42 Cerebral palsy

The term ‘cerebral palsy’ is loose and its boundaries are imprecise. It may be defined as a persisting, but not necessarily unchanging, acquired motor disturbance arising in the perinatal period or infancy, due to non-progressive brain damage. It embraces a wide variety of disorders with differing clinical features and aetiologies. A number of types of cerebral palsy can be distinguished, including 1) hemiplegic cerebral palsy, in which hemiparesis may be associated with other ipsilateral signs of corticospinal tract damage, 2) tetraplegic cerebral palsy, in which tetraparesis may be associated with signs of bilateral corticospinal tract damage, 3) diplegic cerebral palsy, in which weakness and other signs of corticospinal tract injury predominate in the lower limbs producing a picture resembling paraplegia, 4) ataxic cerebral palsy, in which cerebellar features predominate, and 5) dyskinetic cerebral palsy, in which involuntary movements are prominent. Individual patients often show a mixed picture. For example, cerebellar features, with ataxia may be associated with diplegia.

Dyskinetic cerebral palsy forms the basis of this chapter and other types of cerebral palsy are not discussed further, except to make occasional comparisons. Dyskinetic cerebral palsy can be caused by a number of acquired pathological processes, but the two main ones are perinatal hypoxia and jaundice. In addition, some cases that have been classified under the rubric of cerebral palsy may actually have a genetic basis (Fletcher and Marsden 1996). The immediately following section on ‘Dyskinetic cerebral palsy’ deals with all causes of this disorder. Because kernicterus, resulting from neonatal jaundice, shows a number of additional features, these are elaborated separately in the next section entitled ‘Kernicterus’.

Early descriptions of dyskinetic cerebral palsy were given by Little (1843, 1862), Shaw (1873), Bernhard (1884), and Dejerine and Sollier (1888). Little (1843, 1862) distinguished three types of paralysis: hemiplegic rigidity, generalized rigidity (paraplegia or diplegia), and ‘disordered movement’. The latter term referred to patients with involuntary movements. In his paper entitled ‘On Athetosis. Imbecility with Ataxia’, Shaw detailed the onset in infancy, widespread involuntary movements, including involvement of the face and trunk, mutism, and frequent preservation of intellect. In keeping with the times, ‘imbecility’ implied incapacity, rather than reduced intellect. Because little was known about aetiology and pathology, many earlier papers contain a confusing mixture of different clinical syndromes described under a wide variety of names. Permanent neurological disability following neonatal jaundice was first described by Arkwright (1902) and paved the way for delineation of kernicterus as a separate entity. Although Anton (1896) had earlier described striatal abnormalties in dyskinetic cerebral palsy, it was not until 1911 that these were clearly defined and called status marmoratus (Freund and Vogt 1911, Oppenheim and Vogt 1911, Vogt 1911). There were various theories as to the cause of these changes, including inherited degenerative disease (Oppenheim and Vogt 1911, Koch 1949). Gradually evidence of association with perinatal insults, including trauma, hypoxia, and vascular disturbances, has accumulated (Norman 1949, Greenfield 1958). Such factors above, however, only seem to account for a small proportion of the total pool of cerebral palsy (Grant et al. 1989, Hall 1989). The field of cerebral palsies is still somewhat confused and much work remains to be done to clarify the situation.

Dyskinetic cerebral palsy may be defined in the same way as cerebral palsy, mentioned above, with the addition that involuntary dystonic or choreic movements are present. Like other clinical manifestations, involuntary movements may not be apparent for months or years after the cerebral damage occurs, and development of or change in such features does not necessarily imply progressive pathology (see later under ‘Pathophysiological mechanisms’).

Dyskinetic cerebral palsy can be subclassified in several ways. Divisions based on neuropathology are unsatifactory for clinical use and those utilizing aetiology, such as kernicterus, anoxia, and trauma, suffer from the disadvantage that these factors are often unknown or multiple. The most satisfactory clinical subclassification is based on clinical features. Thus, dyskinetic cerebral palsy can be divided into athetotic hemiplegia and double athetosis. Athetotic hemiplegia probably arises from birth trauma with associated cerebral infarction or haemorrhage. The extent to which subependymal haemorrhage or infarction or intraventricular haemorrhage, so common in premature infants, is involved is at present uncertain. These factors are likely to become more important in the genesis of childhood neurological deficits as an increasing number of markedly premature babies are surviving (Editorial 1984, Sinha et al. 1985). This may change the relative mix of disorders making up the entity of cerebral palsy, but it seems likely that even in very low birth weight infants, a substantial proportion of cerebral palsy is not based on such mechanisms (Veelken et al. 1993). In keeping with this, a proportion of cases of early onset athetotic hemiplegia are probably due to congenital malformations rather than trauma, hypoxia, or ischaemia. For example, it may occur with regional cerebral cortical heterotopia, such as occurs in pachygyria (Leuzzi et al. 1993). Athetotic hemiplegia is clinically similar to that occurring later in life, except that it is frequently associated with underdevelopment of the affected limbs and sometimes the contralateral hemicranium. This is discussed under ‘Post Hemiplegic Dystonia’ in Chapter 43, ‘Acquired Secondary Dystonias’ and is not further elaborated here.

The second variety is double athetosis (athetose double), which has been known by a variety of synonyms including ‘Little's disease with involuntary movements’, ‘infantile partial striatal sclerosis’, ‘congential chorea’, and ‘athetotic cerebral palsy’. It is this variety of dyskinetic cerebral palsy which is the subject of the rest of this chapter. This is sometimes further subdivided into 1) pure athetosis, in which involuntary movements and impairment of postural reactions are the only features, 2) ataxic athetosis, in which there are associated cerebellar features, and 3) quadriplegic athetosis, in which there are associated corticospinal tract signs. There is, however, overlap between these groups.

A variety of neuropathological changes are found in dyskinetic cerebral palsy. Although these are sometimes mixed they are largely distinct entities. Histological features in a particular area may be characteristic of specific aetiologies. To some extent, however, this may be artifactual as some disorders selectively affect certain areas and the different responses of these immature brain regions may be more important in determining the eventual appearance than the noxious events themselves.

Perhaps the most characteristic abnormality is that of status marmoratus (etat marbre) or marbelling, which affects the neostriatum, particularly the putamen (Fig. 42.1). The cut surface appears similar to marble with a coarse, mottled appearance. This is due to densely packed, irregularly arranged bundles of myelinated fibres forming large plaques, which often surround areas of gliosis and cyst formation. There is associated loss of neurons and shrinkage of the caudate and putamen. Occasionally these changes involve part of the thalamus (Meyer 1926, Gozzano 1934, Carpenter 1955), although there is sometimes associated thalamic atrophy without status marmoratus (Peffeiffer 1925). Some thalamic neuronal loss has been interpreted as being secondary to neostriatal degeneration (Vogt and Vogt 1920, Holzer 1934). Occasionally the external segment of the globus pallidus is also involved, but here there is loss of myelin, similar to status dysmyelinisatus (see later), rather than an increase in myelin (Onari 1925). It is associated with neuronal loss and gliosis. Status marmoratus may be associated with a variety of other changes, including atrophy of the subthalamic nucleus (Vogt and Vogt 1920, Holzer 1934), cerebellar sclerosis (Onari 1925,

Scholz 1925, Norman 1949), neuronal loss in the dentate and red nuclei, a reduction in the size of the fronto-pontine tract (Alexander 1942), and periventricular softening.

There has been much debate about the cause of status marmoratus. It seems likely to be due to perinatal abnormalities, such as asphyxia and hypotension (Norman 1949, Greenfield 1958).

Status dysmyelinisatus was the term coined by Vogt and Vogt (1920) to describe a rare condition in which there is severe lack of myelin in the globus pallidus, subthalamic nucleus, interconnecting fibre systems, and other pallidal efferents, including pallido-thalamic projections (Fig. 42.2). There is not only a lack of myelin but also loss of axons, degeneration of pallidal and subthalamic neurons, gliosis, and shrinkage. The term is really a misnomer as it implies abnormal development of myelin in keeping with Vogt and Vogt's (1920) interpretation that this was a congenital malformation. It seems, however, that the majority of cases are not the result of perinatal cerebral insults, including hypoxia and hypertension. Kernicterus is perhaps a major cause (Spiegel and Baird 1968, Zeman and Whitlock 1968). A number of other post-icteric changes may occur and these are described below in the section entitled ‘Kernicterus’.

In addition, there are a variety of other patholgical changes which have been reported in athetotic cerebral palsy. These include bilateral atrophy of the neostriatum or globus pallidus, without status marmoratus or status dysmyelinisatus (Scharapow and Tschernomordik 1928, Crothers and Cobb 1930, Papez et al. 1938, Neustaedter 1943). Haemorrhage into subependymal tissues is common in prematurity and may result in periventricular scarring and leukomalacia (Pape and Wigglesworth 1979). The adjacent caudate nucleus is particularly liable to damage but other structures may be affected. Although such changes are more likely to be related to athetotic hemiplegia, they may occasionally be involved in double athetosis.

Carpenter (1950) found that status marmoratus was the commonest abnormality and was present in 16 out of 26 cases of double athetosis. In addition, he noted that rarely this pathology was not associated with involuntary movements, although in some cases associated damage to cerebral cortex and corticospinal pathways may have prevented their appearance. He found a small number of cases of double athetosis unassociated with anatomical change in the striatum or globus pallidus.

Thus, most cases of bilateral athetotic cerebral palsy are associated with status marmoratus or the pathological changes typical of kernicterus. In a few cases there is status dysmyelinisatus. Occasionally other pathological processes, usually damage from vascular lesions, involve the basal ganglia. Scattered damage to other brain areas may be found and rarely athetosis has occurred without structural basal ganglia pathology.

There is a lack of studies demonstrating convincing biochemical abnormality in the brain or cerebrospinal fluid in athetotic cerebral palsy.

The central mechanisms underlying the involuntary movements are uncertain. It is perhaps noteworthy, however, that in status marmoratus both the neostriatum and parts of the thalamus are damaged, with relative preservation of the globus pallidus. This is similar to the pattern of damage in some other forms of dystonia (see under ‘Post Hemiplegic Dystonia’ and ‘Acquired Secondary Dystonias’ Chapter 43). This pattern, however, is not mimicked in kernicterus and status dysmyelinisatus in which the emphasis is on pallidal and subthalamic nucleusdamage. The possibility of proprioceptive loss resulting in pseudoathetosis has been largely ignored but may help explain cases unassociated with basal ganglia lesions and may be a contributory factor in other patients. Jones (1976) reported impaired perception of passive joint movement in children with athetotic cerebral palsy, which was not present in controls with spasticity without athetosis.

Electromyography has revealed a variety of abnormalities. Dystonic movements are characterized by prolonged or sustained activation of muscle groups. Frequently there is simultaneous contraction of antagonists. This process may involve single or multiple levels in the same limb or different limbs simultaneously. There is irregular waxing and waning of the activity.

Electrical stimulation of peripheral nerves reveals a shortening of the silent period following the contraction (Linke 1977). Such stimulation, however, does not significantly alter the involuntary movements, although these can be temporarily suppressed by patient willpower, supporting the generally held concept that central, rather than peripheral, factors are important in the generation of these movements (Linke 1977).

Passive movements also produce abnormalities. Lengthening of muscles causes prolonged or sustained electrical activation. Sometimes there is an element of associated spasticity with a superimposed brief burst of activity immediately following lengthening (Narabayashi et al. 1965). In addition, sudden shortening of muscle may produce a burst of pathological activity in it (Pampiglione 1966). Passive movements of one limb may cause contraction of muscles in other limbs (Pampiglione 1966).

Attempts at voluntary movement reveal a variety of abnormalities. Hallett and Alvarez (1983) have distinguished six different types:

One of the hallmarks of dystonia is that attempts at voluntary movement result in excessive muscular activity, particularly in inappropriate muscles. These may be antagonists or muscles at distant sites, including in other limbs. It has been suggested that athetosis results from inappropriate ‘overflow’ of muscular activity. When this occurs unrelated to voluntary effort, it may represent attempts at postural correction, which occur even in apparently relaxed muscles (Hallet and Alvarez 1983).

Brainstem function or its excitability evaluated by the blink reflex showed significant excitability in the R2 recovery curve to paired stimuli in athetotic cerebral palsy patients compared to controls (Maeoka et al. 1999). This form of hyperexcitabity is thought to be caused by abnormal input into the brainstem interneurons possibly from the basal ganglia and is also seen in primary ‘idiopathic dystonia’ and other extrapyramidal disorders.

Thus, the electromyographic and blink reflex detected patterns of abnormality are similar to those found in other forms of dystonia (see Chapter 35, ‘Generalized Primary Dystonia’).

As mentioned above, cerebral palsy consists of several syndromes which can be caused by a variety of disorders in the perinatal or infant period. The relative frequency of different causes has shown considerable variation over the years. Discovery that rhesus incompatibility was the major cause of kernicterus and widespread application of preventative measures resulted in a decline in new cases of this type of cerebral palsy from the 1950s onwards (Hagberg et al. 1975[a and b], Foley 1983). In 1965 Plum investigated 173 consecutive patients and found that 57% were due to jaundice without asphyxia, 18% to asphyxia without jaundice, 20% to both factors, and only 4% to neither. In more recent publications,

the percentage of post-icteric cases is smaller. Even so, the present proportion of patients with athetotic cerebral palsy on this basis could be substantial. In a review of patients attending a centre for ‘spastic children’ (see Table 42.1), Foley (1983) found that 33% of athetotic cerebral palsy was due to jaundice. Hypoxia was thought to be the cause in a further 43%, while 5% were judged to be due to both. In only 24% were other aetiologies thought to be involved and in this group just over a third had an abnormal birth and a third had suffered perinatal infection or dehydration. Thus, the majority of cases of athetotic cerebral palsy were traced to perinatal jaundice or hypoxia, with a smaller group possibly related to perinatal trauma and infantile illness. In a few patients, inherited abnormalities may have been relevant as there was a family history of cerebral palsy or epilepsy. The various factors are to some extent interrelated and prematurity may predispose to jaundice, hypoxia, and cerebral trauma. Nonetheless, prematurity appeared as a major factor in the jaundiced group, being present in approximately a quarter, whereas birth abnormality was more prominent in the hypoxic group and was recorded in approximately a half (Foley 1983). By contrast, jaundice and hypoxia were uncommon in diplegic or quadriplegic cerebral palsy, being present in only 5% and 15% respectively. Approximately 80% of these children had experienced neither jaundice nor hypoxia, but prematurity and abnormal pregnancy were common and found in approximately 40% and 25% respectively. These figures suggest that brain trauma may be more relevant in these non-athetotic patients. The rate of twinning was abnormally high, being 5% in both the athetotic and non-athetotic groups. Although the proportion of patients with minor external malformations was small, at 5–10% it was considerably above normal.

In a 1992 follow-up study of 219 cases of dyskinetic cerebral palsy Foley (1992) found that only 26% had experienced kernicterus. In the remaining 162 patients 71% were born at term, but in two thirds the birth weight was below the expected mean. There was no relationship between ultimate clinical severity and birth weight, abnormal birth, or documented asphyxia. This led him to postulate that abnormal birth and asphyxia are not the direct cause of cerebral damage but are expressions of a pre-existing condition resulting in susceptibility to the stresses of birth, whether normal or abnormal.

The application of MRI brain scan in the first weeks of life has provided additional information. It has been shown that neonatal hypoxic-ischaemic encephalopathy can in some cases be associated with haemorrhagic lesions in the neostriatum, globus pallidus, and thalamus. It has been reported that 16% of such children have developed athetoid cerebral palsy and that this has been associated with the later development of symmetrical cystic lesions in the posterior putamen (Fig. 42.3). These persistent lesions are not seen in all patients who suffer such haemorrhages, and even if they do occur they do not seem to automatically lead to dyskinetic cerebral palsy (Rutherford et al. 1992). Neonatal convulsions have been a frequent additional factor.

There are numerous other possible aetiological factors, but these are less well defined. They include hypotension, hypoglycaemia, acidosis, vascular accidents, perinatal seizures, electrolyte disturbance, nutritional deficiencies, and other metabolic abnormalities. It is only by carefully recording such events and later correlating them with clinical and pathological findings that their aetiological role in cerebral palsy will be clarified. Nonetheless, although perinatal insults have been regarded as being important causes of athetotic cerebral palsy, it is doubtful that they play a major role in the genesis of cerebral palsy in general (Grant et al. 1989, Hall 1989, Stanley and Watson 1992, Adamson et al. 1995) and inherited factors may be more significant in the former group than has been previously thought.

The deleterious effects of kernicterus have been known for a long time and measures to prevent these have been utilized for decades. In spite of this, athetotic cerebral palsy remains common and it seems likely that in a significant proportion of current cases non-perinatal factors are important. In a group of 251 patients with cerebral palsy no parental age or birth order effects were observed in spastic quadriplegia or diplegia, but a paternal age effect was present in those with athetotic cerebral palsy and congenital hemiplegia, leading the authors to speculate that some of these cases might arise from a fresh dominant mutation (Fletcher and Foley 1993). Fletcher and Marsden (1995) studied 20 unrelated adult index cases of athetotic cerebral palsy and found that four had affected relatives and that the proportion of involved siblings and parents was similar. Some relatives were unaware of the problem until they were examined. It led these workers to propose that among patients covered under the rubric of athetotic cerebral palsy there may be a significant proportion with inherited disorders. The family data suggested autosomal dominant and recessive traits existed. An X-linked form could not be excluded. There was increased paternal age amongst single cases, suggesting some of these might arise because of fresh dominant genetic mutation. In addition, while it is well recognized that dystonia only gradually appears in early childhood and may slowly deteriorate for years, in only three of these index cases had the condition stabilized by 10 years of age and in seven there was worsening after the age of 30. It was felt that this was more in keeping with a progressive neurological disease. These notions challenge traditionally held views about athetotic cerebral palsy, and while it might be argued that these cases do not conform to the definition of cerebral palsy that we have used, namely that of an acquired motor disturbance, they are typical of the type of disorder seen in this group of patients and indeed had been diagnosed as such.

With advances in genetic techniques, researchers have looked into possible genetic causes of cerebral palsy and there are suggestions of genetic influences on the occurrence of cerebral palsy. However, like many common conditions, cerebral palsy exhibits complex inheritance patterns and the best descriptor of the inheritance of cerebral palsy would be that of ‘multifactorial inheritance’. This is in line with the notion of aetiologic and genetic heterogeneity with complex interactions with multiple environmental influences [for a review see Schaefer et al. (2008)].

The incidence of cerebral palsy is dependent on the standard of obstetric, perinatal, and infant care. In developed countries the incidence is between 1 and 3 cases per 1000 live births and there has been a fall towards the lesser figure in recent years (Glenting 1973, Hagberg et al. 1975[a and b]). The frequency does not seem to be continuing to decline, in keeping with the notion that there is a significant residuum of cases that are not due to perinatal factors (Stanley and Watson 1992). The proportion with dyskinetic cerebral palsy has been variously estimated to be between 6 and 25% of the total population of cerebral palsy victims, but the true figure is probably closer to the latter (Hagberg et al. 1975[a], Foley 1983, 1992, Kudrjavcev et al. 1985). Most studies draw no attention to a difference in prevalence between the sexes, but Foley (1983) noted dyskinetic cerebral palsy was twice as common in males.

In most cases the perinatal or infantile disorder that produces subsequent cerebral palsy is recognized, but it is not usually apparent that it has caused permanent brain damage. There may be a neonatal encephalopathy with diminished conscious levels, alteration in tone, and seizures. This is commonly transient and in children who subsequently develop dyskinetic cerebral palsy the clinical features of this can be mild (Rosenbloom 1994). In some cases the causative event is unobserved or unrecorded. There is usually a latent period of months or years, during which it is hoped or assumed that the child is normal. With aging, a pattern of clinical features unfolds revealing the true extent of the cerebral damage (Table 42.2). In the initial stages many signs of cerebral palsy are similar, even in groups that subsequently appear quite different. Early signs tend to be non-specific and include irritability or feeding difficulties. The latter can be due to repetitive jaw opening and tongue protrusion. Primitive reflexes may persist and there may be an overactive startle response. The Moro reflex is still present after the 2nd year in approximately a quarter of cases (Foley 1983). The tonic neck response, which is extension of limbs on the side to which the head is turned and flexion of the opposite ones, usually disappears by 7 months. Even in normal children it may persist in a minor form for much longer. In cerebral palsy, however, this reflex is often abnormally prominent and persistent. The so-called athetoid dance is elicited when the foot is placed on a surface and consists of flexion, abduction, and external rotation at the hip, associated with flexion at the knee and ankle, followed by the reverse movements. This may be a type of tactile avoiding

response and is a common indication of dyskinesia, prior to the appearance of spontaneous involuntary movements. It is to be distinguished from automatic walking, which usually disappears by 4 weeks of age but which can be elicited up to 11 months in some children if the neck is extended (MacKeith 1965). The athetoid dance has been recorded after the 2nd year of life in at least a quarter of patients who subsequently develop athetotic cerebral palsy, although this is probably a substantial underestimate (Foley 1983). True hypotonia or ‘floppiness’ is a common finding, as is defective head and trunk elevation. These latter signs are sometimes misinterpreted as hypotonia, but they are really examples of abnormal postural reflexes and show conspicuous impairment in 85% of cases in the first year of life. In about 40% impaired head and trunk control persist (Foley 1983). ‘Floppiness’ in early development is so prominent that if it is lacking it makes a subsequent diagnosis of athetotic cerebral palsy uncertain.

Abnormal postural mechanisms play a major part in the general picture of psychomotor retardation, which is often the first indication to the parents of abnormality. Delayed or impaired head control, sitting, crawling, standing, and walking are typical. This is usually associated with diminished eye contact, smiling, comprehension, and talking. Hearing difficulties may compound these problems. In a retrospective review of videos taken at 5–8 months of age of patients who subsequently developed dyskinetic cerebral palsy, it was noted that retention of tonic neck, Moro, and Galant responses was common. These were not, however, as specific for this disorder as difficulty in keeping a symmetric supine posture, limited forward extension of the upper limb, poor neck and trunk stability, and asymmetric or excessive opening of the mouth (Yokochi et al. 1993).

In the older child abnormalities are more obvious (Fig. 42.4). Although opisthotonic spasms may occasionally occur from early infancy, the appearance of other dyskinetic movements is usually delayed for months or years. Although, by definition, they appear in all patients with dyskinetic cerebral palsy, Foley (1983) reported that only 47% developed during the 1st year of life, 18% in the 2nd year, 16% in the 3rd year, 10% in the 4th year, and 8% were delayed until the 5th or subsequent years. The pattern of the involuntary movements may also gradually change, progressing from chorea to athetotic movements and eventually ending up with sustained dystonic postures (Zeman and Whitlock 1968). The reverse sequence has also been recorded (Gerrard 1952). The movements are aggravated by emotional stress and relieved by relaxation and sleep. It has been reported that anxiety results in a shift from choreic to dystonic movements (Gerrard 1952), but this is not general experience. If dystonic posturing is severe fixed contractures may develop and the eventual picture may be similar to that seen in the spastic varieties of cerebral palsy (Zeman and Whitlock 1968). Dystonic movements may involve the head, neck, limbs, or trunk. They are usually, but not always, symmetrical (Narabayashi et al. 1965). Although chorea may occur it is relatively infrequent and dystonia is the major involuntary movement. This may be present at rest or can appear on voluntary movement. As mentioned above under ‘Pathophysiological mechanisms’ voluntary movements produce not only local action dystonia but also more widespread inappropriate activation of muscles, including those in distant body sites (Fig. 42.4). At times a complex pattern of movement may contain the reverse of the intended action. Thus, grasping an object may be preceded by over-extension of the digits (‘starfish fingers’) or the hand is withdrawn. When reaching out for something, the head and eyes may be turned away. Facial contortions and a variety of extraneous movements may accompany attempts at simple voluntary activities. All degrees of severiity may be seen, from severe and virtually continuous athetosis to mild dystonic posturing on certain actions (Fig. 42.5).

Muscle bulk is usually normal. Continual activity, however, may eventually cause hypertrophy, particularly in the neck (Foley 1983). Power is difficult to assess. In pure athetosis it is usually normal, but if there is associated corticospinal tract injury, it may be reduced.

Muscle tone is variable. As mentioned above, there may be a phase of hypotonia in early childhood, but later tone is usually normal. Faulty postural reactions with impaired neck and trunk control should not be confused with hypotonia. Persistent dystonia may make it difficult to evaluate tone and proper assessment can only be performed when the limb is relaxed. Sometimes handling the limb produces increased rigidity (‘tension athetosis’). Dystonic muscles may show a progressive increase in muscle fibre activity and tension as they are lengthened (Denny-Brown 1962). In addition, varying degrees of spasticity with a true ‘clasp-knife’ response may occur.

Tendon reflexes and plantar responses are usually normal, but, along with spasticity, hyper-reflexia, and extensor plantar responses, occur in patients with associated pyramidal tract injury. Plum (1965) found pyramidal signs to be more common in post-hypoxic than post-icteric cases. Extensor plantar responses were noted in approximately 50% of the ‘pure asphyxia’ group but in only about 25% of the ‘pure icteric’ group. Hypertonia, hyper-reflexia, and ankle clonus were each present in approximately 30% of the ‘pure hypoxic’ cases and at approximately half this frequency in the ‘pure icteric’ patients.

It is important to keep in mind the possibility of cervical disk disease compromising the cervical cord particularly in patients with dystonic cerbral palsy with severe jerky torticollis. Such patients may improve with effective surgical intervention (Pollak et al. 1998).

As mentioned above under ‘Pathophysiological mechanisms’ there may be proprioceptive abnormalities in some patients (Harris et al. 1974, Jones 1976). On the whole, however, little attention has been paid to sensation and deficits have seldom been reported. Involuntary movements and impaired postural reactions make clinical assessment of cerebellar pathway damage impossible in most patients.

If gait develops, it is usually delayed and unsteady. Approximately two thirds of patients over the age of 10 reviewed by Foley (1983) were still unable to walk, stand, or even sit without support. He found that if independent sitting was possible, walking eventually developed. Foley (1983) found that pure athetosis with or without impairment of postural reactions was present in 38%, ataxic athetosis in 11%, and athetotic quadriplegia in 51% of patients. At the age of 3 years disability was severe in 60% (unable to sit unsupported, feed independently, or move around the floor), moderate in 24% (sitting with minimal support, partially feeding independently, and moving about the floor), and mild in 16% (sitting without support, feeding independently, and walking to some extent). Such figures provide only partial assessment of the spectrum of athetotic cerebral palsy as they were derived from a population referred to a centre for ‘spastic children’ and may not include many patients with mild involvement. Similarly, the most severely affected patients who die in early childhood are not included. Their figures, however, are representative of patients who present with the main management problems.

Severe physical disability, including deafness, speech difficulties, and impaired limb control, makes intellect difficult to assess. Non-verbal means of communication usually have to be employed to make proper assessment, requiring the services of an experienced clinical psychologist. Adverse physical appearance and absence of speech can lead to patients incorrectly being regarded as intellectually retarded. This may tragically result in lack of appropriate educational opportunities. Foley (1983) reported that 31% of cases due to hypoxia and 17% of those due to kernicterus had intelligence quotients above 100%. Other studies, however, have shown lower intelligence in the post-hypoxic group (Plum 1965, Molnar 1973). There tends to be an association between lowest intelligence and severest physical disability, although there were a number of exceptions (Plum 1965, Foley 1983). Signs of pyramidal tract damage are more frequent in the intellectually retarded group (Narabayashi et al. 1965, Plum 1965). The relatively frequent preservation of intellect in the athetotic variety is unlike other forms of cerebral palsy (Foley 1983).

Epilepsy and abnormal electroencephalograms are more frequentin non-athetotic forms of cerebral palsy (Foley 1983). Even in the athetotic group the presence of signs of pyramidal tract damage is associated with an increased incidence of epilepsy and abnormal electroencephalogram (Narabayashi et al. 1965, Plum 1965).

Ocular movements are sometimes impaired, but this is more frequent following jaundice than with other aetiologies. Foley (1983) found 29% of patients with athetotic cerebral palsy had impaired optokinetic nystagmus, 20% had pursuit movement abnormalities with normal automatic saccades, and 18% had impaired conjugate upward gaze. The oculo-cephalic responses were preserved. Many of these cases may have been secondary to kernicterus and these ocular abnormalities are probably uncommon after anoxia or traumatic perinatal damage (see later under ‘Kernicterus’).

Strabismus was present in 12%. Another abnormality of ocular movement, which is common in athetotic cerebral palsy, is the ocular avoiding reaction which consists of turning the head and eyes from the focus of interest. Brief interruptions may allow the object to be viewed.

Hearing loss has been reported in approximately 40% of patients with athetotic cerebral palsy and although it is much more common following jaundice, hypoxia can damage the cochlear nuclei (Fisch 1955, Hall 1964). In approximately 10% of cases in which hypoxia is the cause of the athetosis there is some degree of deafness (Foley 1983).

Foley (1983) found speech was normal in less than 2% of patients. This may be due to several factors, including dystonia affecting muscles of articulation and respiration. Impaired voluntary activity, however, seems more important than variable involuntary contractions (Neilson and O’Dwyer 1981, 1984). Deafness may also be involved. As well as slurring there may be impaired modulation with variation from strangled whispering to explosive speech. Foley (1983) found approximately two thirds of patients unable to express themselves in short phrases of more than a few intelligible words by the age of 5 who were thus effectively speechless. Deafness was not more common in this group. Approximately half of these patients had normal intelligence.

Early feeding difficulties have been mentioned above. These may persist and dysphagia or drooling are common.

Incontinence may result from physical difficulties with toileting, autonomic control, or impaired intellect. The relevance of these various factors has not been defined.

Contractures may be more common in the post-hypoxic group (Plum 1965). Other physical abnormalities include dislocation of hips, kyphoscoliosis, and rarely cervical spondylitic myelopathy (Anderson et al. 1962, Foley 1983). Poor nutritional state can result from diminished caloric intake associated with excessive muscular activity, and nutritional anaemia may occur (Foley 1983).

In many cases the perinatal event responsible for athetotic cerebral palsy will have been recognized and the situation is quite obvious. Under these circumstances, extensive investigation is not required and tests may be limited to psychometric assessment. If, however, this is not the case, alternative diagnoses require exclusion. It must be emphasized that thorough clinical evaluation, including careful history taking and examination, is vital. Particular attention should be paid to family history. It is important not to miss dopa-responsive dystonia, which can sometimes simulate cerebral palsy (Nygaard et al. 1994, Bandmann et al. 1998). Every individual with dystonic cerebral palsy should be offered a trial of levodopa (also see later under ‘Management’). Conditions requiring exclusion are mentioned in Tables 41.1 and b and Table 43.1; of these inherited disorders are more relevant at this age. Attention should also be directed to those conditions mentioned in Table 21.1 and Table 24.1. In most cases tests will include routine haematology, automated biochemistry, studies of copper metabolism, amino acid screening of blood and urine, and brain imaging. Inborn errors of metabolism such as Tay-Sachs disease require specialized enzyme analysis or genetic testing, but specific requirements will depend on the disorder under suspicion.

In general, most children (80%) with cerebral palsy have abnormal neuroradiological findings. On the other hand, 20% of cerebral palsy cases have no abnormality detectable by conventional MR or CT imaging (Korzeniewski et al. (2008). White matter damage is the most common abnormality. Combined grey and white matter abnormalities are more common among children with hemiplegia; isolated white matter abnormalities are more common with bilateral spasticity or athetosis, and with ataxia; isolated grey matter damage is the least common finding. Korzeniewski et al. (2008) provided a systematic review on this topic. The authors found that about 10% of cerebral palsy is attributable to brain malformations.

It is not the purpose of this section to deal with the therapy of the many different aspects of cerebral palsy, which have been well covered elsewhere (Brett 1983, Jones et al. 2007). These patients have multiple problems requiring a multi-disciplinary approach to management. Physiotherapists, speech therapists, teachers, and social workers all have a vital part to play, as well as various medical personnel. Their activities need to be coordinated by a key figure, who is usually a paediatrician or a paediatric neurologist.

Although a variety of drugs may be required, including antispastic agents such as lioresal (Milla and Jackson 1977) or dantrolene sodium (Joynt and Leonard 1980), present comments are restricted to treatment of involuntary movements. Unfortunately, there are few adequate studies in this group of patients on which to base recommendations. On the whole, the principles of treatment of dystonia are the same as those outlined in chapter 35 under ‘Generalized Primary Dystonia’. Benzodiazepines may produce mild improvement. Anticholinergic drugs such as trihexyphenidyl and ethopropazine are perhaps the most likely to be successful, but need to be used in high dosage (Fahn 1983). Levodopa should be tried, not only because of the possibility of dopa-responsive dystonia but also because a small number of patients with what otherwise seems to be typical athetotic cerebral palsy may show significant improvement (Fletcher et al. 1993). A variety of other drugs, including dopamine receptor blocking and stimulating agents, may produce modest improvement in individual cases, but the response is unpredictable and treatment is largely a matter of trial and error. Care must be taken not to aggravate the situation and side effects can easily go unrecognized in patients with communication difficulties. It is often eventually concluded that the degree of benefit does not justify therapy and many patients take no medication for their involuntary movements.

Botulinum toxin injections have been used to treat cerebral palsy. Most commonly they have been employed to lessen spasticity (Koman et al. 1994). Their application to problems caused by dystonia is similar to that which has already been outlined in the preceding chapters. In some cases significant improvement in functional disability in terms of skilled movements as well as posture and gait may be possible (Denislic and Meh 1995).

Infusion of intrathecal baclofen for generalized dystonic cerebral palsy has also been found to be beneficial not only for dystonia (Albright et al. 1998) but also for spasticity (Rawicki 1999). In a pilot study, dystonia scores improved significantly in 10/12 patients with short-term infusion with intrathecal baclofen (Albright et al. 1998). Eight of these patients were then given long-term therapy with programmable infusion pumps with sustained benefit (Albright et al. 1999).

Rarely patients with dystonic cerebral palsy have sudden life-threatening worsening of the dystonic spasms, so-called ‘status dystonicus’ (Manji et al. 1998). This is usually triggered by intercurrent infection or a similar event and is a difficult management problem requiring admission to an intensive care unit. Dystonic spasms can be severe enough to cause myoglobinuria, sometimes even leading to renal failure. Management involves looking after the patient during this period, which is self-limiting, and addressing issues of airway and respiration (as large doses of sedative medication are required), nutrition, infection, and relieving dystonic spasms (Manji et al. 1998).

Unilateral thalamotomy may relieve involuntary movements in contralateral athetotic hemiplegia, as discussed in chapter 43 under ‘Post Hemiplegic Athetosis’. The risks and benefits of this procedure are similar to those in unilateral idiopathic torsion dystonia as mentioned in chapter 35 on ‘Generalized Primary Dystonia’. Double athetosis, which forms the basis of the present chapter, is not suitable for such treatment as the required bilateral thalamotomy carries an unacceptable risk of serious complications (see Chapter 35,‘Generalized Primary Dystonia’). More recently, as for idiopathic generalized dystonia, the internal segment of the globus pallidus has emerged as a target for lesioning, i.e. a pallidotomy, or deep brain stimulation. Bilateral pallidotomy has been reported to have produced marked improvement in dystonia in a patient with dystonic cerebral palsy (Lin et al. 1999).

Another approach to this problem is that of cerebellar stimulation, which was introduced by Cooper et al. in 1973. Subsequent studies by this group (Cooper et al. 1976, 1977, 1978) have been encouraging and have suggested improvement by one or two out of five grades in spasticity in 73% and similar improvement in athetosis in 61% of patients with better effects on proximal limbs and the trunk dexterity compared to the peripheral extremities. Additional reported benefits include improved alertness, behaviour, memory, and cognitive functions (Riklan et al. 1978). Other studies have reported similar results (Larson et al. 1977/1978, Davis et al. 1980, Schvarcz et al. 1980, Sukoff et al. 1980). These encouraging, largely uncontrolled studies have involved many hundreds of patients. By contrast, double blind studies in a smaller number of subjects (Penn et al. 1980, Whittaker 1980, Gahm et al. 1981) have shown little overall effect, although occasional patients seem to have shown dramatic improvement.

This technique was used in patients with combined spasticity and dystonia who have the potential to make use of any therapeutic effect. Initial results appeared encouraging but at the present time remains experimental and must be regarded as unproven.

Electrical stimulation of the cervical spinal cord between C2 and C4 segements via an epidural electrode was also reported to be effective in relieving dystonia (Waltz 1981). Initial results in treatment of primary generalized dystonia were encouraging, but controlled follow-up studies have shown it is ineffective (see Chapter 35, ‘Primary Generalized Dystonia’).

The commonest surgical procedures carried out on these patientsare orthopaedic. Several operations may improve function, including elongation of the Achilles’ tendon, tendon transfer procedures, athrodeses, and correction of joint deformities. In many cases, however, persistent dyskinesia produces a recurrence of the original problem and results in this group of patients are less satisfactory than those in other varieties of cerebral palsy.

The role of physiotherapy in the treatment of dyskinetic cerebral palsy is still debated. There is no good evidence that this treatment reduces involuntary movements and athetosis, which shows considerable variation in direction and amplitude, and discourages the formation of contractures. Contractures may, however, develop in patients with relatively static dystonic postures, and although physiotherapy can alter these postures, they are immediately readopted when treatment is finished. Nonetheless, frequent, passive joint movements performed by parents under the instruction of a physiotherapist may be of benefit in some cases.

Physiotherapy directed towards training of postural control may be useful. Orthotic devices such as splints and corrective footwear have less place in the management of these patients than in other forms of cerebral palsy. Involuntary movements frequently render appliances useless, irritating, and painful. While they may be useful in cases with associated spasticity, they should be used with care.

Speech therapy should not be ignored. Even though it may be difficult to improve articulation, much can be done to develop alternative means of communication. This may involve the language of ‘eye pointing’ or other means of expression. Mechanical aids, such as symbol boards, are important.

Proper assessment of hearing, vision, and intelligence are vital, to enable attainment of potential by the use of appropriate educational techniques. It is easy to mistakenly regard such children as mentally retarded and every effort should be made to meet their educational needs.

Cerebral palsy is generally regarded as a static encephalopathy, which results from perinatal brain damage. Although it is widely accepted that the majority of motor signs are not present at birth and gradually evolve over the first 1–2 years, this has been attributed to the emergence of latent clinical features as the nervous system matures. As mentioned above, less than half the cases of dyskinetic cerebral palsy develop involuntary movements during the first year of life (Foley 1983). In addition, it has long been recognized that the type of involuntary movement may change quite markedly over the years. However, the concept that major neurological deterioration, including the appearance of paresis and dystonia, can occur later in childhood, adolescence, or even adult life in patients with cerebral palsy has not been widely embraced.

As early as 1944 Herz reported the commencement of dystonia in later childhood. A boy who had suffered from motor delay, spastic paraparesis, and seizures following a forceps delivery developed progressive dystonia at 8 years of age. This gradually worsened over the next 10 years and involved the face, limbs, and trunk. In 1950 Ryan noted the development of cervical and limb dystonia in a developmentally normal 4 year old who had suffered anoxia during forceps delivery. Hanson et al. (1970) noted that three similar cases showed delayed onset of tremor, cerebellar signs, and weakness, in addition to dystonia. Other small series have subsequently appeared (Burke et al. 1980, Treves and Korczyn 1986).

The pathophysiological mechanisms underlying such progression in neurological symptoms and signs are quite uncertain. A major consideration is whether these patients have some other neurological disease and the diagnosis of cerebral palsy has been erroneous. Another possibility is that an additional and unrelated disorder is present with cerebral palsy. In many reported cases there has been little attempt to exclude other diagnostic possibilities and some have even had a family history of neurological abnormality (Treves and Korczyn 1986). It has been postulated that an underlying latent genetic tendency to primary generalized dystonia may be brought out by perinatal brain injury, and in six Israeli patients with a diagnosis of cerebral palsy and delyed aggravation or onset of dystonia, four were of Ashkenazi extraction (Treves and Korczyn 1986). Apart from the incidental coexistence of unrelated dystonic disorders, several other mechanisms have been proposed to underlie the onset of such movements. These include the delayed and aberrant regeneration of injured axons with associated faulty myelination (Hanson et al. 1970, Burke et al. 1980). It is difficult, however, to explain delays of 30 or 40 years by invoking such a process. Underlying vascular changes have also been considered as a possible cause (Burke et al. 1980).

The clinical picture is usually one of delayed developmental milestones following birth difficulties, perinatal hypoxia, or even kernicterus (Treves and Korczyn 1986). The features of cerebral palsy subsequently become apparent, as has been outlined above. In some cases, these are relatively mild. Then after a period of apparently static physical signs there is the appearance or worsening of involuntary movement. In a little under half of the reported cases, there has been the similar development of other neurological signs, including bilateral or unilateral limb weakness, tremor, and cerebellar signs (Treves and Korczyn 1986).

The new physical signs may gradually deteriorate over months or years and progression over at least 9 or 10 years has been reported (Herz 1944, Burke et al. 1980). The disability stabilizes in some patients, while in a small number there may be improvement (Burke et al. 1980, Treves and Korczyn 1986). Treves and Korczyn (1986) found over half of their patients were left ‘in a severe invalid state’ after the appearance of such new physical signs.

Management should include careful investigation to exclude other underlying diseases. There is no known treatment to minimize such delayed-onset deterioration and treatment should be along the lines mentioned above under ‘Dyskinetic cerebral palsy’.

In his thesis entitled ‘The Icterus of the Newborn’, Hervieux, in 1847, described discolouration of the basal ganglia by pigment. In 1875 Orth identified crystals of bile pigment in these areas, but it was not until 1903 that Schmorl coined the term ‘kernicterus’ to describe these appearances. A year prior to this Arkwright (1902) reported permanent neurological sequelae in a child surviving severe neonatal jaundice. At 1 year he had ‘no use in the legs’ but by two and a half he could walk with support, although his gait was abnormal. This was the 14th child of a family in which all but the first had severe neonatal jaundice. Eight siblings died in the neonatal period and three others died between the 7th and 16th months of life. Guthrie (1913) reported the second case of persistent neurological damage and was the first to note involuntary ‘choreoathetotic movements’. These were attributed to the basal ganglia changes which have been described earlier. Perhaps surprisingly, the acute neurological features accompanying neonatal jaundice were not described until 1908, when Esch drew attention to the high pitched cry, twitching, rigidity, opisthotonic spasms, and periods of apnoea, progressing to death. The term post-icteric encephalopathy was suggested by Pentschew (1948) to describe the late sequelae. In 1950 Evans and Polani gave an excellent account of the permanent neurological sequelae based on 79 cases. Gerrard (1952) gave a detailed account of the natural history of untreated neonatal jaundice with emphasis on permanent clinical features and pathology. He followed up 220 families. Comprehension of the causes of neonatal jaundice and, in particular, the role played by maternal rhesus antibodies directed against the foetus led to the widespread application of corrective treatment. From the 1950s onwards, the incidence of kernicterus thus diminished and new cases are now rare in developed societies.

Kernicterus is the neurological syndrome produced by neonatal jaundice. The term was originally used to describe the neuropathological changes but has come to be used for both the clinical and pathological features. Similarly, it initially referred to only acute manifestations but has sometimes been used loosely to include permanent changes. For the sake of clarity, this is best avoided and the term post-icteric encephalopathy should be used for long-term complications.

The neuropathological changes in acute kernicterus are striking. As mentioned, with rare exceptions, these are confined to the neonatal period (Waser et al. 1986). There is marked, yellowish discolouration of many structures, including leptomeninges, choroid plexi, and ependyma. These changes, however, are non-specific and may be seen in any severe jaundice. The important findings are in the neural parenchyma (Fig. 42.6). Icteric staining is concentrated in the following structures in decreasing order of frequency: the globus pallidus, subthalamic nucleus, hypocampus, cranial nerve nuclei, cerebellar nuclei, tectal nuclei, vermis, flocculus, and mammillary bodies. In addition lesser degrees of pigmentation are found in the putamen, caudate, thalamus, amygdala, red nucleus, substantia nigra, hypothalamus, brainstem reticular nuclei, pontine grey matter, and lateral geniculate bodies. Very occasionally the cerebral cortex may be affected (Dereymaeker 1949, Bertrand et al. 1952, Haymaker et al. 1961, Larroche 1968). Pigmentation may consist of either diffuse staining or small granules in neurons and glia.

Degeneration of these stained neurons occurs and a range of changes may be seen from apparently intact to ‘ghost’ cells, the latter being empty spaces from which the neurons have disappeared. Histologically, the globus pallidus and subthalamic nucleus are most severely affected, but substantial necrosis may also occur in the hippocampus. In contrast, the thalamic nuclei, although frequently affected macroscopically, usually show only minor damage. The oculomotor, vestibular, and cochlear nuclei virtually always sustain damage and this is often severe. Similarly, destruction of the cerebellar nuclei is usually prominent. Neuronal degeneration in the other structures mentioned above is more variable and, in particular, the putamen and caudate usually show relatively minor changes (Larroche 1968, Spiegel and Baird 1968).

In addition, there are often scattered haemorrhages. These are usually petechial, but there may also be larger bleeds, particularly periventricular, intraventricular, or subarachnoid.

The changes seen in the post-icteric brain mirror those of the acute illness. There is marked neuronal loss with substantial gliosis and, in certain situations, the remaining fibres may lack myelination. The subthalamic nucleus, globus pallidus, and their efferent fibres bear the brunt of the change and sometimes lesions are virtually restricted there (Fitzgerald et al. 1939, van Bogaert 1947, Lund 1955, Meriwether et al. 1955, Soecken 1957). There is often associated hippocampal damage. This distribution of lesions has been claimed to be pathognomonic of previous kernicterus (Malamud 1961). Usually, however, there are also changes in other sites which show damage during the acute phase, particularly the oculomotor, vestibular, cochlear, and cerebellar nuclei. Status dysmyelinisatus, which has been described above under ‘Dyskinetic cerebral palsy’, may be regarded as an extreme variant of these pallidal and subthalamic changes.

Occasionally cortical lesions occur (Bertrand et al. 1952, Crome 1955, Jervis 1959) and demyelination has been reported in cerebral white matter, optic nerves, and spinal cord (Haymaker et al. 1961).

The acute abnormalities in bilirubin metabolism are mentioned below under ‘Pathophysiological mechanisms’. Changes in neurochemistry in acute and chronic stages are uncertain.

Unconjugated or free bilirubin, which is also known as indirect bilirubin because it is involved in the indirect Van den Bergh reaction, is formed from haemoglobin metabolism via the intermediate biliverdin. Unconjugated bilirubin is conjugated to bilrubin diglucuronide in the liver by the action of the enzyme glycuronyl transferase. Bilirubin diglucuronide or direct bilirubin is water soluble and excreted in bile, whereas indirect bilirubin is not water soluble. The latter, however, is transported in plasma attached to albumin and is soluble in lipids. Unconjugated bilirubin is able to cross the blood/brain barrier (Diamond and Schmid 1966) and its entry into brain may be facilitated by increased permeability of this barrier to albumin in the neonate (Arnhold and Zetterstrom 1958). This bilirubin is toxic to neonatal neurons. Similar injury almost never occurs at a later stage and the reason for this selective vulnerability is unknown. Rarely the disorder has been reported in adolescence and adult life and has been attributed to very high levels of unconjugated bilirubin (Ho et al. 1980, Waser et al. 1986). Bilirubin may become fixed to cytoplasmic structures and impair oxidative respiration of the neuron. Although other processes and substances have been suggested to cause the toxicity, unconjugated bilirubin is most likely to be the toxic agent (Day 1954, 1956, Zetterstrom and Ernster 1956, Cowger et al. 1965).

A variety of conditions may cause neonatal jaundice. Basically, however, it is due to overproduction of bilirubin resulting from haemolysis or failure of bilirubin conjugation and excretion. Approximately 90% of cases of kernicterus are due to erythroblastosis foetalis, in which there is haemolytic anaemia and compensatory erythropoiesis. This is usually due to sensitization of a rhesus negative mother by a rhesus positive foetus. This results from the initial or later pregnancies, so that the second or subsequent rhesus positive pregnancies may be affected. Maternal antibodies enter the foetal circulation causing haemolysis. Only about 5% of Rh negative mothers develop such sensitization and erythoblastosis foetalis occurs in approximately 0.1% of pregnancies (Ford 1960). Less commonly, a mother with blood group 0 becomes sensitized to foetal A or B antigens producing similar prenatal homolysis. Occasionally haemolysis may be caused by congential erythrocyte abnormalities such as microsperocytosis or glucose-6-phosphate dehydrogenase deficiency (Smith and Vela 1960, Doxiadis et al. 1961).

Impaired hepatic conjugation of bilirubin may result from deficient glucuronyl transferase activity. This is usually due to delayed maturation of this enzyme system, which in the neonate has only 1–2% of adult activity and increases towards adult levels after about the 3rd week of life. Activity is even more deficient in premature infants and this may be sufficient to cause icterus without associated haemolytic disease (Aidin et al. 1950, Zuelzer and Mudgett 1950). Inherited deficiency of this enzyme, as occurs in the Crigler-Najjar (1952) syndrome, can also result in kernicterus.

Certain drugs occasionally cause or exacerbate the problem and administration of vitamin K can produce haemolysis and inhibit hepatic enzyme activity (Lucey and Dolan 1959). Sulphonamides may encourage kernicterus (Silverman et al. 1956, Blanc and Johnson 1959) and compete with bilirubin for binding to plasma albumin displacing the bilirubin into tissues (O’Dell 1959). A variety of other factors can affect liver cell function in the neonate, and thus septicaemia, anoxia, and hepatitis may all aggravate the situation.

Factors other than bilirubin have been suggested to cause brain damage in kernicterus. Thus anaemia, hypoxia, hypoglycaemia, and acidosis have been claimed to predispose to brain injury resulting from bilirubin deposition (Claireaux 1950, Lucey 1964, Diamond and Schmid 1966, Lending 1966).

Although treatment has made new cases of kernicterus rare in developed countries, there remain a considerable number of affected individuals and Foley (1983) estimated over a third of cases of athetotic cerebral palsy were the result of neonatal jaundice. Haemolytic disease of the newborn was the commonest cause, but only about 20% of untreated cases developed kernicterus (Gerrard 1952). The clinical features of the acute stage and post-icteric encephalopathy are quite different.

The critical period during which kernicterus may develop probablyends about the 3rd week of life (Haymaker et al. 1961), althoughestimates as early as the 8th day have been given (Claireaux 1950). Approximately 340 μmol/L has been regarded as the maximum level to which plasma bilirubin concentration should be allowed to rise in order to prevent kernicterus. This is too high for small infants with hypoxia and other systemic abnormalities (Maisels 1972), whereas full term infants uncomplicated by anaemia, hypoxia, and other metabolic abnormalities may be able to tolerate higher levels (Schiller and Silverman 1961, Jablonski 1962, Koch 1964, Stern and Denton 1965, Wishingrad 1965).

Following birth there is usually a clear interval before onset of clinical features of kernicterus, which usually appear between the 2nd and 5th days of life (Gerrard 1952). The deeply jaundiced child frequently has anaemia, heptatosplenomegaly, and oedema, particularly of the face. Temperature regulation may be impaired and hyperpyrexia or sweating occurs in the absence of infection. The onset of neurological signs is usually gradual but can be quite abrupt, occurring within a quarter of an hour (Gerrard 1952). The infant may be abnormally quiet, inactive, and difficult to feed. Loss of primitive reflexes including sucking and Moro reflexes may occur (Larroche 1968). This is followed by restlessness, irritability, and crying, which may be high pitched and ‘cerebral’. There are bouts of rigidity during which the legs extend and the arms tend to be held with semiflexed elbows against the trunk and fingers clenched over the thumbs. Rigidity of neck and trunk muscles is characteristic and prolonged bouts of opisthotonus occur (Larroche 1968). Handling may provoke these spasms of rigidity. Athetoid movements, particularly of the arms, may occur. Abnormal firmness of muscles to palpation has been noted in some cases (Gerrard 1952). Occasionally rigidity is absent and severe generalized hypotonia occurs (Larroche 1968). Sustained conjugate depression of the eyes (‘the setting sun sign’) is common and other ocular abnormalities occur, including ‘staring’, strabismus, and jerky nystagmoid movements. Convulsions are frequent, especially in the premature, and may occur in two thirds of these patients (Gerrard 1952, Larroche 1968).

In fatal cases the end is often ushered in by irregular breathing, periods of apnoea, and cyanosis. Excessive, frothy, bloodstained, respiratory secretions may be present and reflect a terminal bleeding tendency, which can affect lungs, the brain, and other organs.

Although Claireaux (1950) reported only 5% of children survived infancy, this is unduly pessimistic. Forty-seven percent of Gerrard's (1952) patients died in the first month, another 13% died in the first 3 years of life, and most of the remaining 40% survived to adult life. These figures probably reflect something close to the natural history of kernicterus and date from a period when correction of anaemia by simple transfusion was virtually the only treatment given. As might be expected, the earlier the onset of kernicterus, the worse the prognosis.

Since the 1950s, the mainstay of prevention has been neonatal exchange blood transfusion. More recently this has been supplemented with additional measures, including phototherapy and hepatic enzyme induction by phenobarbitone. Such treatments are beyond the scope of this book and are not discussed further.

It is doubtful if kernicterus ever occurs without causing a post-icteric encephalopathy. The reverse, however, is seen and small numbers of patients develop permanent neurological sequelae following neonatal jaundice, during which the signs of kernicterus are not observed. The residual neurological damage in these cases is usually mild (Gerrard 1952).

Within 3–4 weeks of birth, the acute phase of kernicterus has settled and there follows a latent period of several months, during which the child appears normal. There may, however, be irritability, poor feeding, bouts of vomiting, and constipation. Impaired temperature regulation can be present with unexplained bouts of fever on warm days and profuse sweating in the absence of fever (Gerrard 1952). Primitive reflexes (as discussed above under ‘Dyskinetic cerebral palsy’) often show abnormal persistence, including the Moro and tonic neck responses. An ‘athetoid dance’ may be elicited. During the first year psychomotor retardation usually becomes apparent.

Although minor extensor spasms may occur during the latent period, other involuntary movements are delayed. They have been recorded as early as the 2nd month of life (Gerrard 1952) but commonly appear towards the end of the first year or in the subsequent few years. Although involvement of limbs is commonest, cephalic and axial movements also occur (Larroche 1968). They are occasionally choreic but usually athetotic (Fig. 42.7). Ballismus has been said to occur occasionally by some authors (Spiegel and Baird 1968) but is denied by others (Gerrard 1952). Fixed dystonic postures may occur. Gerrard (1952) claimed that chorea is more common in patients with mild brain damage and is more likely to follow an acute phase in which opisthotonus was absent or slight. He has also suggested that movements improve in some children as they grow up and athetosis gradually gives way to chorea. He has suggested emotional stress results in choreic movements becoming more athetotic. The validity of these observations is uncertain. Involuntary movements were noted by Gerrard (1952) in 90%, by Evans and Polani (1950) in 80%, and by Boreau et al. (1964[b]) in approximately 65% of cases.

As mentioned above, hypotonia is an early sign of post-icteric encephalopathy. In most cases, however, it is transient (Evans and Polani 1950, Gerrard 1952) and disappears as involuntary movements commence. Approximately 70% of cases are said to show hypotonia at some stage, but this has not always been clearly distinguished from impaired postural reactions causing deficient head and trunk control (Gerrard 1952). Patients in which this ‘hypotonia’ is absent tend to be the least and most severely affected (Gerrard 1952). As hypotonia disappears it may be replaced by rigidity. In the most severely affected cases marked rigidity may be present from an early age (Gerrard 1952). Many studies have failed to clearly differentiate true hypertonia and rigidity secondary to dystonic muscle spasms. Hypertonia of the ‘plastic’ type, however, may be present in some patients (Gerrard 1952). ‘Spastic quadriplegia’ has been reported among the most severely affected patients (Gerrard 1952, Malamud 1961). Plum (1965) found 50% of cases had hypertonia, increased knee jerks, or extensor plantar responses, but such signs of pyramidal tract injury were considerably more frequent in post-hypoxic athetotic cerebral palsy. Impairment of neck and trunk control is common with difficulty in head elevation, sitting, and standing. Ataxia, particularly on learning to walk, is present in virtually all cases and may be marked (Gerrard 1952). These features appear largely independent of involuntary movements resulting from damage to the vestibular nuclei or cerebellum, and changes in the flocculo-nodular lobe have been postulated to be particularly important (Gerrard 1952). Of patients who survive the first month, approximately a quarter die within the first 3 years. These patients are severely affected. The remainder survive with varying degrees of handicap. Late onset and mild acute phase is generally associated with less eventual disability (Gerrard 1952).

As with other forms of dyskinetic cerebral palsy, intelligence is difficult to assess. Foley (1983) found intelligence to be lower in athetotic cerebral palsy due to jaundice than that due to hypoxia. Only 17% of the former group had intelligence quotients over 100. While only 14% of Gerrard's (1952) patients had intelligence quotients greater than 100, in 33% they were above 80 and in 71% above 70 on at least one test battery. Thus the majority of patients should be educable, using special techniques to compensate for their disabilities. Past educational achievements have been poor as intelligence has been underestimated due to deafness, speech difficulties, physical disability, and adverse appearance.

It has been suggested that following kernicterus there is often impairment of emotional control (Gerrard 1952). Patients have difficulty in hiding their feelings and are easily delighted, excited, or upset. They may become inappropriately terrified and are easily reduced to tears. While it has been postulated this may be on the basis of hippocampal or hypothalamic damage (Gerrard 1952) it is difficult to exclude the psychological effects of severe disability and its attendant experiences.

As mentioned above, convulsions are common in the most severely affected and premature infants in the acute stage of the disease (Gerrard 1952, Larroche 1968). They are, however, very uncommon in the post-icteric phase (Evans and Polani 1950, Gerrard 1952, Perlstein 1961, Larroche 1968). This is in keeping with the emphasis on basal ganglia pathology, rather than involvement of cerebral cortex.

A variety of ocular abnormalities occur. Intermittent, brief episodes of extreme conjugate elevation or depression of the eyes may occur during the latent period and can be one of the first indications of post-icteric encephalopathy. These rolling movements subside as the other features of brain damage gradually emerge. Perlstein (1961) noted ocular manifestations in 90% of cases of post-icteric encephalopathy, Breakey (1961) in 40%, Boreau et al. (1964[a]) in 40%, and Gerrard (1952) in approximately 5%. This considerable variation in incidence may reflect examination technique. Rarely reduced visual acuity (Zimmerman and Yannet 1933) or cortical blindness (Cappel 1947) occurs. The ‘setting sun’ sign may persist from the acute phase. Impairment of conjugate eye movements is typical of post-icteric encephalopathy. In the mildest cases only saccades are affected, but with more severe involvement pursuit is also defective (Hoyt et al. 1978). Upgaze is most commonly disturbed, but with greater damage downgaze may be affected as well. Sometimes all vertical movement is absent. Occasionally impairment of downgaze may occur with normal upgaze (Breakey 1961, Cogan 1974). Infrequently horizontal gaze is affected and this tends to be associated with severe impairment of vertical movements (Hoyt et al. 1978). Although oculo-cephalic reflexes, caloric responses, and Bell's phenomenon are characteristically intact, confirming the problem is supranuclear, they may occasionally be impaired. Convergence and pupillary responses are usually normal (Hoyt et al. 1978).

Supranuclear paralysis of upgaze appears to result from lesions in the region of the posterior commissure (Pasik et al. 1969) and downgaze from rostral midbrain lesions ventral to the aqueduct (Jacobs et al. 1973, Cogan 1974). It has been suggested that periaqueductal damage is responsible for defects of conjugate vertical gaze in post-icteric encephalopathy (Hoyt et al. 1978). Other ocular abnormalities include strabismus and grossly disorganized ocular movements.

Approximately 80% of patients have some degree of perceptive deafness (Gerrard 1952, Foley 1983). This is usually symmetrical, affecting particularly higher frequencies. This has been attributed to damage to cochlear nuclei, but lesions occur at other levels in the auditory pathways, including geniculate bodies, and these changes may be relevant in some cases (Hardy 1961). Difficulties with language comprehension may be disproportionately severe and some cases may show an element of receptive dysphasia.

Speech difficulties are present in virtually all cases and are similar to those outlined above under ‘Dyskinetic cerebral palsy’.

In rare instances myelopathy with destruction of anterior horn cells and posterior columns has produced weakness, wasting, and areflexia (Dechamps and van Bogaert 1948). Non-neurological signs include greenish discolouration and enamel hypoplasia of the first set of teeth. In severely affected cases physical development may be abnormal with reduced stature and weight.

These have already been covered above under ‘Dyskinetic cerebral palsy’.

This has already been dealt with above under ‘Dyskinetic cerebral palsy’.