General observations

Head size and shape

The head circumference should be measured as part of routine examination of the newborn ( Ch. 14 ), and the importance of documenting head size and head growth as part of neurological assessment cannot be overstressed. Fontanelle size and tension must be recorded.

The newborn skull is not fused, and it is possible to palpate the cranial sutures which should not be ridged or separated too far ( Fig. 40.2 ). Observe any superficial swellings such as cephalhaematoma or subgaleal collections. Fused sutures (craniosynostosis) may need treatment, or may be a clue to an underlying disorder such as Apert’s syndrome. Advice may need to be obtained from a neurosurgeon.

Diagram to show the position of the cranial sutures and the fontanelles.

Orientation and behaviour

Posture, spontaneous movement and tone

Facial expression

Spontaneous facial movements are frequently seen in the normal newborn, although bilateral facial paralysis (as in Moebius syndrome) is much more difficult to diagnose than the more common unilateral facial palsy. Normal facial expression in an otherwise hypotonic and flaccid newborn baby suggests a spinal cord problem. Babies of just a few days old will often imitate facial gestures, for example putting out their tongues.

Limb movement, passive tone and power

Before passive movements are used to assess tone it may be possible to observe spontaneous movements of the limbs against gravity. Failure to move part or all of a limb may be due to pain or paralysis. Limb tone is influenced by the tonic neck reflex in newborns which means it is important to have the head in the midline before beginning to elicit passive movements. These involve gentle flexion of the upper and lower limbs, then rapid extension and observation of recoil. A summary is contained within the protocol suggested by . This examination system, like that of , involves assessing angles made by bending and manipulating the limbs and trunk. These include the popliteal angle ( Fig. 40.3 ), the foot dorsiflexion angle and the scarf sign. A reduced popliteal angle and clusters of abnormal signs are sensitive indicators of later outcome ( ).

Assessment of popliteal angle. Note that the ipsilateral hip joint should be fixed.

Trunk and neck tone and power

Normal term babies have sufficient power in their neck muscles to lift their heads slightly when prone or supine. Preterm babies can manage to turn their heads from side to side but have much less power, with complete head lag when pulled to sit. In order to judge tone in the neck and trunk, babies should be pulled to sit by holding them at the shoulders ( Fig. 40.4 ). The pull-to-sit manoeuvre elicits an attempt to raise the head in a normal term newborn ( Fig. 40.4a ). If the head is unsupported it will gradually fall forwards or backwards: normal term babies will be able to raise their heads to the vertical again from either direction ( Fig. 40.4b ), but it is normal for the head of a term baby to wobble. Truncal tone can be assessed by placing the baby on his side, with one hand on the back and the other manipulating the legs. It is normally easier to flex a baby’s trunk than to extend it.

(a) Pull-to-sit manoeuvre: this full-term baby is attempting to raise his head. (b) After being pulled to sit the baby has raised his head to the vertical position.

Reflexes

Moro reflex

This reflex is usually elicited by allowing the previously supported head of a baby to fall backwards slightly, whereupon the baby extends and adducts both upper limbs, opening the hands ( Fig. 40.5 ). Babies of greater than 33 weeks’ gestation subsequently adduct their arms. The Moro response is present from 28 weeks of gestation and usually disappears by 4 months. Persistence beyond 6 months is always abnormal.

The abduction phase of the Moro response: the baby’s head has been allowed to fall back slightly but is then supported by the examiner’s hand.

Placing and stepping

By stimulating the dorsum of the foot, usually by bringing it into contact with the edge of the couch, a mature baby can be induced to ‘step’ over the edge ( Fig. 40.6 ). The baby’s toes fan out and he lifts his foot up and then places it on the surface. Babies will extend their legs on to a flat surface and ‘support’ their weight when held under the arms. With the feet in contact with a solid surface and the body tilted forwards the baby will ‘walk’.

The stepping reflex, elicited by bringing the dorsum of the baby’s foot into contact with the couch.

Palmar and plantar

The palmar reflex results from stroking the palmar surface of the hand, eliciting a grasp that is often strong enough to lift the baby from the crib ( Fig. 40.7 ). It is present from 26 weeks’ gestation and persists up to 4 months. Stroking the plantar surface of the foot results in curling of the toes in a similar manner to the palmar response ( Fig. 40.8 ).

The palmar grasp reflex.

The plantar grasp reflex.

Examination of vision, visual evoked potentials

The assessment of visual function in newborn babies includes behavioural and electrophysiological techniques.

Behavioural techniques are based on the observation of spontaneous or elicited visual behaviours in the baby. The 26-week gestation preterm baby blinks in response to light; by 32 weeks there is eye closure; by 34 weeks a baby is able to fix and track a bright object briefly. By 37 weeks a baby will turn to soft light, and can track reliably ( Fig. 40.9 ). Optokinetic horizontal nystagmus is present when a term baby looks at a striped rotating drum or a striped tape is moved in front of the baby’s eyes. Changing the width of the stripes or forced-choice preferential looking at striped grids can be used to test visual acuity, which is equivalent to 20/150 vision at term. Vertical or asymmetrical nystagmus should always be investigated ( ).

Fixing and tracking a red pom-pom.

The interpretation of deficient neonatal visual responses, however, is much more difficult. Dubowitz stresses the importance of the loss of previously good visual performance as a disturbing sign. Babies’ eyes are usually in alignment, although a slight horizontal divergence is normal until 6 weeks of age, particularly in preterm babies. Vertical or skew deviation is always abnormal and has been seen in association with germinal matrix haemorrhage/intraventricular haemorrhage ( ). For more information on abnormal and delayed visual development, and squint, see Chapter 33 .

Electrophysiological techniques measure the visual evoked potentials which are produced within the occipital cortex as a result of repeatedly applying an appropriate visual stimulus so that the minute electrical response to it, which will be identical each time, can be extracted from the random background electrical noise (EEG) by computerised averaging. Strobosocopic or flashing red lights are used which can penetrate closed eyelids. The electrical response ‘matures’ with advancing gestation and can be detected from 25 weeks. Study of visual evoked potentials has been found to be of value in predicting outcome after birth asphyxia ( ), and is a sensitive test for the integrity of the visual pathway. Absent visual evoked potentials predicts cortical blindness in preterm infants with extensive cystic leukomalacia ( ), and visual impairment is the most important variable in determining the neurodevelopmental scores in these infants ( ).

Otoacoustic emissions

Otoacoustic emissions were discovered in 1978. Otoacoustic emissions are low-amplitude sound waves which are produced by the inner ear; they occur spontaneously as well as in response to a click stimulus. The automated method depends on the fact that a click stimulus, when presented to an intact hearing ear, evokes an otoacoustic emission which can be detected by a probe lying in the ear canal. Testing with otoacoustic emissions is quicker to administer than with an automated evoked brainstem response method but there are more false-positive results.

Brainstem auditory evoked potential

These indicate electrical events generated in the brainstem auditory pathway in response to sound (usually a click) presented at the ear. The electrical signals are recorded with EEG electrodes on the scalp. The results of many click stimulations are summed by a computer which uses coherent averaging to eliminate the background noise generated by the local EEG signal. The mature pattern consists of seven waves, but these are poorly developed with increased latency and require a larger stimulus in order to elicit them in babies, in whom the response is present from 24 weeks. Automated brainstem response equipment eliminates the need for extensive operator training and is a widely used method of hearing screening.

Subtle

The clinical manifestations of seizures in infants can be extremely subtle. They can be divided into orofacial manifestations, including fixed eye opening, eye deviation, eyelid blinking, sucking, chewing and lip smacking, and limb movements (often described as swimming, boxing or cycling). In addition, apnoeic episodes can be due to seizure and this diagnosis should be considered if there is slow response to bag-and-mask ventilation, particularly in a preterm neonate with an intracranial lesion. Another clue may be associated movements such as eyelid or mouth opening and a bradycardia which starts soon after the collapse. Autonomic changes, such as a change in blood pressure or increased salivation, often accompany subtle seizures and these may provide a clue to the correct diagnosis in the absence of EEG confirmation.

Clonic

Clonic seizures usually involve one limb or one side of the face or body jerking rhythmically, usually at a frequency of 1–4 times per second. This type of seizure is associated with a characteristic EEG discharge consisting of runs of sharp slow-wave complexes which spread ipsilaterally from the hemisphere in which they originate. Clonic seizures in the neonate can have more than one focus or migrate in a non-jacksonian fashion; for example, jerking of one leg can be followed by similar movements in the opposite hand. Clonic seizures are often a clue to an underlying focal lesion such as a cortical infarction and are frequently associated with neonatal stroke ( ). They may also occur in association with a metabolic cause and occasionally herpes encephalitis. Infants are not usually unconscious during clonic seizures.

Tonic

Tonic seizures are much less common than either subtle or clonic seizures in the newborn. Sustained posturing of the limbs or trunk or deviation of the head or eyes are the usual manifestations of tonic seizures in the newborn.

Myoclonic

Myoclonus is characterised by sudden brief and jerky movements which tend to occur in the flexor muscle groups. It can be localised to one muscle group or it may be generalised. It is irregular and arrhythmic and is of high amplitude. Generalised myoclonic seizures resemble salaam spasms and are the type most likely to be associated with EEG change. Myoclonic seizures are most frequently noted in preterm infants with major cerebral pathology and the background EEG pattern is usually abnormal. Myoclonic jerks can also occur in babies who are receiving midazolam for sedation, particularly during weaning ( ). Some babies with serious underlying disorders such as glycine encephalopathy suffer from very troublesome repetitive myoclonic jerking as their only seizure manifestation ( ).

Jitteriness

Jitteriness is an extremely common phenomenon in normal newborns, being observed in 44% of a sample of 936 babies ( ). It is defined as involuntary rhythmic oscillatory movement around a fixed axis that can be either fine (fast (>6 Hz) and of low amplitude) or coarse (slow and of high amplitude) ( ). Fine jittery movements are usually benign or associated with a metabolic disturbance such as hypoglycaemia. Coarse jittery movements are more commonly associated with hypoxic–ischaemic encephalopathy or intracranial haemorrhage. Excessive jitteriness has also been reported in infants born to mothers who use marijuana, and can be a sign of neonatal abstinence syndrome ( Ch. 26 ). Jittering is a symmetrical tremor, without the fast and slow component of a clonic or myoclonic seizure, and occurs at a faster rate of 5–6 times per second. Jittering does not involve the face (unlike subtle seizures), is markedly stimulus-sensitive, and ceases when the limb is held. The autonomic nervous system changes of a seizure, such as tachycardia or hypertension, are never seen in jittering. The EEG does not display electrographic seizure activity and fast-frequency movement artefact is common, synchronous with jittering movements.

Hyperekplexia

Hyperekplexia is a rare disorder caused by autosomal-dominant or recessive modes of inheritance and characterised by generalised muscle rigidity, nocturnal myoclonus and a very exaggerated startle response to auditory, visual and tactile stimuli ( ; ). The startles can look like myoclonic jerks, and the high tone, hyperreflexia and jitteriness can lead to an erroneous diagnosis of seizure ( ). Hyperekplexia is probably the same condition previously known as hereditary stiff-baby syndrome ( ). Although the EEG is normal, the tonic spasms can be dangerous. Severe cases can lead to neonatal cardiac arrest and treatment is warranted. Treatment with clonazepam (0.05–0.2 mg/kg/day) or low-dose clobazam (0.25–0.3 mg/kg/day) usually results in marked improvement, and the episodes usually disappear by the age of 2 years ( ). The disorder is caused by mutations in the alpha subunit of the inhibitory glycine receptor ( ) and has been mapped to chromosome 5 (de Koning-Tijssen and Rees 2007); it can be inherited in an autosomal-dominant fashion, although some forms are autosomal-recessive ( ).

Normal neonatal EEG

The EEG of the normal full-term baby is continuous, contains moderate-voltage mixed-frequency activity, shows fully developed sleep cycles and is reactive to stimuli even within the first 12 hours of birth ( ). The type of continuous activity present depends on whether the baby is awake or in active or quiet sleep (this chapter, part 1). During quiet sleep the EEG may show a pattern called high-voltage slow-wave sleep that consists of continuous medium- to high-voltage delta waves. As quiet sleep continues this pattern may become somewhat discontinuous with periods of low-amplitude beta and theta activity, alternating with 3–5-second bursts of higher-voltage 1–3 Hz activity occurring at 3–10-second intervals. This pattern is called ‘tracé alternant’. In active sleep, the EEG is continuous, of lower voltage and contains mixed-frequency activity. In wakefulness the EEG also shows a lower-voltage mixed-frequency pattern referred to as ‘activité moyenne’. The EEG of a full-term baby is illustrated in Figure 40.15a . Specific normal maturational features that may be present in the full-term EEG are anterior slow dysrhythmia (first apparent from approximately 35 weeks) and frontal sharp transients.

Electroencephalogram recordings showing: (a) normal term activity; (b) normal preterm activity; and seizures in (c) a term baby and (d) a preterm baby.

The most striking feature of the very preterm EEG is long periods of quiescence interrupted only by bursts of high-voltage mixed-frequency waves ( Fig. 40.15b ). The length of quiescent periods (also referred to as interburst intervals) is directly proportional to the degree of prematurity and this normal background pattern is referred to as ‘tracé discontinu’ or discontinuous pattern. This pattern is different to the tracé alternant pattern seen in full-term babies because the periods of quiescence can be completely flat. True quiescence is always less than 15 µV. In tracé alternant the discontinuous pattern is characterised by periods of high-amplitude, mixed-frequency activity alternating with periods of lower-amplitude activity at 25–50 µV (it is never completely flat). The degree of discontinuity seen in the preterm EEG would be very abnormal at term ( ). The maximum interburst interval falls from 60 seconds at 24–26 weeks, to 40 seconds at 27–29 weeks, and 20 seconds at 30–32 weeks ( ; ; ; ). After 33–34 weeks and up to 37 weeks the EEG is discontinuous only in quiet sleep and the interburst interval should be no longer than 10 seconds ( ). After 37 weeks, the EEG is continuous in wakefulness and active sleep, and tracé alternant replaces tracé discontinu in quiet sleep. Specific normal maturational features of the preterm EEG include premature temporal theta activity, which is sharp activity with a characteristic ‘saw-toothed’ appearance seen from approximately 27 weeks, and delta brush activity, which is a combination of very slow delta activity with superimposed fast components, present from approximately 30 weeks.

The abnormal neonatal EEG

The neonatal EEG may be abnormal in a number of ways:

• •
  

  disturbances of continuity, amplitude or frequency

  
  
• •
  

  interhemispheric asymmetry or asynchrony

  
  
• •
  

  abnormal waveforms may be present

  
  
• •
  

  disturbances of sleep state

  
  
• •
  

  seizure activity may be present.

Repetitive periods of true quiescence in the term newborn are abnormal. However anticonvulsants and sedation may induce some periods of quiescence in the term newborn and prolong periods in the preterm baby ( ). characterised the neonatal EEG mainly on the basis of the interburst interval, categorising the EEG of infants <30 weeks as abnormal if the interval was >60 seconds, using a figure of 30 seconds at term. confirmed that an interburst interval of more than 30 seconds was abnormal at term, and presaged a poor outcome.

Hypoxic–ischaemic encephalopathy

This remains the most common cause of neonatal seizures at term, contributing over half the cases to most series. The characteristic time of onset is within 24 hours of birth, and seizures often begin in the first 12–18 hours. Seizures are rare in the first 6 hours unless there has been an antenatal insult ( ). For more information on the management and prognosis of this condition, see pp. 1114–1150 .

In moderate and severe hypoxic–ischaemic encephalopathy, the background EEG pattern can evolve over the first few days after birth. Very suppressed EEG activity is seen for a number of hours after birth and is often followed by a period of seizure activity that, depending on the severity of the insult, can be very difficult to control with anticonvulsants. The seizures also evolve in a characteristic manner in hypoxic–ischaemic encephalopathy over a number of days ( ). When seizures resolve, a burst suppression pattern can be seen for a number of days. Our group have reported delayed lactate clearance in neonates with hypoxic–ischaemic encephalopathy and a high EEG seizure burden ( .

Intracranial haemorrhage

Intraventricular haemorrhage is the most important cause of seizures in preterm babies. A large parenchymal haemorrhage which causes seizures is associated with a poor outcome ( ) (this chapter, part 5). Neonates of any gestation can have seizures because of bleeding into the subarachnoid space, the dural space, the cerebellum or cortex ( ). A diagnosis of intracranial bleeding in a term baby should lead to a search for a coagulation disorder, including vitamin K deficiency, and testing for haemophilia in boys. MRI has shown that a small amount of subarachnoid or subdural bleeding is common in the newborn period, and these collections usually resolve without sequelae.

Focal cerebral infarction (stroke)

Seizures in term infants with normal Apgar scores who remain alert between spasms are likely to be due to focal lesions, most commonly middle cerebral artery infarction. Ten to 15% of seizures in full-term neonates are due to stroke (p. 1108) . On EEG, the area of infarction is the focus of electrographic seizures that generally manifest as clonic seizures on the contralateral side. Seizures often require MRI for identification, and the prognosis is better than when the underlying cause is hypoxic–ischaemic encephalopathy.

The background EEG may be normal or show only mild focal abnormalities, though quiet sleep may enhance background abnormalities ( ). Diagnosis of arterial or venous occlusion in the newborn period should trigger investigations to rule out an underlying thrombotic tendency. EEG is useful for diagnosis and prognosis and should ideally be performed within 24 hours of signs; some neonates will have seizures early in the postnatal period ( ).

Seizures are also the most common presenting sign in cerebral venous sinus thrombosis (p. 1109) . Associated lesions include thalamic haemorrhage, intraventricular haemorrhage and parenchymal haemorrhagic infarction ( ). Ultrasound imaging is not reliable for the detection of stroke or sinus venous thrombosis, which often requires MRI for identification.

Meningitis

Intracranial infections, whether bacterial, non-bacterial or congenital, cause neonatal seizures usually after the first week of life. In a recent French study group B streptococci remained the most common cause of neonatal bacterial meningitis, causing 77% of early-onset and 50% of late-onset cases ( ). Escherichia coli was the most common cause of meningitis in preterm infants.

Aciclovir treatment should be started if the lumbar puncture reveals a high white-cell count in the cerebrospinal fluid (CSF), yet no organisms are seen on Gram stain in a baby who has not been treated with antibiotics, whilst awaiting the results of polymerase chain reaction for herpesvirus. The risks of starting treatment in this situation are minimal, whereas delay will worsen the prognosis. More information on the diagnosis and treatment of neonatal central nervous system infections can be found in Chapter 39 , part 2.

Neonatal abstinence syndrome and other drug-related causes of neonatal seizure ( Ch. 26 )

Withdrawal seizures can occur for the first time at any age up to 3 weeks, with a median time of onset of 10 days. EEG abnormalities are present in 50% of cocaine-exposed neonates, persist up to 1 year, and are associated with an adverse neurodevelopmental outcome. Maternal methadone addiction is more likely to be associated with neonatal withdrawal seizures than heroin ( ). Tremors have been noted in children who received prolonged infusions of narcotics for analgesia ( ), and there has been concern about the effects of midazolam for sedation in preterm babies ( ). A high incidence of benign neonatal sleep myoclonus (BNSM) has been reported in the babies of opioid-dependent mothers ( ).

Hypoglycaemia

Hypoglycaemia can be the sole cause of neonatal seizures and other neurological signs such as apnoea, lethargy and jitteriness. Often hypoglycaemia complicates hypoxic–ischaemic encephalopathy or infection, and hypoglycaemia is common in infants who are small for gestational age ( Ch. 10 ). The adverse outcome associated with the underlying cause makes it difficult to determine the prognosis of uncomplicated hypoglycaemia. However, animal evidence does show that if hypoglycaemia is present during seizures, the risk of brain injury is even higher ( ).There is no doubt that the finding of a low glucose level in a baby who is seizing is an indication for urgent intravenous treatment, and every effort should be made to normalise the glucose level as soon as possible.

Hypocalcaemia

Up until the late 1970s the high phosphate content in cow’s milk-based formula for babies resulted in a high incidence of neonatal seizures due to hypocalaemia ( ). Half the babies in the series of were hypocalcaemic (total serum calcium less than 1.75 mmol/L). Similarly high incidences of late hypocalcaemic seizures were reported prior to the introduction of modern low-phosphate milks; in the late 1960s infants were consuming doorstep cow’s milk or a high-phosphate formula. A higher than usual level of hypocalcaemia has been found as the cause for neonatal seizures in an Indian population in more recent years ( ).

A diagnosis of hypocalcaemia should lead to consideration of CATCH-22 (22q11.2 deletion syndrome), which can be diagnosed with fluorescent in situ hybridization genetic studies. Hypocalcaemic seizures occasionally occur secondary to maternal hypercalcaemia (prolonged intrauterine exposure to high levels) or maternal vitamin D deficiency and the neonatal diagnosis should prompt estimation of the maternal serum calcium. Low magnesium levels frequently accompany hypocalcaemia and require correction before the seizures will respond. Hypocalcaemia is common in ill very-low-birthweight babies and in babies with hypoxic–ischaemic encephalopathy and is probably not causally related to the seizures in these cases. Less often there is congenital hypoparathyroidism or calcium-sensing receptor defects.

Hypernatraemia and hyponatraemia

The most common cause of hypernatraemia is breast milk insufficiency and seizures can occur when the serum sodium level is very high or falls very rapidly. It is recommended that the level be reduced at a rate not exceeding 0.5 mmol/l/h when rehydrating hypernatraemic babies. Babies have also developed hyponatraemic seizures after being given excess solute-free water in intravenous solutions, or orally in the form of cheap alternatives to correctly balanced oral rehydration solutions. A very high, very low or rapidly changing serum sodium occurring in conditions such as the syndrome of inappropriate antidiuretic hormone secretion, Bartter’s syndrome or severe dehydration can cause seizures.

Pyridoxine-dependent seizures

The first case of an infant with intractable seizures controlled by pyridoxine was reported by . It is a rare disorder and seizures can begin during intrauterine life (mothers describe ‘hammering’ movements lasting 15–20 minutes several times a day). Seizures are very resistant to conventional anticonvulsant treatments yet cease within minutes of parenteral pyridoxine (50–100 mg) and return within days of withdrawal. This therapeutic trial can cause hypotonia requiring ventilatory support and should be carried out in an intensive care unit ( ). There is no other way to make the diagnosis, although characteristic EEG abnormalities have been recognised ( ; ). A more recent study has shown that some of the EEG changes seen after pyridoxine administration to neonates with pyridoxine-dependent seizures are also present in other treatment-resistant seizure disorders ( ). Atypical cases that respond more slowly and that show late-onset seizures requiring unusually high doses of pyridoxine (up to 500 mg) have been described ( ; ), and yet others respond to very small doses. Gospe suggests that a trial of pyridoxine should involve 100 mg intravenously every 10 minutes until the seizures stop or a total of 500 mg is reached.

The condition is caused by an inherited metabolic disorder of lysine degradation, resulting in increased urinary alpha-aminoadipic semialdehyde (α-AASA) excretion ( ). In addition to increased urinary α-AASA concentrations, mutations in the ALDH7A1 (antiquitin) gene can also identify pyridoxine-resistant seizures ( ; ). The increased a-AASA concentrations in body fluids result in pyridoxal-5-phosphate deficiency. Pyridoxal-5-phosphate is responsible for converting glutamate into the inhibitory GABA. The condition is autosomal-recessive. Supplementation of the diet with pyridoxine (vitamin B ₆ ) 20–100 mg bd is required for life, and the dose may need to be increased with age ( ). Unfortunately, many of these children have severe cognitive disabilities despite early diagnosis and treatment. A better outcome has been achieved with higher doses of pyridoxine, leading to the suggestion that sufficient pyridoxine should be given to restore the CSF glutamate levels to normal.

Diagnostic tests such as measurements of urinary AASA and pipecolic acid, as well as gene testing for mutations in the antiquitin gene encoding for the AASA dehydrogenase enzyme, are now proving very useful for this disorder ( ; ).

Glycine encephalopathy

Non-ketotic hyperglycinaemia is an inborn error of glycine metabolism in which large quantities of glycine accumulate in all body tissues, including the brain. Neonates exhibit lethargy, hypotonia, apnoea, characteristic hiccups and intractable epileptic seizures that are not specific to this disease. Rapid progression can lead to intractable seizures, coma and respiratory failure. The outcome is invariably poor, and many die before the age of 1 year. Levels of glycine in blood, urine and CSF are very high. The EEG shows a generalised burst suppression pattern characterised by periodic high-amplitude bursts of activity on a near-silent background ( ; ). Dextromethorphan monotherapy (35 mg/kg/day) was associated with cessation of seizures and normalisation of the EEG in a single case, but this regimen is not always successful ( ). A recent report has shown an increase in seizure frequency following valproate treatment ( ).

Glucose transport across the blood–brain barrier is mediated by the facilitative glucose transporter isoform 1 (GLUT-1). A deficiency of this transporter results in impaired energy supply to the brain, and was recognised by . This rare disorder is important because treatment has the potential to lead to a normal neurological outcome, and because the inheritance is autosomal-dominant ( ). The interictal EEG is normal in this disorder, with spike-and-wave discharges generally only emerging during seizures ( ). Babies have a low CSF glucose concentration, with low to normal CSF lactate levels despite normal blood glucose concentrations. Elevated lactate levels would suggest a mitochondrial disorder. The diagnosis should be suspected if the CSF glucose is less than a third of the blood glucose level, and GLUT-1 deficiency can be confirmed with an assay that measures the uptake of ¹⁴ C- O -methyl- d -glucose in erythrocytes. Treatment is with a ketogenic diet, which is usually successful in controlling the seizures but does not always prevent the microcephaly, developmental delay and ataxia. There may be a transient form of the disorder which does not require long-term treatment, but the three cases so far described may have had alternative explanations for the low CSF glucose levels, such as low-grade meningitis or subarachnoid haemorrhage ( ).

Biotinidase deficiency

This is one of the few treatable causes of resistant neonatal seizures, hence the importance of considering this rare autosomal-recessive condition. Biotinidase is responsible for biotin recycling and biotin is an essential cofactor for activation of the carboxylase enzymes. If biotinidase is absent, infantile or early-childhood encephalopathy, seizure disorder, dermatitis, alopecia, neural deafness and optic atrophy develop. In the neonatal period there is usually a skin rash, similar in appearance to seborrhoeic dermatitis. The disease can be diagnosed by simple fluorometric enzyme assay and treatment with biotin is cheap. The EEG shows a burst suppression pattern consistent with encephalopathy ( ).

Benign familial neonatal seizures

This fascinating autosomal-dominant condition was first recognised in 1964 ( ). The onset is within the first week of life and seizures are dramatic, with 80% beginning on the second or third day of life. The seizures ceased after 6 weeks of age in 68% of the largest kindred reported, and rarely persist beyond 6 months ( ).

Seizures show an initial tonic phase with cyanosis followed by clonic movements of the whole body ( ). There is usually a family history of neonatal seizures but they are associated with normal psychomotor development, a normal interictal EEG and a favourable outcome. This rare condition has an autosomal-dominant inheritance with 85% penetrance, and mutations have been found in the genes situated on chromosomes 20q and 8q which code for a family of voltage-gated potassium channels (M (for muscarine) channels). Benign familial neonatal convulsions (BFNC) are thus an example of a ‘channelopathy’. M channels can be kept open with a new AED, retigabine, and it has been suggested that this drug might hold promise for other types of neonatal seizure apart from those in BFNC.

In contrast to pyridoxine-dependent seizures, these fits can be controlled by conventional medication and the prognosis for development is excellent.

Benign non-familial neonatal seizures (fifth-day fits)

This benign self-limiting condition reached epidemic proportions in some Australian maternity units in the late 1970s ( ). Reports also came from France, but only two cases have been seen in Nancy since 1985 and the diagnosis has not been made in Camperdown since 1989 ( ; ). Seizures occur between day 1 and day 7 after birth and are usually partial clonic, rarely generalise and apnoea is common ( ). Seizures last for 1–3 minutes but can become frequent, leading to status epilepticus. The neurological state is usually normal at the onset of seizures and there is no family history of seizures. The interictal EEG may be normal, show generalised or multifocal discharges or show characteristic bursts of sharp waves, sometimes called ‘theta pointu alternant’.

The cause remains a mystery, although low CSF zinc was found in a few cases ( ). A few years ago we cared for a baby with this condition who had marked tonic-clonic seizures which are otherwise very unusual in the newborn period; she has thrived ( ).

Benign neonatal sleep myoclonus

Neurologically normal term neonates can present with BNSM, which is characterised by recurrent rhythmic jerks during sleep and a normal EEG. Jerks disappear during wakefulness and resolve within 3 months. A recent review of the literature which included 164 cases of BNSM found that repetitive jerks were located primarily in the distal part of the extremities, usually the arms but also the legs and very occasionally the face and abdomen ( ). Myoclonus was seen in quiet sleep predominantly but some reports did describe jerks during active sleep. There was also some evidence that an exacerbation of myoclonic jerks occurred when some infants were erroneously treated with AEDs. An interesting finding in this series was that the repetitive jerks did not always stop with gentle restraint and had not resolved by 3 months in one-third of cases. No treatment is required for BNSM and parents should be reassured that the jerks will cease eventually.

Ohtahara syndrome (early infantile epileptic encephalopathy)

This syndrome was first described by Ohtahara and colleagues in 1976 and is one of the age-dependent epileptic encephalopathies (the others being West’s syndrome and Lennox–Gastaut syndrome). Seizures usually develop within the first 10 days of life and may occur as early as the first hour after delivery. The seizure types in Ohtahara syndrome are variable, with the most frequent type being spasms, which may be either generalised and symmetrical or lateralised. Spasms may occur singly or in clusters in both awake and asleep states. Generalised tonic-clonic seizures can develop later in the syndrome. Seizures are usually accompanied by a severe encephalopathy, and are resistant to treatment. Soon after the onset of seizures, the infants become inactive and hypotonic. The syndrome is now believed to be mainly attributable to a cerebral malformation ( ).

The EEG shows a characteristic burst suppression pattern and can be distinguished from the pattern seen in other encephalopathies ( ). According to the Japanese group that has published most of the seminal works on this condition, the bursts must consist of high-amplitude non-synchronised paroxysms lasting 2–6 seconds and the suppression phase must show less than 10 µV or a flat tracing and continue for 3–5 seconds ( ). Suppression and burst phases must appear alternately and regularly every 5 seconds or more and should be seen in both sleep and wake states. During seizures, desynchronisation of the burst suppression pattern is seen. The prognosis is very poor: psychomotor development is arrested and severe neurological abnormalities such as spastic diplegia, hemiplegia, tetraplegia, ataxia, or dystonia develop ( ). Vigabatrin has been tried in a few cases ( ).

Investigation

Essential laboratory investigations include:

• •
  

  blood glucose

  
  
• •
  

  serum calcium, ionised calcium if possible

  
  
• •
  

  serum magnesium

  
  
• •
  

  arterial pH, blood gas

  
  
• •
  

  lactate

  
  
• •
  

  serum sodium

  
  
• •
  

  serum urea and creatinine

  
  
• •
  

  lumbar puncture

  
  
• •
  

  blood culture

  
  
• •
  

  cranial ultrasound scan.

If the cause is not revealed, second-line investigations are suggested in Table 40.4 and include specimens for virology and a congenital infection screen, MRI, samples such as hair or urine to look for maternal ‘street’ drugs, urinary and blood amino acid estimation, chromosomal analysis, blood ammonia and measurement of urinary organic acids. Consideration should be given to a trial of pyridoxine in resistant cases. The value of an EEG examination has already been discussed and an EEG should be obtained if at all possible, and certainly should be done in difficult cases. MRI is superior to computed tomography for most purposes, and should be considered in all cases, and certainly if the cause is not revealed by first-line investigations. Even if the cause is found, the information obtained from MRI can give valuable information about the prognosis.

Treatment

Prognosis

The prognosis depends largely on the cause of the seizures, being worse for those with hypoxic–ischaemic encephalopathy, meningitis and cerebral malformations than hypocalcaemia, benign familial neonatal seizures, subarachnoid haemorrhage or stroke ( ) ( Table 40.6 ). Mortality and morbidity are greater in preterm babies ( ; ). There is some evidence suggesting that seizures are independently associated with a poor outcome but recent evidence is conflicting ( ; ). The background EEG can be helpful, and a normal background EEG with well-organised sleep stages has consistently been shown to be associated with an 80% chance of normal development ( ; ; ). The background EEG features of encephalopathy evolve over time, and it is important not to prognosticate from a recording made too early; both we and others have shown that a low-voltage EEG seen in the first 6 hours of life can recover ( ; ; ).

This evolutionary pattern may have changed somewhat with the advent of therapeutic hypothermia and two studies using continuous aEEG monitoring have suggested that recovery of the EEG is delayed when babies with hypoxic–ischaemic encephalopathy are cooled ( ; ). Rewarming seizures are occasionally seen ( ). The number of electrographic seizures is not in general an indicator of prognosis, nor is the clinical seizure type. Some have suggested that the outcome is worse for babies with a large number of independent electrographic seizure foci, but this work requires confirmation ( ). There is increasing consensus that seizures (including electrographic seizures which are clinically silent) which persist despite third-line AEDs carry a poor prognosis ( ). Adverse outcomes include cerebral palsy and microcephaly with significant learning difficulties.

The risk of subsequent epilepsy after neonatal seizures also depends on the aetiology, and is more likely if spike and sharp-wave activity persists on the EEG at 3 months ( ). The later seizure type includes infantile spasms, minor motor seizures, complex partial and tonic-clonic seizures, which often only emerge after a year or so. In a Dutch study, the incidence of postneonatal epilepsy after treatment of clinical and subclinical neonatal seizures detected with continuous aEEG was 9.4% ( ).

Difficult delivery

The main risk factor for perinatal ICH is dystocia (difficult child birth: Table 40.7 ). Disimpaction of the fetal skull at caesarean section has become a more common cause of ICH due to trauma in our experience, and that of others, as more caesarean sections are performed in the second stage of labour when the head is deeply engaged ( ). There may be an associated skull fracture ( Fig. 40.17 ). From an epidemiologic study from California, ICH occurred in 1 of 2750 infants delivered by caesarean section without labour, 1 in 1900 infants delivered by normal vaginal delivery, 1 in 907 infants delivered by caesarean section during labour, 1 in 860 infants delivered by vacuum extraction and 1 in 664 infants delivered by forceps, in nulliparous women ( ). In a Sheffield study of asymptomatic infants ( ), five of nine infants with SDH were delivered by forceps after failed ventouse, one had had a traumatic ventouse delivery and the other three were born by normal vaginal delivery. Studies show that ICH is commoner after forceps delivery ( ) when compared with vaginal delivery, and it is also commoner after a trial of forceps following a failed ventouse ( ) when compared with delivery by ventouse alone, forceps alone or a normal vaginal birth.

Traumatic damage sustained at the time of disimpaction of the fetal head at caesarean section. (a) Computed tomography (CT) three-dimensional reconstruction of the skull showing a fracture of the right parietal bone. (b) CT scan at 16 hours of age showing subgaleal bleeding, the skull fracture and parenchymal bleeding. (c) T2-weighted axial image showing damage in the right parieto-occipital region with an area of deep haemorrhage. (d) Diffusion-weighted image confirming extensive cerebral trauma.

Maternal associations include primiparity, grand multiparity, pre-eclampsia and placental abruption. Neonatal factors include HIE, low Apgar scores and any bleeding disorder, including thrombocytopenia and haemophilia.

Neonatal bleeding disorders

ICH in babies with HIE or sepsis complicated by a coagulopathy is not uncommon. A study of 66 newborns with ICH showed that at least 12 (19%) had platelet counts of less than 50 × 10 ⁹ /L within the first 48 hours of life and were specifically associated with intraparenchymal haemorrhage and a more severe grade ( ).

Neonatal alloimmune thrombocytopenia ( Ch. 30 ) carries a substantial risk of ICH in the newborn, probably around 1 in 10, many of which occur during intrauterine life ( ; ). These babies are prone to all types of extra-axial and intra-axial haemorrhage ( ).

Primary inherited coagulation disorders are rare but may present with ICH in the newborn. Haemophilia A and B are the commonest of these ( ; ; ). Recent studies suggest that 3.5–4% of all haemophilic boys develop ICH in the newborn period, a figure which represents a significantly increased risk compared to the normal population. Despite the poor outcome, the debate about prophylactic factor VIII still rages ( Ch. 30 ) and of course many are first-born male babies, and the diagnosis is not suspected until the ICH is already very large. Very rarely, deficiency of factors X, VII, XIII and fibrinogen presents in the newborn period. These deficiencies are autosomal-recessive traits and as such are commoner in communities with consanguinity. Ineffective vitamin K prophylaxis, parental refusal of vitamin K and deficiency remain important causes of ICH. Babies with liver disease often present with vitamin K deficiency bleeding, usually intracranial ( ; ).

Structural anomalies

Arteriovenous malformations, aneurysms and tumours are rare causes of ICH at term.

Extracorporeal membrane oxygenation (ECMO)

The need for ECMO or cardiac surgery increases the risk that a term baby will develop symptomatic intraventricular haemorrhage (IVH) ( ; ).There are probably many reasons for this, including anticoagulation, sepsis and sinus thrombosis. Some forms of ECMO require ligation of one carotid artery.

Haemorrhage into an area of venous infarction

It is now appreciated that many parenchymal haemorrhages at term are due to bleeding into an area of venous infarction ( ). This is particularly likely in thalamic haemorrhage (see below) ( ). Hence, bleeding into the deep grey matter at term is often the first sign of a cerebral sinovenous thrombosis (CSVT: see below).

Lumbar puncture

Lumbar puncture is not recommended to assist in the diagnosis of ICH. Clearly, in a sick infant with accompanying signs of neurological dysfunction such as encephalopathy and raised intracranial pressure, lumbar puncture is contraindicated.

If uniformly blood-stained cerebrospinal fluid (CSF) is obtained when a diagnostic lumbar puncture is undertaken it should raise a suspicion of ICH, particularly subarachnoid haemorrhage (SAH).

Electrophysiology

Digital bedside cerebral function monitoring carried out while a conventional multichannel electroencephalogram (EEG) is awaited may reveal electrographic seizures ( p. 1084 ). Conventional multichannel EEG may show focal seizures localizing to the focus of the lesion.

Neuroimaging

Cranial ultrasound (CUS) remains the main modality of imaging of the newborn brain at the bedside and is generally a good technique for imaging intraventricular and parenchymal bleeds. In experienced hands, CUS allows visualisation of bleeds into the cerebellum as well as the basal ganglia and thalami. CUS is of limited value for the detection of subdural haemorrhage and SAH unless there is obvious midline shift.

Computed tomography (CT) scanning is easily available in most centres, where access to MRI may be more limited. CT entails a significant dose of X-ray irradiation, but provides images with a short acquisition time, albeit with low resolution. It is good for visualising skull fractures and will adequately detect modest-sized extra-axial bleeds, although MRI is likely to detect smaller bleeds. The radiation exposure of CT is justified when significant ICH is suspected, if MRI is not available.

MRI, where available, is the imaging modality of choice. A combination of MRI sequences such as T1, T2 and diffusion weighting will allow detection of most intra- and extra-axial bleeds at various stages of evolution. MR angiography, including the neck vessels, should be performed when stroke is suspected (see below).

Tentorial and falx tears

Prolonged and difficult labour caused by cephalopelvic disproportion as the baby’s head passes through the birth canal has been postulated to cause stretching of the dura and tears to the falx and tentorium ( Fig. 40.18 ). The tentorium cerebelli has the transverse sinus running in the horizontal plane and the straight sinus running in the vertical plane (both posteriorly). The superior and inferior sagittal sinuses both meet the straight sinus within the tentorium. A severe tentorial tear can disrupt these large veins, causing haemorrhage into the posterior fossa. A tear to the falx is less common, causing damage to the inferior sagittal sinus, with blood seen above the corpus callosum on imaging. Most perinatal SDHs are peritentorial ( ).

(a) Forces on the tentorium (small arrows) as the result of traction on the vertex during delivery (large arrow).

(b) Sagittal magnetic resonance image showing a posterior fossa subdural collection (arrowed) in a baby delivered by forceps after failed ventouse.

Occipital osteodiastasis

This is the result of serious trauma, and was often found in term infants who died after breech extraction, which is now rarely seen. The occipital bone has four parts which are not completely ossified at birth, and are separated by cartilage. Hyperextension of the head during breech extraction can exert enough pressure on the occipital bone to cause traumatic separation at the cartilaginous joint at the junction of the squamous and lateral or condylar parts, with injury to the occipital sinus causing haemorrhage into the posterior fossa ( ). suggests that this lesion may be more common than has been recognised because it is easily missed at postmortem, in the absence of imaging.

Convexity haemorrhage

These are typically crescentic-shaped supratentorial collections lying on the convex surface of the brain which have traditionally been thought to be caused by ruptured bridging veins. Hence depending on the site of the rupture of the vessel, they may also be associated with SAH.

Asymptomatic subdural haemorrhage

In view of the fact that asymptomatic SDH is common, propose that the relatively large inner vascular plexus in the dura membrane of the newborn may be the origin of many SDHs, as opposed to the bridging veins.

Convexity haemorrhage

Most SDH is asymptomatic. Clinical signs may be non-specific and a high degree of vigilance and index of suspicion is important after a difficult delivery. The most common clinical features are seizures and apnoea. Seizures may be focal, particularly in cases of a supratentorial convexity haematoma overlying a cerebral contusion. Careful examination in such a baby may reveal neurological signs. A major convexity SDH may cause herniation of the temporal lobe through the tentorial notch and a distinct palsy of the third cranial nerve, with a dilated pupil that is poorly reactive to light.

Babies are often well in the first few hours of life but then go on to develop signs of raised intracranial pressure, including bulging fontanelle, poor feeding, irritability and seizures.

Infratentorial haemorrhage

Major infratentorial haemorrhage is now quite rare, although the MR studies mentioned above show that most subdural bleeding is peritentorial. Babies may be born with depressed Apgar scores or deteriorate later due to infratentorial clot swelling and compression of the brainstem. The clot may block free flow of CSF, causing hydrocephalus. These infants become obtunded, with opisthotonic posturing, bradycardia, loss of respiratory drive and dilated, poorly reactive pupils. Death may ensue over a matter of hours unless the pressure is relieved.

Medical management

Most ICHs can be managed conservatively. Seizures should be treated. Thrombocytopenia should be corrected with platelet transfusion and deranged coagulation should be treated with fresh frozen plasma, vitamin K and cryoprecipitate appropriately. Remember that a first-born male may be the first in his family with haemophilia, and if the diagnosis is missed and the baby dies, the family cannot benefit from antenatal diagnosis in future pregnancies. The baby may require respiratory and haemodynamic support.

Neurosurgical management

Neurosurgical input may be appropriate in cases of symptomatic ICH, particularly in the presence of an associated skull fracture, midline shift, signs of raised intracranial pressure and focal neurological signs. Sixteen of 53 infants with ICH in Holland ( ) developed hydrocephalus due to obstruction of free flow of CSF. Imaging revealed midline shift in 21/53 infants, three of whom were treated with craniotomy.

The place of surgical intervention, particularly in infratentorial bleeds, is a subject for debate. The consensus view seems to be that, in the absence of brainstem compression or hydrocephalus, conservative management is appropriate. Indications for neurosurgery include the following ( ):

• •
  

  signs of life-threatening brainstem compression such as apnoea, bradycardia and hypotension

  
  
• •
  

  acute obstructive hydrocephalus with raised intracranial pressure

  
  
• •
  

  a very large clot in the posterior fossa.

Neurosurgical procedures used in these circumstances include aspiration of clot using needle aspiration techniques or burrhole trephine, external ventricular drain for obstructive hydrocephalus and posterior fossa craniectomy. In a series of 15 infants with infratentorial SDH ( ) surgical evacuation was performed in eight. Outcomes were similar for both the conservatively managed and surgical intervention groups. Five of the 15 infants had moderate or profound delay.

Prognosis

reported cerebral palsy in four of 34 survivors of their series of 53 ICHs. Adverse outcome was associated with intraparenchymal bleeds and associated HIE. Other studies also show that coexisting HIE in infants with ICH puts them at increased risk of adverse outcome compared to infants with ICH alone ( ). Some children develop epilepsy.

Clinical presentation

A fluctuant swelling that crosses suture lines develops on the scalp after birth. Fluctuance, size and position help to distinguish subgaleal haemorrhage from cephalohaematoma, which does not cross the suture lines and does not become fluctuant until 48 hours of age. Some infants may deteriorate rapidly, sometimes when they are still in the labour ward. The head size may visibly increase and the infant becomes pale, sweaty and tachycardic. Some authors suggest that each centimetre increase in head circumference corresponds with a loss of 40 ml of blood into the subaponeurotic space ( ). The baby may develop systemic shock with DIC and coagulopathy.

Investigations

The haematocrit may drop rapidly. The baby may develop a metabolic acidosis with a rising lactate. The infant may be anaemic and thrombocytopenic and have deranged coagulation. Measuring the head circumference at frequent intervals can help.

Management

The key to management of this condition is a high index of suspicion and prompt and early recognition ( ; ). Delay in recognition of the condition may worsen outcome. recommends at least 8 hours of observations for all babies following a difficult instrumental delivery regardless of the need for resuscitation or Apgar scores. Aggressive management of the blood loss with blood and blood products is essential to avoid death from hypovolaemic shock and DIC, and secondary hypoxic–ischaemic brain damage.

Prognosis

A study of 42 cases from Taiwan found that 13 (31%) had a poor outcome: five died, four had epilepsy, three had severe auditory impairment and two had cerebral palsy. Outcome is related to the size of the haemorrhage and hence the degree of supportive treatment required. Infants who need mechanical ventilation, pressor support and large volumes of blood products, all reflecting the severity of haemorrhage, are at risk of worse outcome, as are factors such as coagulopathy, metabolic acidosis and renal impairment ( ). Good outcomes have been reported, as described above, following early recognition and aggressive replacement of blood and coagulation factors.

Aetiology and pathogenesis

The cause of PAIS is not always clear. The most commonly cited hypothesis is that of a placental embolus travelling into the arterial tree as a paradoxical embolus, because of the frequency with which the left middle cerebral artery territory is involved and because of the presence of a patent foramen ovale in fetal and early neonatal life. There is an association with persistent pulmonary hypertension which tends to support this mechanism ( ). Other associations include meningitis ( ), congenital heart disease, particularly if surgical repair is required ( ), intravascular catheters and ECMO ( Tables 40.9 and 40.10 ). Older studies report an association with perinatal hypoxic ischaemia, but these data are from the pre-MRI era and there were no cases of PAIS in the TOBY trial, which had strict entry criteria for the definition of HIE ( ). The previous association probably arose from the misclassification of babies with seizures; further, some babies with well-established infarction have developed acute neonatal signs. However, it remains the case that babies with stroke often have a complicated perinatal history ( ; ). Dissection of the internal carotid artery or its branches is very rare ( ): one of 215 German cases had arterial dissection demonstrated ( ). There is a single case report of a 5-month-old child who presented with a left hemiplegia and a right Horner’s syndrome. MRI revealed reduced blood flow in the internal carotid artery ( ). The cause was ascribed to a whiplash injury to the artery during fetal life, when the mother was involved in a road traffic accident. Congenital abnormalities of the neck vessels are also possible causes of PAIS.

Clinical presentation

Commoner in males, the commonest clinical feature of PAIS in the neonatal period is seizures, particularly focal seizures in the first 3 days of life. Babies with PAIS have usually been well before presentation, and often remain well between seizures. Infants diagnosed outside the neonatal period commonly present with abnormal hand preference or evolving hemiparesis.

Investigations

A full blood count and haematocrit may reveal polycythaemia. Conventional or amplitude-integrated EEG (aEEG) may identify focal or generalised seizures; the background activity is often normal, and can be a useful guide to prognosis ( ). Echocardiography is indicated. An initial thrombophilia screen consisting of protein C, protein S, fibrinogen, antithrombin, lipoprotein a, anticardiolipin antibodies, lupus anticoagulant, partial thromboplastin time and international normalised ratio should be carried out, with a follow-up screen at 3–6 months (activated protein C resistance, factor V Leiden, prothrombin gene mutation, MTHFR, lipoprotein a, homocysteine, factors VIII/IX/X) ( ).

Imaging

In experienced hands, CUS may reveal echogenic foci at sites of infarction ( ), but the gold-standard investigation for PAIS is MRI ( ) ( Fig. 40.22 ). MR is preferable to CT, because of the radiation dosage associated with CT. CT is justified in an emergency, when it is important to determine whether or not there is a space-occupying subdural haematoma that might need neurosurgical intervention, or when there is thought to be significant ICH or trauma (bony windows can be obtained with CT). CT acquisition times are shorter and this can be a factor in critically ill babies.

Images from a baby with an extensive right middle cerebral artery stroke. (a) Ultrasound image showing midline shift, loss of normal anatomical detail and increased echodensity on the right. (b) Computed tomography scan the same day demonstrating an extensive region of loss of density. (c) Axial T2-weighted magnetic resonance image showing widespread area of abnormality involving the deep grey matter and posterior limb of the internal capsule. (d) Axial diffusion-weighted image (DWI) confirming the significant infarction. (e) Axial DWI showing pre-Wallerian degeneration (arrowed).

Diffusion-weighted sequences may reveal restriction at affected territories of recent infarction ( Fig. 40.22d ) and sequences using MR angiography may reveal sites of arterial narrowing. studied conventional T1 and T2 images and diffusion-weighted images (DWI) that were first imaged in the neonatal period, from 21 infants with unilateral PAIS. All DWI images showed high signal intensity in the affected region until day 4 (similar findings to Lequin’s group in France). The cortex showed high signal intensity on T2 and low signal intensity on T1 until day 6, when the signal intensities reversed. Secondary changes in the thalamus and brainstem were seen in the first week of life and atrophic changes were seen after 4 weeks. These authors reported that the pattern of changes in signal intensities on conventional MRI and DWI were remarkably consistent in their patient group, leading them to conclude that PAIS in symptomatic term-born infants occurs within a very limited timeframe around birth. has provided helpful anatomical templates with which to identify the affected artery.

Management

During the acute phase of PAIS supportive measures such as adequate hydration, maintenance of normal glucose, pH and oxygen levels and anticonvulsants for seizures and antibiotics/antivirals for infection are important. Routine thrombolysis is not recommended as there are not sufficient data regarding its effectiveness or safety. In cases of PAIS with an ongoing documented cardioembolic source treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) may be appropriate ( ), but specialist advice should be sought.

Outcome

PAIS in the middle cerebral artery territory may result in hemiplegia in up to 50% of children, the likelihood being predictable from neonatal MRI ( ). Three-site involvement of the hemisphere, basal ganglia and posterior limb of the internal capsule is strongly associated with later contralateral hemiplegia irrespective of the size of the infarct ( ; ). The presence of pre-Wallerian degeneration in the cerebral peduncles also helps to predict the outcome ( Fig. 40.22e ) ( ). Later cognitive impairments, epilepsy and behaviour problems remain relatively common adverse outcomes ( ), with language delay in 25% ( ). In one group of 63 term and preterm children with PAIS, 54% developed epilepsy in childhood ( ), and cognitive difficulty is often present in those with epilepsy. Most children will walk, and recurrence is very rare in children without underlying cardiac disease.

Aetiology and pathogenesis

Risk factors are similar to that for PAIS, with haemoconcentration and dehydration particularly important ( ). Following CSVT venous pressure escalates in the occluded vessels and haemorrhagic infarction can develop in the region of brain drained by the sinus, because of venous congestion, vasogenic oedema, and increased capillary hydrostatic pressure ( ). The resulting brain injury may vary from venous congestion to the recognised ischaemic infarction involving the cortex, subcortical white matter and the deep nuclear grey matter. Haemorrhagic transformation of any infarcted cerebral tissue is the norm.

CSVT is frequently associated with secondary intraventricular, intraparenchymal and basal ganglia and thalami haemorrhage in term infants, and is thought to result from back pressure to distal draining veins. A 10-year review of patients from centres in the Netherlands ( ) identified 52 neonates with CSVT, of whom half had associated thalamic haemorrhage, half had associated IVH and 79% had intraparenchymal haemorrhage. As discussed above, and as demonstrated in Figure 40.20 , most term babies with thalamic haemorrhage have underlying CSVT.

Clinical features

In the Dutch study of 52 neonates with CSVT there was a male preponderance (75%) ( ). The commonest symptoms were seizures (81%), focal in a fifth of patients, followed by apnoeas. Fifteen per cent of infants had suffered sepsis or meningitis and 13% were born to mothers with pregnancy-related hypertension.

Investigations

The key to diagnosis of CSVT (arguably even more so than with PAIS) is a high index of suspicion so that appropriate and specific investigation to demonstrate diminished blood flow through cerebral venous sinuses can be carried out. Colour Doppler flow studies at the bedside may demonstrate reduced flow in affected venous sinuses. MR may show the clot, or venogram studies may identify regions of decreased flow-related enhancement in venous sinuses ( Fig. 40.23 ). In the Dutch study ( ), half of the infants had multiple sinus involvement, superior sagital sinus was affected in 23% and straight sinus in 15%. In addition to the associated haemorrhage, infarcts may be seen in the parasagittal white matter and the basal ganglia. All other investigations are as for PAIS.

(a) Midline sagittal T1-weighted magnetic resonance image (MRI) showing thrombus within the superior sagittal sinus (arrowed). (b) Axial T1-weighted MRI showing area of infarction in the right middle cerebral artery territory (white arrow) together with thrombus in the sagittal sinus (arrowhead).

Management

Rehydration is necessary in a dehydrated newborn. In an infant with primary polycythaemia dilutional exchange transfusion may be needed. Seizures and infections will require treatment with anticonvulsants and antibiotics respectively.

At present there are few data on therapeutic efficacy and safety of antithrombotic treatment in newborns with CSVT ( ), and international practice is hugely variable ( ). In the absence of significant ICH, particularly if the thrombus is noted to propagate, anticoagulation with UFH or LMWH may be used with specialist haematology input and close monitoring of anti-Xa, heparin and activated partial thromboplastin time levels. The aim should be rapidly to achieve anti-Xa levels of 0.5–1.0 U/ml ( ). Once commenced, treatment may need to be continued for several weeks until improved flow through the cerebral venous sinuses is established.

Outcome

Perinatal stroke is the leading known cause of hemiplegic cerebral palsy ( ). In all, 30–50% of infants with CSVT will go on to have a motor deficit ( ; ). Other common deficits resulting from perinatal stroke include epilepsy, deficits in language, vision and cognitive outcomes.

Definitions

Hypoxic–ischaemic brain injury of the term and near-term infant remains a significant problem throughout the world. Hypoxaemia is defined as the ‘diminished amount of oxygen in the blood supply’ and cerebral ischaemia as the ‘diminished amount of blood perfusing the brain’; ischaemia is the more important of the two forms of oxygen deprivation since it also results in deprivation of glucose which is also crucial in the genesis of neuronal injury ( ). Asphyxia is the result of an impairment of exchange of the respiratory gases oxygen and carbon dioxide. Thus, in addition to hypoxia, asphyxia has the important additional feature of producing elevated levels of carbon dioxide, which results in a number of additional metabolic and physiological features which include acidosis and increased cerebral blood flow (CBF) ( ). Hypoxia–ischaemia may occur acutely or chronically and is most commonly associated with maternal factors (hypotension, severe hypoxia), cord factors (prolapse, occlusion), placental factors (insufficiency and abruption) and uterine factors (rupture). Neonatal postnatal events such as shock, respiratory or cardiac arrest can also lead to hypoxic–ischaemic injury.

Neonatal encephalopathy (NE) is the clinical manifestation of disordered neonatal brain function in the term infant in the early neonatal period, manifested by respiratory difficulties, depression of tone and reflexes, subnormal level of consciousness and often seizures ( ). The aetiology of NE is varied, with many genetic, metabolic and infective conditions presenting with similar clinical signs (Hankins et al. 2003) ( Tables 40.11 and 40.12 ). The disorder is termed hypoxic–ischaemic encephalopathy (HIE) if there is evidence that intrapartum asphyxia is the cause of the encephalopathy resulting in neurologic depression or seizures. An important concept that is recurrent in many studies is that the human injury of HIE does not follow a wholly reproducible pattern: the etiology, extent of hypoxia or ischaemia, maturational stage of the brain, regional CBF and general health of the infant prior to the injury can all impact on the extent of brain injury as well as the outcome following injury.

The term HIE is often incorrectly used synonymously with NE. The term NE is a clinical description of disordered neurological function that does not require assumptions about pathogenesis or aetiology. The diverse risk factors, causal pathways and aetiologies, which may lead to NE in a developed country such as Australia, are listed in Table 40.13 . The case-control study of NE in Western Australia showed that many antecedents of NE are present before the onset of labour. Intrapartum risk factors included maternal pyrexia, persistent occipitoposterior position and acute intrapartum events; however in over 70% of cases of NE there was no evidence of intrapartum hypoxia ( ). This is very different to the situation in many low-income countries where mothers are stunted, do not access antenatal care, have high stillbirth rates and receive poor obstetric care. Under these conditions intrapartum factors probably remain more important in the causation of NE ( ). For example, in a case-controlled study in Kathmandu, there was evidence of intrapartum hypoxia–ischaemia in 60% of encephalopathic infants. Independent risk factors for NE included short maternal stature, high maternal age, lack of antenatal care and multiple birth ( ); intrapartum risk factors included non-cephalic presentation, prolonged rupture of membranes, cord prolapse and uterine rupture.

Since 1996 there have been three consensus statements addressing the diagnosis of intrapartum asphyxia ( ; ; ). These consensus statements emphasise the use of multiple markers for the diagnosis – some signs are considered essential and others supportive. With advances in cerebral imaging technology, the two most recent statements take the findings from cerebral imaging into consideration as supportive evidence of intrapartum asphyxia ( ; ). This may cause problems, particularly in countries with poor access to this advanced technology. The diagnosis of intrapartum asphyxia has been restricted to certain types of cerebral palsy in these two most recent statements ( Table 40.14 ). As cerebral palsy is an eventual outcome, which may take several years to be confirmed, it is difficult for this to be used as an essential diagnostic criterion for an acute condition such as intrapartum asphyxia.

Epidemiology

Mid- and low-resource settings

Infants born in the world’s least developed countries have a high risk of intrapartum-related injury and of intrapartum stillbirth ( ). Almost one-quarter of the world’s 4 million annual neonatal deaths are caused by perinatal asphyxia; 22% and 99% of these deaths occur in low- and mid-resource settings respectively ( Fig. 40.24 ). Severe infections are responsible for a further 26% of total estimated deaths ( ) and at times it is difficult to differentiate between the two conditions ( Fig. 40.25 ). The estimated that an annual 1 million survivors of ‘birth asphyxia’ may develop cerebral palsy, learning difficulties or other difficulties, although these numbers are difficult to estimate.

Direct causes of neonatal death worldwide. Birth asphyxia is the direct cause of almost a quarter of the 4 million neonatal deaths worldwide. Infection is also a very significant problem.

(Adapted from Lawn et al. 2005.)

Variation in neonatal mortality rate (NMR) between countries.

(Reproduced from Lawn et al. 2005, with permission.)

Precise estimates of NE and HIE incidence are uncertain as there is a lack of data from low- and mid-income countries and a complete absence of data from community-based settings where most of the burden of perinatal hypoxia–ischaemia falls. In 2006, an admission audit to the special care baby unit at Mulago Hospital, Kampala, Uganda revealed a moderate to severe NE incidence of 17.9/1000 term live births (M Nakakeeto, personal communication). In the Indian subcontinent, the Indian National Neonatal–Perinatal Database suggests an overall NE incidence of 14 per 1000 live births. As there is such a wide range in neonatal mortality rate (NMR) across countries throughout the world, a recent systematic review for the Global Burden of Disease Project estimated the incidence of NE by NMR category. In very-low-mortality settings (NMR< 5) ( Fig. 40.25 and Table 40.15 ), the median incidence of NE is 1.9 per 1000 live births (range 0.7–6.0) compared with 26.5 per 1000 live births in the highest mortality settings (based on a single study) – a 14-fold disparity. Countries with NMR 6–15, 16–30 and 31–45 have an estimated median (range) incidence of NE of 6.7 (4.7–8.7), 9.8 (3.6–10.2) and 13.4 (5.5–22.2) ( ). South Asia and Africa, with large numbers of births and deaths, account for 73% of all intrapartum-related neonatal deaths worldwide.

Table 40.15

Variation in the incidence of neonatal encephalopathy (NE) and NE case-fatality for 193 countries organised according to five categories of neonatal mortality, as a marker of health system performance

	CATEGORY 1 VERY LOW MORTALITY NMR <5	CATEGORY 2 LOW MORTALITY NMR 6–15	CATEGORY 3 MODERATE MORTALITY	CATEGORY 4 HIGH MORTALITY NMR 31–45	CATEGORY 5 VERY HIGH MORTALITY NMR >45
Incidence of NE median (range)	1.9 (0.7–6.0)	6.7 (4.7–8.7)	9.8 (3.6–10.2)	13.4 (5.5–22.2)	26.5 (26.5)
NE case-fatality median (range)	21% (17–37)	12% (12%)	19% (10–28%)	31% (20–33%)	No data

 

Country groupings for neonatal mortality rates (NMRs) are adapted from the Lancet neonatal survival series (Lawn et al. 2005: Fig. 1). (Data adapted from Lawn et al. 2009.)

Sensitising factors

Fetal responses to hypoxia–ischaemia

Animal models of acute, near-total hypoxia–ischaemia have demonstrated that fetal arterial P o ₂ drops during acutely induced hypoxia–ischaemia from 25 mmHg to levels below 5 mmHg within 5 minutes, whereas arterial P co ₂ rises from 45 to 100 mmHg within 10 minutes, and pH drops from 7.30 to 6.80 within 10 minutes ( ; ). The fetus will respond to acute hypoxia–ischaemia in a number of ways, aiming to reduce energy consumption and to maintain cerebral oxygenation as much as possible. Body movements will be reduced, which is sometimes the first sign of fetal compromise reported by pregnant women. However, this is a very non-specific finding in term fetuses. With a lowering of Pa o ₂ , oxygen extraction from the blood will increase.

In the experimental animal, the response to acute fetal hypoxia includes three phases ( ). First, a redistribution of blood flow directs a greater fraction of cardiac output to the heart and central nervous system without creating metabolic acidosis. The initial rapid fall in fetal heart rate and redistribution of blood flow away from peripheral organs during hypoxia or asphyxia are key fetal adaptations generally believed to help maintain perfusion of vital organs and reduce myocardial work ( ). More profound hypoxia results in metabolic acidosis as the oxygen supply becomes inadequate to the skeletal muscles and some viscera with increasing diversion of cardiac output to the heart and brain. The final stage of fetal hypoxia corresponds to an inadequate oxygen supply to all organs, including the heart and brain. The fetus and the newborn infant both respond initially to acute hypoxia with shallow breathing followed by cessation of respirations, termed primary apnoea. After the period of primary apnoea, gasping (deep irregular respirations) develops, then respirations gradually become weaker until the onset of secondary or terminal apnoea when all respiratory effort ceases. Heart rate decreases from baseline during primary apnoea, decreases even lower during gasping and eventually ceases after several minutes of secondary apnoea. Blood pressure initially increases during primary apnoea and gasping, but then rapidly decreases during secondary apnoea ( Fig. 40.26 ) ( ). Primary and secondary apnoea is not precisely distinguishable at birth – both present as a newborn who is not breathing and whose heart rate is slow. Tactile stimulation during primary apnoea can restore spontaneous respirations. Secondary apnoea requires assisted ventilation to restore spontaneous breathing ( ).

Changes in fetal heart rate (FHR, bpm, top panel), mean arterial pressure (MAP, mmHg, second panel), femoral blood flow (FBF, ml/min, third panel) and carotid blood flow (CaBF, ml/min, bottom panel) in 0.6, 0.7 and 0.85 gestation fetuses during complete umbilical cord occlusion. FHR, MAP, FBF and CaBF data represent 1-minute averages and are expressed as a percentage of baseline. The period of umbilical cord occlusion for each group is indicated by the rectangles. Data are mean ± se .

(Data from Wassink et al. 2007.)

There is an initial period of compensation followed by progressive decompensation which ends by profound systemic hypotension and cerebral hypoperfusion. MAP initially rises with intense peripheral vasoconstriction; at this time CaBF is maintained at around baseline, but with suppression of electroencephalogram activity – although total brain flow does not change, within the brain, blood flow is diverted away from the cerebrum and increased in the brainstem. As umbilical cord occlusion was continued MAP eventually fell. The key mediators include impaired cardiac function secondary to hypoxia, acidosis, depletion of myocardial glycogen and cardiomyocyte injury and loss of the initial peripheral vasoconstriction. Once MAP falls below baseline, CaBF falls in parallel and there is loss of redistribution of flow within the brain.

Production of meconium can be induced by severe fetal hypoxia–ischaemia. In combination with gasping this may lead to meconium aspiration, and development of the meconium aspiration syndrome after birth ( Ch. 27 , part 2). In chronic fetal hypoxia, which may be the result of several maternal diseases such as severe anaemia, pregnancy-induced hypertension or pre-eclampsia, the fetus will produce erythropoietin to augment erythrocyte production through extramedullar haematopiesis. Increased numbers of erythroblasts have been reported to be a sign of chronic fetal hypoxia–ischaemia ( ).

Mechanisms of brain injury

Initiating role of energy failure

Severe hypoxia–ischaemia rapidly results in cessation of cerebral oxidative metabolism, accumulation of cerebral lactate and rapid depletion of adenosine triphosphate (ATP). This initial decrease in ATP is capable of triggering a series of additional mechanisms that begin with failure of the ATP-dependent Na ⁺ ,K ⁺ pump ( Fig. 40.27 ) ( ). If the initial insult is very severe, the acute result is Na ⁺ influx followed by Cl ⁻ and water influx, cell swelling, cell lysis and early death by necrosis. In the more usual less severe insult, membrane depolarisation occurs and is followed by extracellular accumulation of glutamate, increased cytosolic Ca ²⁺ and a cascade of events leading to a more delayed cell death, principally apoptotic, although necrosis may also occur. Cell swelling can be demonstrated in vivo within 30 minutes using diffusion-weighted MRI techniques ( ). The details of the activated cascade of events are discussed below.

Relation between energy depletion and cell death. Early cell death is mainly necrosis and the more important later cell death is mainly apoptosis. ATP, adenosine triphosphate.

The accumulation of lactate and H ⁺ is initially beneficial as it leads to the generation of ATP from phosphocreatine (PCr) (due to the shift in creatine phosphokinase reaction) and an increase in CBF (due to the effect of acidosis on vascular smooth muscle). However, as severe tissue acidosis develops, detrimental effects of increased lactate and H ⁺ develop: autoregulation is lost, phosphofructokinase activity is inhibited, leading to reduced ATP production, and acidosis itself leads to neuronal injury and necrosis ( ).

Release of excitatory amino acids

Excitotoxicity is an important mechanism of injury in the brain ( ). Glutamate is the predominant excitatory amino acid neurotransmitter in the brain, and most neurons and many glia possess receptors for glutamate ( ). Neuronal pathways mediating vision, hearing, somatosensory function, learning and memory use glutamate as their neurotransmitter ( ). There are three major groups of glutamate receptors: (1) N -methyl- d -aspartate (NMDA); (2) α-amino-3-hydroxy-5-methylisoazole-4-propionic acid (AMPA); and (3) kainic acid. Normally, glutamate is contained within the presynaptic nerve terminal until release is stimulated by neuronal depolarisation ( ); when release into the synaptic cleft does occur, the neurotransmitter is quickly taken up by high-capacity glutamate transporters in astroglia that surround synapses and nerve terminals ( ).

Extracellular glutamate concentrations increase significantly with hypoxic–ischaemic insults ( ; ) and CSF levels of glutamate of asphyxiated newborns are substantially higher than those of healthy newborn infants ( ). Extracellular glutamate increases because of two reasons: firstly, impaired uptake of glutamate; and secondly, excessive release. Compared to the adult brain, the immature brain is especially vulnerable to activation of the NMDA receptor by glutamate ( ). In addition the topography of glutamate receptors, particularly NMDA and APMA receptors, corresponds to the topography of the hypoxic–ischaemic neuronal injury ( ). Further evidence of the central role that glutamate plays in hypoxic–ischaemic injury is the neuroprotection seen with the use of glutamate receptor blockers even when administered after termination of the insult ( ). Stimulation of the NMDA receptor leads to Ca ²⁺ influx in to the cell and a large number of deleterious effects, described below ( Fig. 40.28 ).

A simplified diagram of the pathways leading to apoptotic cell death. VSCC, voltage-selective calcium channels; NPBI, non-protein-bound iron; eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; O2 ⁻ •, superoxide; ONOO ⁻ , peroxynitrite.

Pathways of cell death

Whilst necrotic cell death is prominent in the immediate and acute phases of severe cerebral insults, the predominant mode of cell death during the delayed phase of injury appears to be apoptosis ( ). This may be particularly true with less severe insults and apoptotic cell death seems to be more important in damage to the developing brain than after adult stroke ( ). In necrosis, death is triggered by an overwhelming insult, resulting in loss of membrane integrity and leaking cytoplasmic contents into the extracellular matrix. In contrast, cells dying by apoptosis carry out a highly conserved and regulated genetic programme ( Fig. 40.29 ). They do not lose membrane integrity until late on and the organelles remain intact until the final stages when cell fragments are ‘shrink-wrapped’ in the contracting plasma membrane and bud off as apoptotic bodies, which are subsequently phagocytosed by healthy neighbouring cells. Apoptosis requires time and energy: although apoptosis and necrosis were considered distinct, there is a growing knowledge that dying cells may display a hybrid of apoptotic and necrotic features ( ; ). The presence of a ‘continuum’ phenotype of cell death that varies on a cell-by-cell basis suggests that the phenotype of cell death is dependent on the energy available to drive the apoptotic pathways to completion ( ).

Gender differences in neonatal apoptotic cell death after hypoxia–ischemia . Female neurons preferentially release cytochrome c from mitochondria and die as a result of subsequent activation of caspase 3. Male neurons are influenced more by the excitotoxic pathway and die mainly through the apoptosis-inducing factor (AIF)-dependent pathway. NMDA, N -methyl- d -aspartate; ROS, reactive oxygen species.

(Courtesy of Dr Cora Nijboer.)

Multiple apoptotic pathways have been shown to be involved in neonatal hypoxic–ischaemic cell death. As previously discussed, excitotoxicity, oxidative stress and other factors lead to injury of the mitochondrial membrane. An increase in the permeability of the mitochondrial membranes to molecules of less than 1500 Da in molecular weight (termed the mitochondrial permeability transition) plays an important role in multiple pathways to cell death ( ). Mitochondrial permeability transition leads to release of proapototic factors into the cytoplasm, including cytochrome c, apoptosis-inducing factor (AIF), caspase-9 and endonuclease ). Release of cytochrome c and procaspase-9 into the cytoplasm leads to activation of caspase-9 3–24 hours after the insult and is followed by conversion of procaspase-3 to active caspase-3 6–48 hours after injury ( ). Caspase-3 activation results in proteolysis of essential cellular proteins, including cytoskeletal proteins and kinases, and can commit the cell to the morphological changes characteristic of apoptosis, including nuclear fragmentation ( ). This cytochrome c-mediated pathway is also referred to as the intrinsic pathway. Activated caspase-3 has been shown in human postmortem brain tissue of full-term neonates with severe perinatal asphyxia.

Some cell surface receptors respond to cytokine (inflammatory) stimulation, resulting in activation of cell death signalling programmes. The TNF receptor superfamily (TNFRSF) belongs to this group of cytokine-responsive receptors. Fas death receptor is one of the most extensively studied TNFRSF members ( ). The apoptotic pathway that is regulated by Fas receptor involves caspase-8 and is referred to as the extrinsic pathway. Caspase-8 leads then to caspase-3 activation.

A caspase-independent apoptotic pathway has also been extensively studied. Poly(ADPribose) polymerase (PARP-1) is a nuclear enzyme that transfers adenosine diphosphate ribose groups from NAD+ to nuclear proteins and facilitates DNA repair. PARP activation consumes NAD+ needed for mitochondrial energy production, which in turn triggers release of cytochrome c and activation of caspases ( ).

A knowledge of these pathways of cell death has led to a very important discovery about gender-specific cell death pathways: being male or female is likely to influence the efficacy of neuroprotective agents and the cells that are most at risk. Male neurons die mainly through activation of an AIF-dependent pathway while female neurons preferentially release cytochrome c from mitochondria and die as a result of subsequent activation of caspase 3 ( ). Male neurons also have lower levels of glutathione following nitrosative stress than neurons from females. These sex-related differences in cell death pathways are present in neonatal mice and rats in vivo ( ). Gender influenced the neuroprotective efficacy of 2-iminobiotin treatment, which was neuroprotective and reduced cytochrome c release and caspase activation only in females ( ). The glutamate antagonist dextromethorphan was protective against stroke in male but not female mice at 12 days of age – this supports the greater influence of the excitotoxic pathway in immature males ( ).

This new information about gender differences in neuronal death pathways in experimental models is clinically relevant to perinatal asphyxia. The 2005 Surveillance of Cerebral Palsy in Europe study reported that male babies are at higher risk for cerebral palsy than females. In low-birthweight infants cognitive and motor outcome of brain injury is worse in males than in females ( ). In future studies it will be important to determine the influence of gender in asphyxiated infants undergoing neuroprotective therapies and optimisation of therapy may require different agents for males and females.

Cerebral blood flow and autoregulation

In healthy neonates CBF is maintained within certain limits by autoregulation when arterial P co ₂ or blood pressure fluctuates. Studies using xenon clearance or Doppler ultrasound have demonstrated that autoregulation was impaired in full-term neonates with perinatal asphyxia, making cerebral perfusion pressure passive ( ; ; ). Infants with the poorest outcomes (isoelectric amplitude-integrated electroencephalogram (aEEG), death) had the highest values for CBF and no autoregulation or CO ₂ reactivity. Infants with burst suppression and moderate to severe brain injury had slightly elevated values for CBF and impaired autoregulation but sustained reactivity to CO ₂ . Infants without evidence of brain injury had normal values for CBF, intact autoregulation and reactivity to CO ₂ . This cerebral hyperaemia occurring in infants with perinatal asphyxia has been confirmed with Doppler studies and near-infrared spectroscopy studies. These studies showed an increase in CBF and decreased resistance between 6 and 130 hours. Other near-infrared spectroscopy studies have confirmed this loss of vascular reactivity, increase in cerebral blood volume and CBF ( ) as seen before in the fetal sheep ( ). The postasphyxial newborn is in a state of vasoparesis and cerebral hyperaemia which correlates with the degree of brain injury. This state of maximal vasodilation may be related to the effects of elevated H ⁺ , prostaglandins, adenosine, free radicals or nitric oxide. It is unknown, however, whether it is an adaptive mechanism to preserve brain injury or whether it causes additional injury.

Animal models of term hypoxia–ischaemia

The use of animal models in the study of perinatal asphyxia has a long history. ( ) noted that, in newborn rabbits asphyxiated by submersion, respiration survived for 27 minutes, whereas in adult rabbits breathing ceased after 2 minutes. In 1870, Bert saw a similar resistance to asphyxia in the newborn rat submerged in water – respiratory movements lasted 30 minutes whereas in 20-day animals respirations ceased in 1.5 minutes ( ). Animal studies have shown that the premature animal is more tolerant of asphyxia than the term infant, which is in turn more resistant to asphyxia than the adult. These early studies have also shown that males appear to be less resistant than females and that high temperature, thyroxine, insulin or adrenalectomy reduces resistance to asphyxia.

The primate neonatal model shows very clearly that the pattern of brain injury is affected by the severity and type of hypoxia–ischaemia. Two distinct patterns of injury were described in the 1950s–1970s – acute total asphyxia ( ) and chronic partial asphyxia ( ). Acute total asphyxia was induced in monkeys near term by detaching the placenta at hysterotomy under local anaesthesia, keeping the fetal membranes intact. Eleven to 16 minutes later the fetuses were delivered from their membranes and resuscitated. Two to 9 days later the monkeys were euthanised: there was a common pattern of symmetrical injury to the ventral posterior nuclei of the thalamus, putamen, globus pallidus, inferior colliculus, gracile and medial cuneate nuclei – a very similar topographical distribution to that seen in infants with basal ganglia and thalamus (BGT) injury following, for example, a sentinel event. The cerebral cortex was damaged in only one out of five monkeys and there was no relationship with cerebral vascular distribution. The injury began with primary nerve cells with secondary damage of myelin sheaths and astrocytic reaction.

In the mid-1970s, established a different model of chronic partial asphyxia in the rhesus monkey to investigate the effect on the newborn monkey brain. Intrauterine asphyxia was produced in the pregnant term monkey by breathing halothane of a high enough concentration to cause a significant drop in mean blood pressure in the mother. Each fetus was exposed to asphyxia for 1–5 hours. At the end of the period of asphyxia, each fetus was delivered surgically, intubated and ventilated with 100% oxygen. Monkeys were given sodium bicarbonate and dextrose for correction of the acidosis and taken off the ventilator when able to breathe on their own. Five of the eight asphyxiated newborn monkeys exhibited low Apgar scores and delayed seizures starting from 14.5 hours after delivery. Following an average of 46 hours of survival the brains were perfusion-fixed and the pattern of brain injury assessed. A mainly symmetrical pattern of parasagittal injury was seen, involving the convexity of the hemispheres, particularly the paracentral and posterior parieto-occipital areas ( Fig. 40.30a ). In some newborn monkeys basal ganglia damage was present; however injury to brainstem structures was absent. In around half the animals there was an asymmetry and in these cases the left side was always more affected. A primate model of perinatal asphyxia is still used for neuroprotection studies ( ). These findings are very similar to the pattern of injury in newborn infants who have experienced chronic partial asphyxia ( Figs 40.30b and c and 40.31 ).

(a) Symmetical foci of haemorrhagic injury of the newborn rhesus monkey following chronic partial hypoxia–ischaemia. Intrauterine asphyxia was produced in the pregnant term monkey by breathing halothane of a high enough concentration to cause a significant drop in mean blood pressure in the mother. Each fetus was exposed to asphyxia for 1–5 hours. A symmetrical pattern was seen involving the convexity of the hemispheres, particularly paracentral and posterior parieto-occipital.

(Reproduced with permission from Brann and Myers 1975.)

(b) Distribution of the major cerebral arteries. The distribution of injury as shown by the shaded area is in the border zones and end fields of these arteries. (c) Full-term neonate born after vacuum extraction for fetal bradycardia. Seizures occurred from 6 hours after birth. Magnetic resonance imaging at 3 T on day 4 showed watershed lesions on T2-weighted imaging (left), diffusion-weighted imaging (middle) and apparent diffusion coefficient map (right) in the area of the anterior and middle cerebral arteries, and middle and posterior cerebral arteries. Follow-up at 3 years showed a Griffiths developmental quotient of 97 and a preference for her left hand.

Magnetic resonance imaging at 1.5 T on day 3 of T1-weighted imaging (top left, movement artifacted), T2-weighted imaging (top middle) and apparent diffusion coefficient map (top right). There are bilateral parieto-occipital and frontal oedema with loss of the cortical ribbon and cortical restricted diffusion, in keeping with parasagittal watershed infarction. There is some oedema in the thalami and posterior limb of the internal capsule. Appearances are in keeping with a watershed-predominant pattern. Proton magnetic resonance spectroscopy (PRESS, TE 288 ms) of the left thalamus and basal ganglia (left) and left posterior white matter (PWM) (right) are shown below. The peak area ratios from the spectra are shown in the table. Although lactate/NAA peak area ratio is raised in both brain areas, the most significant changes are in the PWM voxel. Naa, N -acetyl aspartate; Cho, choline; Cr, creatine; Lac, lactate.

Patterns of injury

Using MRI, the patterns of hypoxic–ischaemic brain injury that have been described in pathology studies in the past can now be demonstrated with superb detail and resolution in vivo in human neonates ( ).

Basal ganglia/thalamus pattern

The BGT pattern of injury is the most common pattern seen in infants with HIE ( ) when there has been a sentinel event such as a ruptured uterus or placental abruption during labour ( ) involving ‘acute near-total asphyxia’. This pattern is associated with more severe neonatal signs, more intensive resuscitation at birth, more severe encephalopathy and more severe seizures ( ). These deep nuclear structures are very susceptible to acute perinatal hypoxic–ischaemic injury because of their high metabolic rate and high concentration of NMDA receptors. BGT injury predominantly affects bilaterally the central grey nuclei (ventrolateral thalami and posterior putamina) and perirolandic cortex (especially around the central sulcus, interhemispheric fissure and insula) ( Fig. 40.32 ). Brainstem injury often accompanies the BGT pattern of injury. Lesions are often seen in the midbrain (the inferior colliculus) and pons and the cerebellar vermis ( ). This finding is in keeping with the studies of and ( ) of asphyxiated monkeys with total asphyxia, and the primate studies of (see above).

Full-term neonate with severe perinatal asphyxia. Magnetic resonance imaging at 3 T on day 4 showing swelling of the basal ganglia on T1-weighted imaging (top left), signal changes in the basal ganglia and thalamus on diffusion-weighted imaging (top right), and apparent diffusion coefficient map (bottom right) and extension of the abnormalities into the cerebral peduncles (bottom left).

BGT lesions vary in extent and severity ( Fig. 40.33 ). Mild lesions are focal lesions in the ventrolateral nuclei of the thalamus and posterior putamen. Moderate lesions are defined as multifocal areas or more diffuse abnormalities on T2, involving several regions of the basal ganglia. In severe injury there is widespread abnormal signal intensity – this may involve the whole of the BGT area but often the caudate is spared. White-matter injury may occur with severe BGT injury as part of the original insult or occur secondarily to the BGT lesions and is seen later in infancy and associated with poor head growth ( ).

T1-weighted image (top left), T2-weighted image (top centre) apparent diffusion coefficient map (top right). Proton magnetic resonance spectroscopy (MRS) (PRESS, TE 288ms) spectra from basal ganglia and thalamus and posterior white matter (PWM). The ¹ H MRS metabolite peak area ratios are shown in the table. (a) Normal full-term infant scanned at 1.5 T on day 4. The MRI and MRS findings are within the normal range. A normal PLIC is seen as high signal on T1-weighted images and low signal but a more ovoid shape on T2-weighted images.(b) Full-term infant with Sarnat Stage 2 neonatal encephalopathy scanned on day 4. Bilateral moderate basal ganglia swelling and oedema with restricted diffusion are seen on the apparent diffusion coefficient map. ¹ H MRS peak area ratios demonstrate a raised lac/ N -acetyl aspartate (NAA) peak area ratio in both the basal ganglia and thalamus (BGT) and PWM; the upright lactate doublet can be seen clearly at 1.3 ppm and the NAA peak height is reduced. (c) Full-term infant with Sarnat Stage 3 neonatal encephalopathy scanned on day 6. There is marked swelling and oedema in the BGT, midbrain and pons, in keeping with profound hypoxic–ischaemic brain injury. There are also diffuse oedema and swelling in the cerebral hemisphere white matter. ¹ H MRS peak area ratios show markedly raised lactate/NAA ratios due to a markedly raised lactate and reduced NAA. A peak is seen also at 1.1 ppm due to propan-1,2 diol, the carrier for phenobarbital. (d) Full-term infant with Sarnat Stage 3 neonatal encephalopathy scanned on day 1. There are bilateral BGT infarction (including lentiform and caudate nuclei), infarction of the perirolandic cortex and both hippocampi. There is involvement of both cerebral hemispheres, in keeping with very severe global hypoxic–ischaemic injury. The lactate doublet is significantly raised in both BGT and PWM.

The posterior limb of the internal capsule (PLIC) is actively myelinating at term-equivalent age and is also very susceptible to injury at this stage of development ( ). Damage to the PLIC usually correlates with the severity of the BGT lesions. On MRI it can be described as normal, equivocal and abnormal. A normal PLIC is myelinating at term age and on MRI is seen as high signal on T1-weighted images and low signal but more ovoid shape on T2-weighted images ( Fig. 40.33a ). An abnormal PLIC has loss or reversed signal intensity on T1- and T2-weighted images ( Fig. 40.33c,d ); an equivocal PLIC is one with reduced or asymmetrical signal intensity ( Fig. 40.33b ).

Outcome

A total of 20–30% of infants with HIE die in the neonatal period and 15–20% of children may die in the first 2–3 years. have observed that the best predictor of death is the presence of brainstem lesions. They found that 50% of infants with brainstem lesions died in the neonatal or infant period.

Survivors face a range of functional impairments which include cerebral palsy, feeding problems, speech and language problems, visual and hearing impairment, later seizures and cognitive impairment. Cerebral palsy affects three-quarters of infants with HIE with BGT lesions and the severity of the BGT lesions is the best predictor of motor problems. The signal intensity of the PLIC is the best predictor of the ability to walk at 2 years ( ). From their extensive experience in following infants with HIE, Martinez-Biarge et al. have produced very comprehensive flow charts for likely outcome for mild, moderate or severe BGT in surviving infants ( Fig. 40.34a–c ).

(a) Flow chart showing patterns of outcome with mild basal ganglia and thalamus (BGT) injury. (b) Flow chart showing patterns of outcome with moderate BGT injury. (c) Flow chart showing patterns of outcome with severe BGT injury. DQ, developmental quotient; PLIC, posterior limb of internal capsule.

(Reproduced from Martinez-Biarge et al. 2010.)

Global pattern

Involvement of the subcortical white matter and cortex can be seen, referred to as the ‘white cerebrum’, as diffusion-weighted imaging (DWI) shows an almost completely white cerebrum, in contrast with a normal-looking cerebellum. These patients show severe NE and the condition tends to be fatal. In the rare surviving neonate, multicystic encephalomalacia will develop ( Fig. 40.35 ). Another important cause of multicystic encephalomalacia is central nervous system infection, especially with herpesvirus.

Full-term neonate with severe perinatal asphyxia and ‘white-brain’ pattern of injury. Magnetic resonance imaging on day 3 shows diffuse swelling of the brain (T2-weighted image, left), elevated signal intensity in the whole cerebrum (diffusion-weighted imaging, middle) and a striking discrepancy between the severe abnormalities in the cerebrum and the spared cerebellum (apparent diffusion coefficient map, right).

Cerebral energy metabolism associated with hypoxia–ischaemia

Magnetic resonance spectroscopy (MRS) has been used to study brain energy metabolism non-invasively; over the last 30 years phosphorus-31 ( ³¹ P) and proton ( ¹ H) MRS have provided unique information on cerebral energy metabolism during the evolution of brain injury following hypoxia–ischaemia in the newborn infant ( ), neonatal rat ( ) and newborn piglet ( ; ). In human infants, shortly after intrapartum hypoxia–ischaemia ³¹ P MRS often reveals apparently normal cerebral energetics ( ). However, in infants with adverse outcome, despite adequate oxygenation and circulation, PCr and nucleotide triphosphate (NTP, mainly ATP) decline, and Pi increases, in the first days of life ( ; ; ; ). These metabolic changes were termed ‘secondary energy failure’ (SEF) on the basis that they followed impaired intrapartum cerebral energy generation (resulting in transiently reduced PCr and NTP and increased Pi), which resolved following resuscitation ( ). It was assumed that SEF was consequential to a pathological mechanism initiated by intrapartum hypoxia–ischaemia and/or reperfusion/reoxygenation. ¹ H MRS provides complementary information to ³¹ P MRS (in particular cerebral lactate, a marker of anaerobic metabolism and N -acetyl aspartate (NAA), an abundant amino acid found mostly in neurons in the central nervous system ( )) and because of the greater sensitivity of the ¹ H nucleus, data can be obtained from smaller regions of the brain. NAA appears as a singlet peak in the ¹ H MR spectrum and is easier to quantify than lactate ( Fig. 40.33a–d ). The roles of NAA include action as: (1) an osmolyte ( ); (2) a supplier of acetate for myelin sheath synthesis ( ); (3) a facilitator of mitochondrial energy generation ( ); and (4) a ligand for some metabotropic glutamate receptors ( ). Cerebral lactate increases and NAA decreases during transient hypoxia–ischaemia; these metabolites return almost to baseline levels after successful resuscitation, only to be followed by a secondary increase in lactate and slower reduction in NAA in the hours that follow. These ¹ H MRS changes occur in parallel with the energy disruption (reduction in PCr/exchangable phosphate pool (EPP) and NTP/EPP) seen on ³¹ P MRS ( Fig. 40.36 ).

The biphasic pattern of energy failure associated with a transient hypoxic–ischaemic insult visualised using ³¹ P MRS (top) and ¹ H MRS (bottom) in the UCL piglet model. ³¹ P MRS: Nucleotide triphosphate (NTP)/exchangeable phosphate pool (EPP = Pi + PCr + NTP) is shown on the y -axis. The change in NTP/EPP during transient hypoxia–ischaemia (HI), resuscitation, the latent phase (period between the recovery from acute HI and the evolution of secondary energy failure (SEF)) and SEF itself are shown. A ³¹ P MR spectrum from a severely asphyxiated baby is shown on the top right. ¹ H MRS: Lactate (Lac)/ N -acetyl aspartate (NAA) is shown on the y -axis. The change in Lac/NAA during transient HI, resuscitation, latent phase and SEF are shown. A ¹ H MR spectrum from a severely asphyxiated infant is shown on the bottom right.

During the acute energy depletion, some cells undergo primary cell death, the magnitude of which will depend on the severity and duration of HI. Following perfusion, the initial hypoxia-induced cytotoxic oedema and accumulation of excitatory amino acids typically resolve over 30–60 minutes with apparent recovery of cerebral oxidative metabolism (latent phase). It is thought that the neurotoxic cascade is largely inhibited during the latent phase and that this period provides a ‘therapeutic window’ for therapies such as hypothermia and other agents. Cerebral oxidative metabolism may then secondarily deteriorate 6–15 hours later (as SEF). This phase is marked by the onset of seizures, secondary cytotoxic oedema, accumulation of cytokines and mitochondrial failure. Mitochondrial failure is a key step leading to delayed cell death.

We have used the composite biomarker consisting of the ratio of the cerebral lactate (Lac) and NAA peak areas at TE 288 ms (Lac/NAA) in our MRS studies of NE. The reciprocal changes in Lac and NAA concentrations increase the sensitivity to detect even minor neural injury, as well as enabling assessment of more severe injury. A recent meta-analysis of the prognostic accuracy of MR methods demonstrated that thalamic ¹ H MRS Lac/NAA peak area ratio acquired between days 5 and 14 is a highly sensitive and specific biomarker of long-term neurodevelopmental outcome in infants with NE ( ). Lac/NAA was more predictive than any other MRI technique including early and late conventional MRI, presence or absence of the normal signal from the PLIC and apparent diffusion coefficient (ADC) imaging.

Biphasic impairment of cerebral energy metabolism with transient hypoxia–ischaemia has been demonstrated in the newborn piglet ( ; ; ); these studies provided a basis for the realisation that rescue treatment after hypoxia–ischaemia may reverse or ameliorate SEF. Experimental studies with moderate hypothermia ( ) and other potential therapies soon followed ( ). Recent work in the piglet model has shown that hypothermia extends the therapeutic window for other pharmacological therapies and the more severe the hypoxia–ischaemia, the shorter the therapeutic window ( ).

Biomarkers of brain injury

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. Biomarkers are needed in infants with HIE to predict which infants are most at risk of an abnormal outcome and who would benefit most from neuroprotective intervention (early biomarkers) and to predict long-term outcome following neuroprotective interventions (late biomarkers) ( ).

Fetal compromise

The intrapartum period is a time of risk for asphyxia; intrapartum care aims to identify those babies who are experiencing hypoxia–ischaemia. The fetus is generally well adapted to cope with the physiological stress normally imposed by labour, but on occasion the ‘reserve capacity’ is overwhelmed. The aim of intrapartum monitoring is to detect this.

Clinical manifestations of hypoxic–ischaemic encephalopathy

Management of hypoxic–ischaemic encephalopathy

Investigations

When encephalopathy has developed following resuscitative efforts at birth with evidence of perinatal asphyxia and following a sentinel event, a diagnosis of HIE is likely to be correct. Nevertheless, coexisting or predisposing conditions such as infection or trauma or metabolic disorder also need to be considered. A protocol will help ensure the most appropriate investigations are carried out and important ones not left out. Suggested first-, second- and third-line investigations are described in recent reviews on NE and summarised in Table 40.22 ( ).

Table 40.22

Suggested first-, second- and third-line investigatons for neonatal encephalopathy

	INVESTIGATIONS
First-line *	Cord blood gases and lactate Biochemistry, haematology and metabolic parameters Cardiac and hepatic enzymes Screen for infection (± lumbar puncture) Tests for congenital infection Cranial ultrasound EEG/aEEG MRI within 14 days
Second-line	Investigation for metabolic or genetic disorders if any dysmorphic features, parental consanguinity, abnormal intracranial anatomy, severe growth restriction, unusual pattern of injury on MRI scan, normal-looking MRI scan with ongoing neurological problems
Third-line	Consider further investigation for metabolic disorders (e.g. non-ketotic hyperglycinaemia, sulphite oxidase deficiency, biotidinase eficiency, mitochondrial disorders, peroxisomal disorders, carbohydrate glycosylation defects, carnitine or acyl carnitine disorders, disorders of lysosomal enzymes) Consider investigation for neuromuscular diseases (e.g. nerve conduction studies, electromyogram, muscle biopsy) Consider thrombophilia screen in cases with focal haemorrhage, infarction or thrombosis Store blood for future DNA analysis

 

EEG, electroencephalogram; aEEG, amplitude-integrated electroencephalogram; MRI, magnetic resonance imaging.

(Modified from Azzopardi et al. 2010.)

* According to local protocols.

Cranial ultrasound

cUS has been used extensively in neonatal practice, since it is a convenient technique to visualise the neonatal brain through the anterior fontanelle serially without moving or disturbing the patient in a neonatal intensive care setting.

cUS scanning is helpful to exclude structural abnormality suggesting metabolic and other diagnoses, detect calcification and cysts suggestive of viral infection and detect atrophy suggestive of long-standing damage. It will also identify cerebral haemorrhage. Sequential observation of the evolution of injury following a recent hypoxic–ischaemic insult at birth is helpful both for defining the pattern of lesion and timing its onset. Brain swelling is a non-specific finding on cUS, which supports the diagnosis of hypoxia–ischaemia, but is not always present. The presence of ‘slit-like’ ventricles on the first day of life, however, is a very non-specific finding, since many healthy neonates have small ventricles. The ultrasound appearances of cerebral oedema include loss of the normal anatomical detail with obscuration of the sulcal markings and closure of the interhemispheric and sylvian fissures. The brain has a sparkly appearance with increased echoreflectance.

Following acute and severe hypoxia–ischaemia, echogenicity of the BGT may be seen to appear 24–48 hours after birth. The thalami appear egg-shaped and echoreflectant. In the coronal view the internal capsule remains of normal echogenicity and gives rise to a ‘stripe’ as it sits between the thalami and lentiform nuclei, both of which are abnormally echoreflectant ( ). A clear and persistent abnormality of the thalami and basal ganglia on cUS correlates with MRI findings, which indicate a poor prognosis ( ) ( Fig. 40.37 ). Similarly, the appearance of a hyperechoic line running through the central grey matter is also a poor prognostic sign. Early detection may be facilitated by additional scanning with a low transducer frequency of 5 MHz – this lower transducer frequency allows deeper penetration in larger infants or those with thick hair and enables visualisation of deeper structures (i.e. the BGT in large infants and the posterior fossa) ( ). MRI is necessary to determine the exact site and extent of injury and involvement of the PLIC.

Cranial ultrasound of a full-term neonate with severe perinatal asphyxia, day 3. Left: coronal image, right: parasagittal image. Both views show severe injury to the basal ganglia and thalamus.

Due to its localisation at the brain’s convexity, the watershed or parasagittal injury pattern is not easily detectable with cUS. It often shows as a ‘tramline’ appearance of the cortex, that is, broadening of the hypoechogenic cortical rim combined with increased echogenicity of the subcortical white matter. Increasing the transducer frequency to 10 MHz will improve detection of this injury pattern with cUS; however, confirmation by MRI is indicated ( ). Doppler studies of CBF velocity showing a low resistance index are predictive of a poor outcome ( ).

Electrophysiology (EEG, aEEG, evoked responses)

Neurophysiology plays an important role in determining the severity of the insult in the newborn infant after hypoxia–ischaemia. In earlier studies the multichannel EEG was used to predict neurodevelopmental outcome ( ; ). In these studies, the EEG was usually performed after the first 12–24 hours. The electrical background activity was more predictive than the presence or absence of seizure activity. Since multichannel recordings have practical limitations, more compact systems, available within the intensive care unit, providing immediate access and storage of signals at the cot side over long period of time, are now increasingly being used. With this technique a single- or two-channel EEG is recorded from biparietal electrodes. The filtered signal is rectified, smoothed and amplitude-integrated before it is written out on a semilogarithmic scale at slow speed (6 cm/h). aEEG has a high concordance with the standard EEG ( ; ). The method is not always reliable for detection of seizures but works well in many babies and the neonatal staff can be taught to interpret the result. The results obtained using aEEG to predict outcome are similar to those obtained using EEG: a very early trace showing burst suppression or no activity can normalise by 6 hours and the baby may do well, but persisting burst suppression or isoelectric activity carries a poor prognosis ( ; ; ).

Over the last 20 years several studies have confirmed that the aEEG pattern in the first 6 hours of life is strongly predictive of outcome in infants with NE ( ; ). The speed of recovery, as well as the severity of the abnormality, in the aEEG trace is prognostically valuable ( ). The predictive value of aEEG has been shown to extend to infants who were monitored after 24 hours of age and to infants with encephalopathy caused by conditions other than hypoxia–ischaemia, such as metabolic conditions ( ), sepsis or meningitis ( ).

Sleep–wake cycling (SWC) is present in healthy term newborns and is a sign of brain integrity. A good neurodevelopmental outcome was predicted by the onset of SWC before 36 hours in 82% of infants with NE in one study ( ). Ideally, aEEG recording should be continued long enough for the onset of SWC to be determined.

The aEEG can be classified according to pattern or voltage criteria ( ; ). The voltage criteria are based on assessment of the lower and upper voltage margins of aEEG background ( ) ( Fig. 40.38 ). This method was used for selecting into the Cool-Cap and Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy (TOBY) trials infants with encephalopathy ( ; ). The voltage classification ( Fig. 40.39a–d ) is easier to use for clinicians with little experience in reading aEEG, but one should always try to assess the underlying pattern ( Fig. 40.40a–e ). It has been shown that a burst suppression pattern may be read as a normal voltage pattern when a ‘drift of the baseline’ brings the lower margin above 5 µV ( ). The facility of inspecting the raw EEG in the new digital aEEG machines improves the accuracy of the interpretation of the aEEG. However, although some artifacts are easy to recognise, in many cases the recognition of an artifact requires an ability to interpret the EEG.

(a) Amplitude-integrated encephalogram (aEEG) classification based on voltage criteria. Based on assessment of the lower and upper voltage margins of aEEG background ( ). (b) aEEG classification based on pattern. A, continuous normal voltage; B, discontinuous normal voltage; C, burst suppression; D, continuous low voltage; E, flat trace ( ).

(a) Normal voltage on amplitude-integrated encephalogram (aEEG: upper margin >10 µV, lower margin >5 µV) and sleep cycling. Continuous mixed-frequency activity on EEG. (b) Moderately abnormal voltage on aEEG (upper margin > 10 µV, lower margin < 5 µV); EEG shows discontinuity. (c) Severely abnormal voltage on aEEG (upper margin <10 µV, lower margin <5 µV), EEG shows infrequent bursts of low-amplitude activity. (d) Severely abnormal voltage plus seizures. Bilateral high-amplitude seizures on EEG cause transient upward deflection of upper and lower margin of aEEG.

(a) Continuous normal voltage (CNV) pattern on amplitude-integrated encephalogram (aEEG). Continuous activity with voltage 10–25 µV and sleep–wake cycling (SWC). EEG shows continuous mixed-frequency activity. (b) Discontinuous normal voltage pattern on aEEG (DNV, discontinuous trace, where the voltage is predominantly above 5 µV) with no sleep cycling. EEG shows low-amplitude activity alternating with higher-amplitude bursts. (c) Burst suppression pattern on aEEG (BS, discontinuous background pattern; periods of very low voltage intermixed with bursts of higher amplitude). EEG shows transient isolated bursts of mixed-frequency activity with prolonged periods of inactivity. (d) Continuous low-voltage pattern on aEEG (CLV, continuous background pattern of very low voltage around 5 µV). EEG activities are continuous but low-amplitude. (e) Flat trace pattern on aEEG (FT, inactive tracing with activity below 5 µV). EEG shows inactivity.

Recent studies show that therapeutic hypothermia changes the predictive value of early aEEG ( ; ). Normalisation of an infant’s aEEG while being cooled occurs later: in an infant who develops normally and who is not cooled, the aEEG would be expected to return to normal by 24 hours, whereas in an infant who is cooled and develops normally, it may take as long as 48 hours for the aEEG to normalise. In one study the time to normal aEEG was a better predictor than time to SWC; however never achieving SWC always predicted poor outcome ( ).

Computed tomography (CT)

CT scans have been used in the past in full-term neonates with hypoxia–ischaemia. MRI is superior to CT in all aspects and in most places CT has been replaced by MRI. Even the presence of calcifications, until recently only possible with ultrasound or CT scans, can be demonstrated with appropriate MRI sequences (susceptibility-weighted imaging). In a study comparing MRI with CT on day 3 in infants with NE, CT was able to detect the predominant pattern of injury with a 67% agreement with DWI MRI ( ). The risk of exposure to ionising radiation with CT must be kept in mind and MRI used if at all possible.

MRI and MRS

MRI is the optimal imaging modality for the early evaluation of brain injury in full-term neonates with perinatal asphyxia. Hypoxic–ischaemic changes of the brain can be visualised with higher spatial resolution, sensitivity and specificity than with cUS and CT. The pattern of brain injury may not be fully apparent until after the first 4–7 days on conventional MRI, but may be seen with DWI. The main patterns of injury are: (1) basal ganglia-predominant; (2) watershed-predominant; or (3) severe global injury. The severity and duration of hypoxia–ischaemia (acute total or chronic partial) influence the pattern of injury; the patterns of injury and their likely outcome are discussed in the section on patterns of injury, above.

Proton MRS is increasingly available and provides important prognostic data during the first week ( ; ). A reduction in NAA and elevation of Lac in the thalamus/basal ganglia ( ). Evolving abnormalities on MRS during the hours and days after birth and the use of MRS as a surrogate outcome measure are described in the section on cerebral energy metabolism associated with hypoxia–ischaemia, above.

DWI may help clinicians detect hypoxic–ischaemic lesions earlier than standard T1- or T2-weighted imaging. A reduced apparent diffusion coefficient can be calculated, showing reduced values (restricted diffusion) during the first few days after the insult, with pseudonormalisation by the end of the first week ( ) ( Fig. 40.41 ). Sequential imaging has shown that lesions in the basal ganglia may vary in size and site during the first week after birth ( ). The appearance of new areas of reduced diffusion simultaneous with pseudonormalisation of areas that had reduced diffusion at earlier times results in entirely different patterns of injury on ADC maps acquired at different time points.

Time course of the diffusion abnormality following perinatal brain injury in newborn infants. D _av has been normalised to reference values for newborn infants (D _av ratio). The maximum reduction in D _av ratio of approximately 35% occurs between days 2 and 3. Pseudonormalisation is noted after the seventh day.

(Adapted from McKinstry et al. 2002.)

Therapeutic hypothermia

A series of large randomised clinical trials has now shown that mild to moderate induced hypothermia ( ; ; ; ) (also termed targeted temperature management): (1) decreases death and disability among infants with less severe aEEG abnormalities ( ); (2) decreases death and moderate/severe disability; and (3) increases the number of survivors without disability ( ; ; ). Therapeutic hypothermia under intensive care settings appears safe; although thrombocytopenia and arrhythmias are more frequent with therapeutic hypothermia, these can be corrected with appropriate clinical care ( ; ). Inotropic support was used more commonly in cooled infants but this may have been due to physician bias ( ). Furthermore, there are suggestions that the favourable outcome of cooled infants at 18 months may be associated with favourable outcome at age 7–8 ( ).

Therapeutic hypothermia is now widely offered to infants with NE in high-income countries ( ). In the UK, in May 2010, the National Institute for Health and Clinical Excellence recommended that therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury should be offered to ‘carefully selected infants … in units experienced in the care of severely asphyxiated infants [who] enter the details of infants undergoing cooling into the UK TOBY cooling register’ ( ; http://www.nice.org.uk/nicemedia/live/11315/48809/48809.pdf ). No large trials have assessed the safety and efficacy of therapeutic hypothermia in neonatal encephalopathy in low resource settings and there is concern that risk factors and population differences may alter risks and benefits of this therapy in such settings ( ).

Meta-analysis of trials with 18 months of follow-up suggests a number needed to treat of approximately 9, with a relative risk for death or disability of 0.81 (95% CI 0.71–0.93; P < 0.002) ( ). This advance is the culmination of >40 years of basic and clinical research ( ), and provides a strong platform from which to improve outcomes further. Eligibility criteria in the trials included a pH <7.0 or a base deficit of >16 mmol/L in umbilical cord blood or any blood during the first hour after birth. If blood gas was not available, additional criteria were required. These included an acute perinatal event and either a 10-minute Apgar score of 5 or less or assisted ventilation initiated at birth and continued for at least 10 minutes. A neurological exam with the presence of moderate to severe encephalopathy, and in some trials aEEG with specific findings, were required. Infants outside inclusion criteria for previously published clinical trials, including infants of 36 weeks’ gestation, infants who present outside the previously studied 6-hour window and infants with encephalopathy not attributable to HIE, remain in the unstudied realm for cooling therapy. US studies are underway to determine whether cooling for longer and deeper (96 hours to 32°C) provides better neuroprotection or whether cooling initiated after 12 hours from birth is beneficial.

Experimental studies, however, indicate that the earlier cooling is commenced, the better the outcome ( ). This is particularly critical since the therapeutic window is substantially reduced with increasing severity of injury ( ). Guidelines are in place for cooling infants prior to and during transport to a cooling centre in the UK ( ). Once in a cooling centre, servo-controlled cooling devices are generally used (Tecotherm and Criticool) and whole-body cooling is practised more frequently than selective head cooling ( ; ). Accumulating evidence from adult cooling studies emphasises the importance of rewarming as slowly as possible, by a maximum of 0.5°C over 2 hours. Key points in the clinical management during therapeutic hypothermia are shown in Table 40.23 and Figure 40.42 . It is very important to avoid overcooling below 30°C, as this has been associated with adverse outcomes in experimental studies ( ). It is essential to monitor rectal temperature continuously, especially during transport. In the UK, continued surveillance via the national registry is needed to detect unusual complications and audit in therapeutic hypothermia. In particular, further experience needs to accumulate in understanding the safety of therapeutic hypothermia applied to infants with systemic complications associated with perinatal asphyxia, such as pulmonary hypertension or myocardial ischaemia; none of the trials were powered to study this.

Table 40.23

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Basic genetics
2. Care of the normal small baby and convalescent NICU graduate
3. Haematology
4. Cardiovascular disease

Stay updated, free articles. Join our Telegram channel

Join