea and other symptoms of autonomic instability are common.

Myoclonic jerking is present in 10–25 % of newborns undergoing withdrawal. Whether these movements are seizures or jitteriness is not clear. Definite seizures occur in fewer than 5 %. Maternal use of cocaine during pregnancy is associated with premature delivery, growth retardation, and microcephaly. Newborns exposed to cocaine, in utero or after delivery through the breast milk, often show features of cocaine intoxication including tachycardia, tachypnea, hypertension, irritability, and tremulousness.

Diagnosis

Suspect and anticipate drug withdrawal in every newborn whose mother has a history of substance abuse. Even when such a history is not available, the combination of irritability, hyperactivity, and autonomic instability should provide a clue to the diagnosis. Careful questioning of the mother concerning her use of prescription and nonprescription drugs is imperative. Blood, urine, and meconium analyses identify specific drugs.

Management

Symptoms remit spontaneously in 3 to 5 days, but appreciable mortality occurs among untreated newborns. Benzodiazepines or chlorpromazine, 3 mg/kg/day, may relieve symptoms and reduce mortality. Consider phenobarbital 8 mg/kg/day for refractory cases. Secretion of morphine, meperidine, opium, and methadone in breast milk is insufficient to cause or relieve addiction in the newborn. Levetiracetam 40 mg/kg/day is a good option for seizures.

The occurrence of seizures, in itself, does not indicate a poor prognosis. The long-term outcome relates more closely to the other risk factors associated with substance abuse in the mother.

Clinical Features

The 22q11.2 syndrome encompasses several similar phenotypes: DGS, velocardiofacial syndrome (VCFS), and Shprintzen syndrome. The acronym CATCH is used to describe the phenotype of cardiac abnormality, T-cell deficit, clefting (multiple minor facial anomalies), and hypocalcemia. The identification of most children with DGS is in the neonatal period with a major heart defect, hypocalcemia, and immunodeficiency. Diagnosis of children with VCFS comes later because of cleft palate or craniofacial deformities.

The initial symptoms of DGS may be due to congenital heart disease, hypocalcemia, or both. Jitteriness and tetany usually begin in the first 48 hours after delivery. The peak onset of seizures is on the third day but a 2-week delay may occur. Many affected newborns die of cardiac causes during the first month; survivors fail to thrive and have frequent infections secondary to the failure of cell-mediated immunity.

Diagnosis

Newborns with DGS come to medical attention because of seizures and heart disease. Seizures or a prolonged Q-T interval brings attention to hypocalcemia. Molecular genetic testing confirms the diagnosis.

Management

Management requires a multispecialty team including cardiology, immunology, medical genetics, and neurology. Plastic surgery, dentistry, and child development contribute later on. Hypocalcemia generally responds to parathyroid hormone or to oral calcium and vitamin D.

Clinical Features

The time of onset of symptoms depends upon the underlying disorder. Early onset is generally associated with perinatal asphyxia, maternal diabetes or intracranial hemorrhage, and late onset with inborn errors of metabolism. Hypoglycemia is rare and mild among newborns with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia and is invariably severe in those with 3-methylglutaconic aciduria, glutaric aciduria type 2, and disorders of fructose metabolism.

The syndrome includes any of the following symptoms: apnea, cyanosis, tachypnea, jitteriness, high-pitched cry, poor feeding, vomiting, apathy, hypotonia, seizures, and coma. Symptomatic hypoglycemia is often associated with later neurological impairment.

Diagnosis

Neonatal hypoglycemia is defined as a whole blood glucose concentration of less than 20 mg/dL (1 mmol/L) in premature and low-birth-weight newborns, less than 30 mg/dL (1.5 mmol/L) in term newborns during the first 72 hours, and less than 40 mg/dL (2 mmol/L) in full-term newborns after 72 hours. Finding a low glucose concentration in a newborn with seizures prompts investigation into the cause of the hypoglycemia.

Management

Intravenous administration of glucose normalizes blood glucose concentrations, but the underlying cause must be determined before providing definitive treatment.

Clinical Features

Mild HIE is relatively common. The newborn is lethargic but conscious immediately after birth. Other characteristic features are jitteriness and sympathetic over-activity (tachycardia, dilatation of pupils, and decreased bronchial and salivary secretions). Muscle tone is normal at rest, tendon reflexes are normoreactive or hyperactive, and ankle clonus is usually elicited. The Moro reflex is complete, and a single stimulus generates repetitive extension and flexion movements. Seizures are not an expected feature, and their occurrence suggests concurrent hypoglycemia, the presence of a second condition or a more significant HIE.

Symptoms diminish and disappear during the first few days, although some degree of over-responsiveness may persist. Newborns with mild HIE are believed to recover normal brain function completely. They are not at greater risk for later epilepsy or learning disabilities.

Newborns with severe HIE are stuporous or comatose immediately after birth, and respiratory effort is usually periodic and insufficient to sustain life. Seizures begin within the first 12 hours. Hypotonia is severe, and tendon reflexes, the Moro reflex, and the tonic neck reflex are absent as well. Sucking and swallowing are depressed or absent, but the pupillary and oculovestibular reflexes are present. Most of these newborns have frequent seizures, which may appear on EEG without clinical manifestations. They may progress to status epilepticus. The response to antiepileptic drugs is usually incomplete. Generalized increased intracranial pressure characterized by coma, bulging of the fontanelles, loss of pupillary and oculovestibular reflexes, and respiratory arrest often develops between 24 and 72 hours of age.

The newborn may die at this time or may remain stuporous for several weeks. The encephalopathy begins to subside after the third day, and seizures decrease in frequency and eventually stop. Jitteriness is common as the child becomes arousable. Tone increases in the limbs during the succeeding weeks. Neurological sequelae are expected in newborns with severe HIE.

Diagnosis

EEG and MRI are helpful in determining the severity and prognosis of HIE. In mild HIE, the EEG background rhythms are normal or lacking in variability. In severe HIE, the background is always abnormal and shows suppression of background amplitude. The degree of suppression correlates well with the severity of HIE. The worst case is a flat EEG or one with a burst-suppression pattern. A bad outcome is invariable if the amplitude remains suppressed for 2 weeks or a burst-suppression pattern is present at any time. Epileptiform activity may also be present but is less predictive of the outcome than is background suppression.

MRI with diffusion-weighted images are helpful to determine the full extent of injury. The basal ganglia and thalamus are often affected by HIE.

Management

The management of HIE in newborns requires immediate attention to derangements in several organs and correction of acidosis. Clinical experience indicates that control of seizures and maintenance of adequate ventilation and perfusion increases the chance of a favorable outcome. A treatment approach involves either whole body or selective head cooling ( ).

A separate section details the treatment of seizures in newborns. The use of intravenous levetiracetam is promising ( ). Seizures often cease spontaneously during the second week, and long-term anticonvulsant therapy may not be necessary. The incidence of later epilepsy among infants who had neonatal seizures caused by HIE is 30–40 %. Continuing antiepileptic therapy after the initial seizures have stopped does not influence whether the child goes on to develop epilepsy as a lifelong condition.

Clinical Features

Two phenotypes are associated with the same enzyme defect. One is an acute, overwhelming disorder of the newborn; the other is a chronic infantile form. Newborns with the acute disorder are normal at birth but within a few days become lethargic, refuse to feed, and vomit. The clinical syndrome is similar to MSUD except that the urine smells like “sweaty feet” instead of maple syrup. Sixty per cent of affected newborns die within 3 weeks. The survivors have a clinical syndrome identical to the chronic infantile phenotype.

Diagnosis

The excretion of isovaleryl-lysine in the urine detects isovaleric acidosis. Assays of isovaleryl-CoA dehydrogenase activity utilize cultured fibroblasts, and molecular testing is available. The clinical phenotype correlates not with the percentage of residual enzyme activity, but with the ability to detoxify isovaleryl-CoA with glycine.

Management

Dietary restriction of protein, especially leucine, decreases the occurrence of later psychomotor retardation. l -Carnitine, 50 mg/kg/day, is a beneficial supplement to the diet of some children with isovaleric acidemia. In acutely ill newborns, oral glycine, 250–500 mg/day, in addition to protein restriction and carnitine, lowers mortality.

Clinical Features

Affected children appear normal at birth. In 80 % of those with complete mutase deficiency, the symptoms appear during the first week after delivery; those with defects in the synthesis of adenosylcobalamin generally show symptoms after 1 month. Symptoms include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and hypotonia after the initiation of protein feeding. Leukopenia, thrombocytopenia, and anemia are present in more than one half of patients. Intracranial hemorrhage may result from a bleeding diathesis. The outcome for newborns with complete mutase deficiency is usually poor. Most die within 2 months of diagnosis; survivors have recurrent acidosis, growth retardation, and cognitive impairment.

Diagnosis

Suspect the diagnosis in any newborn with metabolic acidosis, especially if associated with ketosis, hyperammonemia, and hyperglycinemia. Demonstrating an increased concentration of methylmalonic acid in the urine and elevated plasma glycine levels helps confirm the diagnosis. The specific enzyme defect can be determined in fibroblasts. Techniques for prenatal detection are available.

Management

Some affected newborns are cobalamin responsive and others are not. Management of those with mutase deficiency is similar to propionic acidemia. The long-term results are poor. Vitamin B ₁₂ supplementation is useful in some defects of adenosylcobalamin synthesis, and hydroxocobalamin administration is reasonable while awaiting the definitive diagnosis. Maintain treatment with protein restriction (0.5–l.5 g/kg/day) and hydroxocobalamin (1 mg) weekly. As in propionic acidemia, oral supplementation of l -carnitine reduces ketogenesis in response to fasting.

Clinical Features

Most affected children appear normal at birth; symptoms may begin as early as the first day after delivery or delayed for months or years. In newborns, the symptoms are nonspecific: feeding difficulty, lethargy, hypotonia, and dehydration. Recurrent attacks of profound metabolic acidosis, often associated with hyperammonemia, which respond poorly to buffering is characteristic. Untreated newborns rapidly become dehydrated, have generalized or myoclonic seizures, and become comatose.

Hepatomegaly caused by a fatty infiltration occurs in approximately one-third of patients. Neutropenia, thrombocytopenia, and occasionally pancytopenia may be present. A bleeding diathesis accounts for massive intracranial hemorrhage in some newborns. Children who survive beyond infancy develop infarctions in the basal ganglia.

Diagnosis

Consider propionic acidemia in any newborn with ketoacidosis or with hyperammonemia without ketoacidosis. Propionic acidemia is the probable diagnosis when the plasma concentrations of glycine and propionate and the urinary concentrations of glycine, methylcitrate, and β-hydroxypropionate are increased. While the urinary concentration of propionate may be normal, the plasma concentration is always elevated, without a concurrent increase in the concentration of methylmalonate.

Deficiency of enzyme activity in peripheral blood leukocytes or in skin fibroblasts establishes the diagnosis. Molecular genetic testing is available. Detecting methylcitrate, a unique metabolite of propionate, in the amniotic fluid and by showing deficient enzyme activity in amniotic fluid cells provides prenatal diagnosis.

Management

The newborn in ketoacidosis requires dialysis to remove toxic metabolites, parenteral fluids to prevent dehydration, and protein-free nutrition. Restricting protein intake to 0.5–l.5 g/kg/day decreases the frequency and severity of subsequent attacks. Oral administration of l -carnitine reduces the ketogenic response to fasting and may be useful as a daily supplement. Intermittent administration of nonabsorbed antibiotics reduces the production of propionate by gut bacteria.

Clinical Features

The clinical spectrum of perinatal HSV infection is considerable. Among symptomatic newborns, one-third has disseminated disease, one-third has localized involvement of the brain, and one-third has localized involvement of the eyes, skin, or mouth. Whether infection is disseminated or localized, approximately half of infections involve the central nervous system. The overall mortality rate is over 60 %, and 50 % of survivors have permanent neurological impairment.

The onset of symptoms may be as early as the fifth day but is usually in the second week. A vesicular rash is present in 30 %, usually on the scalp after vertex presentation and on the buttocks after breech presentation. Conjunctivitis, jaundice, and a bleeding diathesis may be present. The first symptoms of encephalitis are irritability and seizures. Seizures may be focal or generalized and are frequently only partially responsive to therapy. Neurological deterioration is progressive and characterized by coma and quadriparesis.

Diagnosis

Culture specimens are collected from cutaneous vesicles, mouth, nasopharynx, rectum, or CSF. Polymerase chain reaction is the standard for diagnosis herpes encephalitis. The EEG is always abnormal and shows a periodic pattern of slow waves or spike discharges. The CSF examination shows a lymphocytic leukocytosis, red blood cells, and an elevated protein concentration.

Management

The best treatment is prevention. Cesarean section should be strongly considered in all women with active genital herpes infection at term whose membranes are intact or ruptured for less than 4 hours.

Intravenous acyclovir is the drug of choice for all forms of neonatal HSV disease. The dosage is 60 mg/kg per day divided in 3 doses, given intravenously for 14 days in skin/eye/mouth disease and for 21 days for disseminated disease. All patients with central nervous system (CNS) HSV involvement should undergo a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the CSF is polymerase chain reaction (PCR) negative and normalized. Therapy continues until documenting a negative PCR. Acute renal failure is the most significant adverse effect of parenteral acyclovir. Mortality remains 50 % or greater in newborns with disseminated disease.

Clinical Features

The initial symptom is focal seizures or lethargy beginning any time during the first month. Intracranial pressure remains normal, lethargy slowly resolves, and seizures tend to respond to anticonvulsants. The long-term outcome is uncertain and probably depends upon the extent of hemorrhagic infarction of the hemisphere.

Diagnosis

CT venogram or MR venogram are the standard tests for diagnosis. CT venogram is a more sensitive and accurate imaging modality.

Management

Anticoagulation may decrease the risk of thrombus progression, venous congestion leading to hemorrhage and stroke, and facilitate re-canalization of the venous sinus. Response to therapy varies widely, and dosages of low molecular weight heparin frequently require readjustment to maintain therapeutic anti-Xa levels of 0.5–1 U/mL. A starting dose of 1.7 mg/kg every 12 hours for term infants, or 2.0 mg/kg every 12 hours for preterm infants, may be beneficial ( ). Ultimately, therapeutic decisions must incorporate treatment of the underlying cause of the thrombosis, if known.

Clinical Features

Blood in the subarachnoid space probably originates from tearing of the superficial veins by shearing forces during a prolonged delivery with the head molding. Mild HIE is often associated with subarachnoid hemorrhage (SAH), but the newborn is usually well when an unexpected seizure occurs on the first or second day of life. Lumbar puncture, performed because of suspected sepsis, reveals blood in the CSF. The physician may suspect a traumatic lumbar puncture; however, red blood cell counts in first and last tube typically show similar counts in subarachnoid hemorrhage and clearing numbers in traumatic taps. Most newborns with subarachnoid hemorrhages will not suffer long-term sequelae.

Diagnosis

CT is useful to document the extent of hemorrhage. Blood is present in the interhemispheric fissure and the supratentorial and infratentorial recesses. EEG may reveal epileptiform activity without background suppression. This suggests that HIE is not the cause of the seizures, and that the prognosis is more favorable. Clotting studies are needed to evaluate the possibility of a bleeding diathesis.

Management

Seizures usually respond to anticonvulsants. Specific therapy is not available for the hemorrhage, and posthemorrhagic hydrocephalus is uncommon.

Clinical Features

Subdural hemorrhage is usually the consequence of a tear in the tentorium near its junction with the falx. Causes of tear include excessive vertical molding of the head in vertex presentation, anteroposterior elongation of the head in face and brow presentations, or prolonged delivery of the aftercoming head in breech presentation. Blood collects in the posterior fossa and may produce brainstem compression. The initial features are those of mild to moderate HIE. Clinical evidence of brainstem compression begins 12 hours or longer after delivery. Characteristic features include irregular respiration, an abnormal cry, declining consciousness, hypotonia, seizures, and a tense fontanelle. Intracerebellar hemorrhage is sometimes present. Mortality is high, and neurological impairment among survivors is common.

Diagnosis

MRI, CT or ultrasound visualizes the subdural hemorrhages.

Management

Small hemorrhages do not require treatment, but surgical evacuation of large collections relieves brainstem compression.

Clinical Features

Newborns experience seizures soon after birth. The seizures are usually multifocal clonic at onset and progress rapidly to status epilepticus. Although presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. The seizures only respond to pyridoxine. A seizure-free interval up to 3 weeks may occur after pyridoxine discontinuation. Outcome may be improved and cognitive deficits decreased with early diagnosis and treatment.

Atypical features include late-onset seizures (up to age 2 years); seizures that initially respond to antiepileptic drugs and then do not; seizures that do not initially respond to pyridoxine but then become controlled; and prolonged seizure-free intervals occurring after stopping pyridoxine. Intellectual disability is common.

Diagnosis

Suspect the diagnosis in newborns with an affected older sibling, or in newborns with daily seizures unresponsive to anticonvulsants, with progressive course and worsening EEGs. Characteristic of the infantile-onset variety is intermittent myoclonic seizures, focal clonic seizures, or generalized tonic-clonic seizures. The EEG is continuously abnormal because of generalized or multifocal spike discharges and tends to evolve into hypsarrhythmia. An intravenous injection of pyridoxine, 100 mg, stops the clinical seizure activity and often converts the EEG to normal in less than 10 minutes. However, sometimes 500 mg is required. When giving pyridoxine IV, arousals may look like improvement in EEG since hypsarrhythmia is a pattern seen initially during sleep. Comparing sleep EEG before and after pyridoxine is needed to confirm an EEG response. CSF neurotransmitter testing is available to confirm the diagnosis.

Management

A lifelong dietary supplement of pyridoxine, 50–100 mg/day, prevents further seizures. Subsequent psychomotor development is best with early treatment, but this does not ensure a normal outcome. The dose needed to prevent mental retardation may be higher than that needed to stop seizures.

Clinical Features

Infants develop seizures during the first week of life that are not responsive to anticonvulsants or pyridoxine.

Diagnosis

A characteristic peak on CSF electrophoresis confirms the diagnosis ( ).

Management

Treat the disorder with folinic acid supplementation, 2.5–5 mg twice daily.

Clinical Features

The female-to-male ratio is 20:1. An erythematous and vesicular rash resembling epidermolysis bullosa is present on the flexor surfaces of the limbs and lateral aspect of the trunk at birth or soon thereafter. The rash persists for the first few months and a verrucous eruption that lasts for weeks or months replaces the original rash. Between 6 and 12 months of age, deposits of pigment appear in the previous area of rash in bizarre polymorphic arrangements. The pigmentation later regresses and leaves a linear hypopigmentation. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails may be associated. Some have retinal vascular abnormalities that predispose to retinal detachment in early childhood.

Neurological disturbances occur in fewer than half of the cases. In newborns, the prominent feature is the onset of seizures on the second or third day, often confined to one side of the body. Residual neurological handicaps may include cognitive impairment, epilepsy, hemiparesis, and hydrocephalus.

Diagnosis

The clinical findings and biopsy of the skin rash are diagnostic. The basis for diagnosis is the clinical findings and the molecular testing of the IKBKG gene.

Management

Neonatal seizures caused by incontinentia pigmenti usually respond to standard anticonvulsant drugs. The blistering rash requires topical medication and oatmeal baths. Regular ophthalmological examinations are needed to diagnose and treat retinal detachment.

Clinical Features

The usual provoking stimulus for cyanotic spells is anger, pain, frustration, or fear. The infant’s sibling takes away a toy, the child cries, and then stops breathing in expiration. Cyanosis develops rapidly, followed quickly by limpness and loss of consciousness. Crying may not precede cyanotic episodes provoked by pain.

If the attack lasts for only seconds, the infant may resume crying on awakening. Most spells, especially the ones referred for neurological evaluation, are longer and are associated with tonic posturing of the body and trembling movements of the hands or arms. The eyes may roll upward. These movements are mistaken for seizures by even experienced observers, but they are probably a brainstem release phenomenon. Concurrent EEG shows flattening of the record, not seizure activity.

After a short spell, the child rapidly recovers and seems normal immediately; after a prolonged spell, the child first arouses and then goes to sleep. Once an infant begins having breath-holding spells, the frequency increases for several months and then declines, and finally cease.

Diagnosis

The typical sequence of cyanosis, apnea, and loss of consciousness is critical for diagnosis. Cyanotic syncope and epilepsy are confused because of lack of attention to the precipitating event. It is not sufficient to ask, “Did the child hold his breath?” The question conjures up the image of breath-holding during inspiration. Instead, questioning should be focused on precipitating events, absence of breathing, facial color, and family history. The family often has a history of breath-holding spells or syncope.

Between attacks, the EEG is normal. During an episode, the EEG first shows diffuse slowing and then rhythmic slowing followed by background attenuation during the tonic-clonic, tonic, myoclonic or clonic activity.

Management

Education and reassurance. The family should be educated to leave the child in supine with airway protection until he or she recovers consciousness. Picking up the child, which is the natural act of the mother or observer, prolongs the spell. If the spells occur in response to discipline or denial of the child’s wishes, I recommend caretakers comfort the child but remain firm in their decision, as otherwise children may learn that crying translates into getting their wish. This may in turn reinforce the spells.

Clinical Features

The provocation of pallid syncope is usually a sudden, unexpected, painful event such as a bump on the head. The child rarely cries but instead becomes white and limp and loses consciousness. These episodes are truly terrifying to behold. Parents invariably believe the child is dead and begin mouth-to-mouth resuscitation. After the initial limpness, the body may stiffen, and clonic movements of the arms may occur. As in cyanotic syncope, these movements represent a brainstem release phenomenon, not seizure activity. The duration of the spell is difficult to determine because the observer is so frightened that seconds seem like hours. Afterward the child often falls asleep and is normal on awakening.

Diagnosis

Pallid syncope is the result of reflex asystole. Pressure on the eyeballs to initiate a vagal reflex provokes an attack. I do not recommend provoking an attack as an office procedure. The history alone is diagnostic.

Management

As with cyanotic spells, the major goal is to reassure the family that the child will not die during an attack. The physician must be very convincing.

Clinical Features

Febrile seizures not caused by infection or another definable cause occur in approximately 4 % of children. Only 2 % of children whose first seizure is associated with fever will have nonfebrile seizures (epilepsy) by age 7 years. The most important predictor of subsequent epilepsy is an abnormal neurological or developmental state. Complex seizures, defined as prolonged, focal, or multiple, and a family history of epilepsy slightly increase the probability of subsequent epilepsy.

A single, brief, generalized seizure occurring in association with fever is likely to be a simple febrile seizure. The seizure need not occur during the time when fever is rising. “Brief” and “fever” are difficult to define. Parents do not time seizures. When a child has a seizure, seconds seem like minutes. A prolonged seizure is one that is still in progress after the family has contacted the doctor or has left the house for the emergency room. Postictal sleep is not part of seizure time.

Simple febrile seizures are familial and probably transmitted by autosomal dominant inheritance with incomplete penetrance. One-third of infants who have a first simple febrile seizure will have a second one at the time of a subsequent febrile illness, and half of these will have a third febrile seizure. The risk of recurrence increases if the first febrile seizure occurs before 18 months of age or at a body temperature less than 40°C. More than three episodes of simple febrile seizures are unusual and suggest that the child may later have nonfebrile seizures.

Diagnosis

Any child thought to have an infection of the nervous system should undergo a lumbar puncture for examination of the CSF. Approximately one-quarter of children with bacterial or viral meningitis have seizures. After the seizure from CNS infection, prolonged obtundation is expected.

In contrast, infants who have simple febrile seizures usually look normal after the seizure. Lumbar puncture is unnecessary following a brief, generalized seizure from which the child recovers rapidly and completely, especially if the fever subsides spontaneously or is otherwise explained.

Blood cell counts, measurements of glucose, calcium, electrolytes, urinalysis, EEG, and cranial CT or MRI on a routine basis are not cost effective and discouraged. Individual decisions for laboratory testing depend upon the clinical circumstance. Obtain an EEG on every infant who is not neurologically normal or who has a family history of epilepsy. Infants with complex febrile seizures may benefit from an EEG or MRI.

Management

Because only one-third of children with an initial febrile seizure have a second seizure, treating every affected child is unreasonable. Treatment is unnecessary in the low-risk group with a single, brief, generalized seizure. No evidence has shown that a second or third simple febrile seizure, even if prolonged, causes epilepsy or brain damage. I always offer families the option to have diazepam gel available for prolonged or acute repetitive seizures.

I consider the use of anticonvulsant prophylaxis in the following situations:

• 1.
  

  Complex febrile seizures in children with neurological deficits.

  
  
• 2.
  

  Strong family history of epilepsy and recurrent simple or complex febrile seizures.

  
  
• 3.
  

  Febrile status epilepticus.

  
  
• 4.
  

  Febrile seizures with a frequency higher than once per quarter.