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Etiology of the Congenital Cerebral Motor Disorders
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Motor abnormalities that have had their onset early in life are numerous and diverse in their clinical manifestations. Marked prematurity is an associated factor in a large proportion of cases. Each year, approximately 50,000 infants weighing less than 1,500 g are born in the United States; approximately 85 percent survive. Of these, 5 to 15 percent have a motor disorder of cerebral origin and 25 to 30 percent are found to be mentally impaired at school age (Volpe, 1995; also Hack et al). It is helpful to categorize a given case according to the extent and nature of the motor abnormality. A careful history of prenatal, perinatal, or postnatal insults to the developing nervous system must be sought; certain correlations of these factors with the resulting pattern of neurologic deficit are outlined below. Most patients with these motor abnormalities reach adult years. Many but not all have epilepsy in addition to the motor abnormalities and there is an unavoidable overlap in considering the causes and mechanisms of these three clinical states.
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The following discussion is given from the perspective of the three major etiologic syndromes: matrix hemorrhages in the immature infant, hypoxic-ischemic encephalopathy, and certain other developmental motor abnormalities including those due to intrauterine stroke.
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Germinal Matrix (Subependymal) Hemorrhage in Premature Infants
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In low-weight and premature immature infants (20 to 35 weeks' gestational age), there sometimes occurs, within a few days after birth, a catastrophic decline in cerebral function, usually preceded by respiratory distress (hyaline membrane disease) with spells of cyanosis and apnea. Also evident are deficiencies of brainstem automatisms (sucking and swallowing), bulging of the fontanels, and sanguineous CSF. If the infant becomes completely unresponsive, death usually ensues within a few days. Autopsy discloses a small lake of blood in each cerebral hemisphere (often asymmetrically distributed), occupying the highly cellular (subependymal) germinal matrix zone, near the caudate nucleus at the level of the foramen of Monro. This region is supplied by the lenticulostriate, choroidal, and Heubner recurrent arteries and is drained by deep veins, which enter the vein of Galen. In approximately 25 percent of cases, the blood remains loculated in the matrix zone, while in the majority it ruptures into the lateral ventricle or adjacent brain tissue. In a series of 914 consecutive autopsies in newborns, subependymal hemorrhage was found in 284 (31 percent); practically all of these neonates were of low birth weight, according to Banker and Bruce-Gregorios.
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Lesser degrees of this cerebral hemorrhage are now being identified by ultrasonography (Fig. 38-14) and CT scans, and it is apparent that many infants with smaller hemorrhages survive. Some rapidly develop an obstructive hydrocephalus and require a ventricular shunt. In others, the hydrocephalus stabilizes and there is clinical improvement. Several series of surviving cases have now been followed for many years. Those in whom the hemorrhage was more extensive are often left with motor and intellectual handicaps.
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Viewed from the perspective of cerebral palsy, just over half of the patients in the Swedish series of Hagberg and Hagberg with spastic diplegia had matrix hemorrhages, leukomalacia (see further on), or both. Congenital hemiplegia or quadriplegia was observed at a lower frequency. In another series of 20 cases of posthemorrhagic hydro-cephalus (Chaplin et al), 40 percent had significant motor deficits and more than 60 percent had IQ scores of less than 85. In an experience with 12 less severely affected surviving cases (mean birth weight 1.8 kg and gestational age of 32.3 weeks), R.D. Adams noted that only 1 had a residual spastic diplegia and 9 had IQs in the low-normal or normal range (personal communication).
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The cause of matrix hemorrhage is not entirely clear. In all probability it is related to greatly increased pressure in the thin-walled veins of the germinal matrix coupled with a lack of adequate supporting tissue in these zones. During periods of unstable arterial or venous blood pressure that occur with the pulmonary disorders of immature infants, these thin-walled vessels rupture. These infants are also prone to the development of another characteristic lesion of the cerebral white matter (periventricular leukomalacia; see below), and the neurologic deficits resulting from these two lesions may be additive.
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Control of the respiratory distress of prematurity may reduce the incidence of matrix hemorrhages and periventricular leukomalacia. Claims have been made that the administration of indomethacin ethamsylate, a drug that reduces capillary bleeding, and the intramuscular injection of vitamin E for the first 3 days after birth and possibly the use of betamethasone or other corticosteroids appears to be of value in reducing the incidence of periventricular hemorrhage (Benson et al; Sinha et al; see also Volpe [1989] for discussion of control of cerebral hemodynamics and effects of medications in the neonatal period). Acetazolamide and furosemide, which reduce the formation of spinal fluid, have been widely used in the treatment of posthemorrhagic hydrocephalus. However, in a large-scale controlled study, the effects were negligible and shunt placement was required to control worsening hydrocephalus (see International PHVD Drug Trial Group in the references).
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Periventricular Leukomalacia
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These are zones of necrosis of white matter in the deep territories of cortical and central arteries. They lie lateral and posterolateral to the lateral ventricles, in a position to involve the occipital radiations and the sensorimotor fibers in the corona radiata (first described by Banker and Larroche; see also Shuman and Selednik). The white matter lesions occur in about one-third of cases of subependymal hemorrhage as mentioned, but they may develop independently in both premature and full-term infants who have suffered hypotension and apnea. In a study of 753 preterm infants, those born at 28 weeks' gestation or less were at highest risk of this complication; the combination of intrauterine infection and premature rupture of membranes carried a 22 percent risk (Zupan et al). Survivors often manifest cerebral hemiplegia or diplegia and variable degrees of mental impairment. The motor disorder is usually more severe than the cognitive and language impairment. Increasingly, small lesions of this nature are being identified in term infants by cerebral imaging including ultrasound.
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The mechanism of this type of periventricular infarction has been debated, and the terminology and clinical features, insofar as they overlap with germinal matrix hemorrhage, have been confusing. In recent years, most theories and experimental evidence converge on the notion that these represent regions of venous ischemia and infarction.
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Hypoxic-Ischemic Damage and Neonatal Encephalopathy
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It has been estimated that in the range of 1 to 6 of every 1,000 live births manifests a neonatal encephalopathy (as quoted in the review by Ferriero). The seriousness of the condition is further emphasized by the associated mortality rate of 20 percent in the newborn period and the 25 percent rate of neurodevelopmental disability in survivors. Little's conception of the hypoxic-ischemic form of "birth injury," enunciated in 1862, has been reconsidered over the years. Although it is evident that many newborns suffer some degree of perinatal asphyxia, relatively few seem to manifest brain damage. Moreover, many, if not most, infants with a variety of cerebral motor syndromes appear to have passed the parturitional (perinatal) period without mishap, indicating the greater importance of other prenatal and postnatal causative factors. Nonetheless, severe neonatal asphyxia of term or preterm babies can be an important cause of spastic, dystonic and ataxic syndromes, often accompanied by seizures and mental delay in development.
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This field has been sullied by an unprecedented rise in malpractice litigation, spawned in part by the belief that early detection of asphyxia and rapid delivery would have prevented the motor, epileptic, and cognitive problems of birth injury. The fallacy of this assumption is highlighted both by the below comments and by the observation that the incidence of cerebral palsy has not changed in term infants over the past 30 years, despite the institution of fetal monitoring and more frequent cesarean sections.
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One has the impression that the brain tolerates hypoxia and reduced blood flow in the immediate postnatal period better than at any other time in life. Indeed, animal experimentation supports this view. Not until the arterial oxygen tension is reduced dramatically to 10 to 15 percent of normal does brain damage occur, and even then the impaired function of other organs contributes to the damage. It is probably correct to think of the encephalopathy in terms of both hypoxia and ischemia, both of which usually occur in utero and are expressed postnatally by recognizable clinical syndromes.
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Fenichel (1990), following the original work of Sarnat and Sarnat and of Levene and colleagues, has found it helpful to divide the encephalopathies that follow a complicated birth into three purely descriptive groups according to their severity, each having a prognostic value beyond that of the Apgar score: (1) In newborns with mild hypoxic-ischemic encephalopathy, the symptoms are maximal in the first 24 h and take the form of hyperalertness and tremulousness of the limbs and jaw (the "jittery baby") and a low threshold of the Moro reaction. The tone of the limbs is normal except for a mild increase in head lag during traction. The reflexes are brisk and there may be ankle clonus. The anterior fontanel is soft. The EEG is normal. Recovery is usually complete and the risk of handicap is low. (2) Newborns with moderate hypoxic-ischemic encephalopathy are lethargic, obtunded, and hypotonic, with normal movements. After 48 to 72 h, the neonate may improve (having passed through a jittery hyperactive phase) or worsen, becoming less responsive in association with convulsions, cerebral edema, hyponatremia, and hyperammonemia from liver damage. The EEG is abnormal. Fenichel associates epileptiform activity and voltage suppression with an unfavorable outcome. Abnormal visual and auditory evoked potentials are other poor prognostic signs. (3) In neonates with severe hypoxic-ischemic encephalopathy, stupor or coma is present from birth; respirations are irregular, requiring mechanical ventilation. There are usually convulsions within the first 12 h. The limbs are hypotonic and motionless even during attempts to elicit the Moro response. Sucking and swallowing are depressed or absent, but pupillary reactions and eye movements may at first be retained, only to be lost as the coma deepens.
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It is in the second and third categories, that is, the states of moderate to severe encephalopathy, where correction of the respiratory insufficiency and the metabolic abnormalities permits survival, that a number of motor abnormalities (corticospinal, extrapyramidal, and cerebellar) and developmental delay eventually emerge. Included in the category of severe hypoxic-ischemic encephalopathy are also newborns with a variety of developmental anomalies of the brain and other organs. However, clouding the issue of causality is the absence of perinatal complications in a large number of children with cerebral palsy and the large number of normal babies who are born after complicated deliveries. Notably, only a few cases result from often blamed intrapartum factors such as forceps delivery, breech presentation, cord prolapse, abruptio placentae, and maternal fever.
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In addition, such infants may have been exposed to certain prenatal risk factors (toxemia of pregnancy, antepartum uterine hemorrhage, maternal hypotension, and certain epidemiologic associations such as hypothyroidism or fertility treatment), or their growth may have been abnormal (small-for-date babies). Some of these babies are born at term; others are premature, and the birth process may or may not have been abnormal. One must then consider the possibility, originally pointed out by Sigmund Freud, that the abnormality of the birth process, instead of being causal, was actually the consequence of prenatal pathology. The latter might include preterm intrauterine hypoxia-ischemia.
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Other evidence of multifactorial etiology in the "causation" of cerebral palsy has been provided by Nelson and Ellenberg, who found that maternal developmental delay, birth weight below 2,000 g, and fetal malformation were among the leading predictors. Breech presentation was another factor, and one-third of these cases also had some noncerebral malformation. Twenty-one percent of the 189 children in their series had also suffered some degree of asphyxia. Additional determinants were maternal seizures, a motor deficit in an older sibling, two or more prior fetal deaths, hyperthyroidism in the mother, preeclampsia, and eclampsia. In children with cerebral diplegia born at term, likely contributory factors that were operative in nearly half included toxemia of pregnancy, low birth weight for age, placental infarction, and intrauterine asphyxia.
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The factors enumerated above are involved to different degrees in the outcome of pregnancies but are informative because they bring to light the significant proportion of cases of cerebral birth injury in which hypoxia-ischemia, matrix hemorrhages, and leukomalacia were not operative. In this group, can be included the symmetrical porencephalies and hydranencephalies.
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Thus the complexity of assigning a cause for cerebral palsy is evident. In respect to the motor disorders discussed below, hypoxic-ischemic perinatal injury is still the most commonly specified cause of neonatal encephalopathy but is often unrelated to a permanent defect of cerebral palsy. This statement has been amply confirmed by a large and often cited study from Western Australia that detected neonatal encephalopathy in 3.8 of 1,000 live term births but was able to identify causative intrapartum factors alone in only 5 percent (Badawi et al). Furthermore, only 10 percent of all the infants with neonatal encephalopathy developed spastic quadriplegia, according to Evans and colleagues.
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Imaging studies of cerebral palsy have increasingly appeared and it has even been suggested, perhaps with excessive enthusiasm, that all such children undergo scanning. Cowan and colleagues (2003) used MRI to determine the proportion of infants with a neonatal encephalopathy who had antenatal brain injury. Excluding those with major congenital malformations or obvious chromosomal abnormalities, 80 percent of cases had no established lesion or brain atrophy. In contrast, those with only seizures and no neonatal encephalopathy in 69 percent of cases had evidence of antenatal damage on MRI; infarctions because of thrombophilic disorders were most common. An MRI–clinical correlative study of children with cerebral palsy by Bax and colleagues in The European Cerebral Palsy Study came to similar conclusions but found that periventricular leukomalacia of prematurity was the most common MRI change, present in 42 percent of infants, followed in frequency by basal ganglionic damage (13 percent), cortical-subcortical lesions (9 percent), malformations (9 percent), and focal infarcts (7 percent). These authors found a correspondence between the clinical and MRI findings. These studies demonstrate the utility of MRI in identifying neonatal forms of encephalopathy and indicate that few are the result of obstetric accidents. Added difficulty is caused by the fact that the clinical signs of perinatal injury may emerge only when the maturational process of the nervous system exposes them at a later period of life. Woodward and coworkers suggested that the MRI pattern is predictive of developmental outcome in preterm infants, but this requires corroboration.
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Much of the resources of neonatal intensive care is devoted to sustaining oxygenation and blood pressure, and reducing hyperbilirubinemia in premature and full-term but ill infants. Techniques such as the predelivery administration of corticosteroids in premature births to promote lung maturity, attempting to bring early births to 34 to 36 weeks' gestation, and the treatment of maternal infection have all contributed to improved outcomes in children.
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The avoidance of the ostensible causes of cerebral palsy has been discussed in previous sections and endlessly in the medical literature. None of the usually assigned causes of birth injury, particularly perinatal hypoxia-ischemia, explains most cases. In addition, several trials have investigated the effects of induced hypothermia for severe neonatal encephalopathy from hypoxia but have given mixed results. Attempts to ameliorate brain injury by the use of hypothermia, a technique that has met with success in adult cardiac arrest, have given conflicting results. A randomized trial by Shankaran and colleagues using systemic hypothermia administered to infants with neonatal encephalopathy or a need for resuscitation showed a reduction in death or moderate to severe disability from 62 to 44 percent and a small benefit in IQ at age 7 that was not statistically significant. Hypothermia was applied soon after birth, at a mean of about 4 hours. The effects were seen mostly among infants with only moderate and not severe encephalopathy and none of the measures of mental and psychomotor disability was improved by cooling. Previous trials, such as the one reported by Azzopardi and colleagues, had shown no difference in outcomes but used different techniques, mainly selective cerebral cooling. Cooling appears promising but requires further study, and at the time of this writing, has not been widely adopted. It is also unclear if the short-term followup will be reflected at school age and beyond.
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Clinical Syndromes of Congenital Spastic Motor Disorders
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The most frequent motor disorder evolving from the four major categories of neonatal cerebral disease—matrix hemorrhage, periventricular leukomalacia, hypoxic-ischemic encephalopathy, kernicterus (discussed further on)—is spastic diplegia; that is, a motor disturbance that is severe in the lower limbs and mild in the upper, as discussed below. In addition, hypoxic-ischemic injury occurring in the term or preterm infant may take the form of a hemiplegia, double hemiplegia (quadriplegia), or a mixed pyramidal–extrapyramidal or spastic–ataxic syndrome.
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A second form of motor disorder is characterized by the development of severe spastic quadriplegia and developmental delay. The major insult is usually intrapartum asphyxia and attendant fetal distress. Usually such infants will have required resuscitation and will have had low 5-min Apgar scores and seizures, which have important predictive value in this circumstance. The pathologic lesions of the brain in this second group consist of hypoxic-ischemic infarction in distal fields of arterial flow, primarily in the cortex and white matter of parietal and posterior frontal lobes, leaving a ulegyric sclerotic cortex.
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A third group, discussed below, is characterized mainly by extrapyramidal abnormalities, combining athetosis, dystonia, and ataxia in various proportions. After reviewing the results of several large series of congenital and neonatal motor disorders, we have concluded that spastic diplegia occurs in 10 to 33 percent of cases, spastic quadriplegia in 19 to 43 percent, extrapyramidal forms in 10 to 22 percent, and mixed forms in 9 to 20 percent.
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Spastic Diplegia ("Little Disease")
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The pattern of paralysis is more variable than the term spastic diplegia implies; actually, several subtypes may be distinguished: paraplegic, diplegic, quadriplegic, pseudobulbar, and generalized. Pure paraplegic and pseudobulbar types are relatively rare. The eponymic "Little disease" has been applied mainly to the spastic diplegic type, but it also has been attached to all forms of motor cerebral palsy in some older writings.
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Usually all four extremities are affected, but the legs much more than the arms, which is the real meaning of diplegia. Hypotonia—with retained tendon reflexes and hypoactivity—is usually present initially. Only after the first few months will evident weakness and spasticity appear, first in the adductors of the legs. The plantar reflexes, which often take on ambiguous direction in the normal infant, here are clearly extensor, a finding that is pathologic at any later age. Also, stiff, awkward movements of the legs, which are maintained in an extended, adducted posture when the infant is lifted by the axillae, often do not attract attention until several weeks or months have passed. Seizures occur in approximately one-third of the cases, and it is not uncommon to observe a delay in all developmental sequences, especially those that depend on the motor system.
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Once walking is attempted, usually at a much later date than usual, the characteristic stance and gait become manifest. The slightly flexed legs are advanced stiffly in short steps, each describing part of an arc of a circle; adduction of the thighs is often so strong that the legs may actually cross (scissors gait); the feet are flexed and turned in with the heels not touching the floor. In the adolescent and adult, the legs tend to be short and small, but the muscles are not markedly atrophic, as they are in spinal muscular atrophy. Passive manipulation of the limbs reveals spasticity in the extensors and adductors and slight shortening of the calf muscles. The arms may be affected only slightly or not at all, but there may be awkwardness and stiffness of the fingers and, in a few, pronounced weakness and spasticity. In reaching for an object, the hand may overpronate and a grasp may be difficult to release. Speech may be well articulated or noticeably slurred, and in some instances the face is set in a spastic smile. Scoliosis is frequent and may secondarily give rise to root compression and impaired respiratory function. As a rule, there is no disturbance of sphincteric function, although delay in acquiring voluntary bowel and bladder control is usual. Athetotic postures and movements of the face, tongue, and hands are present in some patients and may actually conceal the spastic weakness.
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One subtype of spastic diplegia is associated with a relatively slight diminution in head size and of intelligence. As indicated above, there is no unifying neuropathology; the condition occurs independently of matrix hemorrhages and periventricular leukomalacia as well as with them. The frequency of cerebral spastic diplegia, which is closely related to the degree of prematurity, has declined significantly since the introduction of neonatal intensive care facilities, and there is reason to believe that genetic factors are of more importance.
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Infantile Hemiplegia and Quadriplegia
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Hemiplegia is a common condition of infancy and early childhood. The functional difference between the two sides may be noticed soon after birth, but more often it is not perceived by the mother until after the first 4 to 6 months of life. In a second group, the child is in excellent health for a year or longer before the abrupt onset of hemiplegia (see below). In hemiplegia that dates from earliest infancy—that is, congenital hemiplegia—the parents first notice that movements of prehension and exploration are carried out with only one arm. A manifest hand preference at an early age should always raise the suspicion of a unilateral motor defect. The affection of the leg is usually recognized later, that is, during the first attempts to stand and walk. Sitting and walking are usually delayed by a few months. In the older child, there is evident hyperactivity of tendon reflexes and usually a Babinski sign. The arm is held flexed, adducted, and pronated, and the foot assumes an equinovarus posture. Sensory and visual field defects can be detected in some patients. A mental slowness may be associated with infantile hemiplegia but is less common and lesser in degree than with cerebral diplegia. There may also be speech delay, regardless of the side of the lesion; when this is present, there is usually developmental delay and bilaterality of motor abnormality. Convulsions occur in 35 to 50 percent of children with congenital hemiplegia, and these may persist throughout life. They may be generalized but are frequently unilateral and limited to the hemiplegic side (or the contralateral side if the hemiplegia is severe). After a series of seizures, the weakness on the affected side will be increased for several hours or longer (Todd paralysis). Gastaut and associates have described a hemiconvulsive–hemiplegic syndrome in which progressive paralysis and cerebral atrophy are attributed to the convulsions. As months and years pass, the osseous and muscular growth of the hemiplegic limbs is impeded, leading to an obvious hemiatrophy of the body.
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With respect to the causation of congenital hemiplegia, it is generally agreed that perinatal asphyxia is only one of the possibilities. In the series of 681 children with "cerebral palsy" collected by Hagberg and Hagberg, there were 244 with hemiplegia of whom 189 were full-term babies and 55 were preterm. Prenatal risk factors were identified in only 45 percent, and mostly in the infants born prematurely. In nearly half of the cases, there was no clue as to the time in the intrauterine period when the cerebral lesion occurred.
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In another group—acquired infantile hemiplegia—a normal infant or young child, usually between the ages of 3 and 18 months, develops a massive hemiplegia, with or without aphasia, within hours. The disorder often begins with seizures, and the hemiplegia may not be recognized until the seizures have subsided. In Banker's series of autopsy cases, there was arterial or venous thrombosis in some cases, but instances without vascular occlusions were found. Some of the latter cases, in which arteriography had been normal, may have been embolic, possibly of cardiac origin. In the recent era, imaging has shown a large area of cerebral infarction, consistent with a stroke in the territory of the middle cerebral artery (Fig. 38-15). If the stroke occurs at an early age, the recovery of speech may be complete, though reduced scholastic capacity remains. The degree of recovery of motor function varies. Often, as the deficit recedes, the arm becomes involved by athetotic, tremulous, or ataxic movements; there may be an interval of months or years between the hemiplegia and the athetosis.
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Destructive lesions underlie most of the cases of infantile hemiplegia and some cases of bilateral hemiplegia (as well as many cases of seizures in the first few days of life). The pathologic change is essentially that of ischemic necrosis. In many cases, the lesions must have been acquired in utero. Precipitant delivery, fetal distress, and prepartum uterine hemorrhage may have been indications, more so than causes, of the process. What is most notable is that the ischemia tends to affect the tissues lying in arterial cortical border zones; there may also be venous stasis with congestion and hemorrhage occurring particularly in the deep central structures such as the basal ganglia and periventricular matrix zones. If they are purely hypoxic, the lesions should be bilateral. Myers has reproduced such lesions in the neonatal monkey by reducing the maternal circulation for several hours. As the lesions heal, the monkeys develop the same gliotic changes in the cortex and white matter of the cerebrum (lobar sclerosis) and the "marbling" (état marbré) that characterizes the brains of patients with spastic diplegia and double athetosis (see below).
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The quadriplegic state differs from bilateral hemiplegias in that the bulbar musculature is often involved in the latter and developmental delay is more severe. The condition is relatively rare and is usually a result of a bilateral cerebral lesion. However, one should also be alert to the possibility of a high cervical cord lesion. In the infant, this is usually the result of a fracture dislocation of the cervical spine incurred during a difficult breech delivery. Similarly, in paraplegia, with weakness or paralysis limited to the legs, the lesion may be either a cerebral or a spinal one. Sphincteric disturbances and a loss of somatic sensation below a certain level on the trunk always point to a spinal localization. Congenital cysts, tumors, and diastematomyelia are more frequently causes of paraplegia than of quadriplegia. Another recognized cause of infantile paraplegia is spinal cord infarction from thrombotic complications of umbilical artery catheterization.
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Extrapyramidal Syndromes
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The spastic cerebral diplegias discussed above shade almost imperceptibly into the congenital extrapyramidal syndromes. These children are found in every cerebral palsy clinic, and, ultimately, they reach adult neurology clinics. Corticospinal tract signs may be absent and the student, familiar only with the syndrome of pure spastic diplegia, is always puzzled as to their classification. Some cases of extrapyramidal type are undoubtedly attributable to severe perinatal hypoxia and others to diseases such as erythroblastosis fetalis with kernicterus. To state the probable pathologic basis and future course of these illnesses, it is useful to separate the extrapyramidal syndromes of prenatal-natal origin (which usually become manifest during the first year of life) from the acquired or hereditary postnatal syndromes, such as familial athetosis, Wilson disease, dystonia musculorum deformans, and the hereditary cerebellar ataxias, which become manifest later.
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This is probably the most frequent of the congenital extrapyramidal disorders. Two types stand out—one that is caused by hyperbilirubinemia or Rh incompatibility (kernicterus; see below) and hypoxic-ischemic encephalopathy. With control of neonatal hyperbilirubinemia (by use of anti-Rh immune globulin, exchange transfusions, and phototherapy), kernicterus has almost disappeared, whereas the severe hypoxic-ischemic form regularly continues to be seen. Rarely, a congenital, nonhemolytic icterus or a glucose-6-phosphate dehydrogenase deficiency produces the same syndrome.
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Like the spastic states, double athetosis may not be recognized at birth but only after several months or a year has elapsed. In some cases, the appearance of choreoathetosis is for unexplained reasons delayed for several years; it may seem to progress during adolescence and even early adult life. It must then be differentiated from some of the inherited metabolic and degenerative extrapyramidal diseases. Chorea and athetosis dominate the clinical picture, but bewildering combinations of involuntary movements—including dystonia, ataxic tremor, myoclonus, and even hemiballismus—may be found in a single case. At times, we have been unable to classify the movement disorder because of its complexity. It should be noted that practically all instances of double athetosis are also associated with a defect in voluntary movement.
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Choreoathetosis in infants and children varies greatly in severity. In some, the abnormal movements are so mild as to be misinterpreted as restlessness or "the fidgets"; in others, every attempted voluntary act provokes violent involuntary spasms, leaving the patient nearly helpless. The clinical features of choreoathetosis and other involuntary movements are discussed in Chap. 4.
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Early hypotonia, followed by delayed motor development, is the rule in these cases. Erect posture and walking may not occur until the age of 3 to 5 years and may never be attained in some patients. Tonic neck reflexes or fragments thereof tend to persist well beyond their usual time of disappearance. The plantar reflexes are usually flexor, although they may be difficult to interpret because of the continuous flexion and extension of the toes. Sensory abnormalities are not found. Because of the motor and speech impairment, patients are often erroneously thought to be mentally slow. In some, this conclusion is doubtless correct, but intellectual function is adequate in many others.
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A variety of rehabilitative measures have been tried: physiotherapy, surgery, sensory integrative therapy, progressive patterned movement, and various undocumented forms of neuromuscular facilitation. We agree with Hur, who has critically reviewed this subject, that properly controlled studies provide no proof of the success of any of them. Surely, with growth and development, new postures and motor capacities are acquired. The less-severely affected patients make successful occupational adjustments. The more-severely affected children rarely achieve a degree of motor control that permits them to live independently. One sees some of these unfortunate persons bobbing and twisting laboriously as they make their way in public places.
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Imaging studies are seldom of diagnostic value. Mild cerebral atrophy and loss of volume of the basal ganglia are seen in some cases, and cavitary lesions are present in some of the severe anoxic encephalopathies. The EEG is rarely helpful unless there are seizures.
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The most frequent pathologic finding in the brain has been a whitish, marble-like appearance of the putamen, thalamus, and border zones of the cerebral cortex. These whitish strands represent foci of nerve cell loss and gliosis with condensation of bands of transversing myelinated fibers—so-called status marmoratus (état marbré). This lesion does not develop if the insult occurs after infancy, that is, after myelination has completed its early developmental cycle.
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This is now a rare cause of extrapyramidal motor disorder in children and adults. Such cases are the neurologic sequelae of erythroblastosis fetalis secondary to Rh and ABO blood incompatibilities or to a deficiency of the hepatic enzyme glucuronosyltransferase. The symptoms of kernicterus appear in the jaundiced neonate on the second or third postnatal day. The infant becomes listless, sucks poorly, develops respiratory difficulties as well as opisthotonos (head retraction), and becomes stuporous as jaundice intensifies. The serum bilirubin is usually greater than 25 mg/dL. In acidotic and hypoxic infants (e.g., those with low birth weight and hyaline membrane disease), the kernicteric lesions develop with much lower levels of serum bilirubin.
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A proportion of infants with this disease die within the first week or two of life. Many of those who survive are developmentally delayed, deaf, hypotonic, and totally unable to sit, stand, or walk. There are exceptional patients, however, who are mentally normal or at most only slightly limited. They develop a variety of persistent neurologic sequelae—choreoathetosis, dystonia, and rigidity of the limbs—a picture not too different from that of cerebral spastic diplegia with involuntary movements. Kernicterus should always be suspected if an extrapyramidal syndrome is accompanied by bilateral deafness and paralysis of upward gaze. Later, in childhood there may be a greenish pigmentation of the dental enamel.
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Neonates who die in the acute postnatal stage of kernicterus show a unique yellow staining (icterus) of nuclear masses at one time was called the "Kern nuclei" and gave the disease its name in the basal ganglia, brainstem, and cerebellum. In those surviving this postnatal insult, the pathologic changes consist of a symmetrically distributed nerve cell loss and gliosis in the subthalamic nucleus, the globus pallidus, the thalamus, and the oculomotor and cochlear nuclei; these lesions are the result of the hyperbilirubinemia. In more than 30 cases examined by R.D. Adams, the immature cerebral cortex including the hippocampus was spared. In the newborn, unconjugated bilirubin can pass through the poorly developed blood–brain barrier into these nuclei, where it is assumed to be directly toxic. Acidosis and hypoxia exacerbate the effect. Also in the newborn, the development of hyperbilirubinemia is enhanced by a transient deficiency of the enzyme glucuronosyltransferase, essential for the conjugation of bilirubin. Hereditary hyperbilirubinemia, caused by lack of this enzyme (Crigler-Najjar syndrome), may exhibit the same effects on the nervous system at a later period of infancy or childhood as hyperbilirubinemia because of Rh incompatibility.
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Immunization, phototherapy, and exchange transfusions designed to prevent high levels of unconjugated serum bilirubin have been shown to protect the nervous system from the toxic effects of erythroblastosis fetalis. If the blood bilirubin level can be held to less than 20 mg/dL (10 mg/dL in premature infants), the nervous system may escape perinatal damage. The effective use of these measures has practically eradicated this disease.
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Both kernicterus and ischemic état marbré must be differentiated clinically from hereditary choreoathetosis, the Lesch-Nyhan syndrome, and—later in life, from ataxia-telangiectasia and Friedreich ataxia.
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Congenital and Neonatal Ataxias
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In these patients, difficulty in standing and walking cannot be attributed to spasticity or paralysis. Hypotonia and poverty of movement are the initial motor abnormalities—as they are in athetoid cerebral palsy. The cerebellar deficit becomes manifest only later when the patient begins to sit, stand, and walk. There may or may not be a delay in reaching the normal motor milestones. Attempts to attain sitting balance early on reveal an unsteadiness that is not soon overcome, even with practice. Reaching for a proffered toy is accomplished by jerky, incoordinated movements. The first steps are unsteady, as would be expected, with many tumbles, but the gait remains clumsy. Instability of the trunk may be accompanied by similar, more or less rhythmic bobbing movements of the head—titubation. Despite the severity of the ataxia, the muscles are of normal size, and voluntary movements, although weak in some patients, are possible in all the limbs. The tendon reflexes are present, and the plantar reflexes are either flexor or extensor. In some cases, the ataxia is later associated with spasticity rather than hypotonia (spastic-ataxic diplegia). Relative improvement may occur in later years. In the older child, a cerebellar gait, ataxia of limb movements, nystagmus, and uneven articulation of words are readily distinguished from myoclonus, chorea, athetosis, dystonia, and tremor.
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In only a few cases have the pathologic changes been studied. Aplasia or hypoplasia of the cerebellum has been observed, but sclerotic lesions of the cerebellum are more common. The CT scan or MRI verifies the cerebellar atrophy. However, in a few cases of a cerebellar-like tremor in adults under our care that had been attributed to neonatal injury the MRI did not show cerebellar atrophy. A cerebral and cerebellar lesion may coexist in patients with congenital ataxia, which is the reason for the term cerebrocerebellar diplegia.
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Several risk factors have been identified in the congenital ataxias. Most importantly, cerebellar ataxia may be the most prominent or sole effect of neonatal ischemia-hypoxia. A genetic factor is operative in some cases (Hagberg and Hagberg). Mercury poisoning in utero is another cause of congenital ataxia. The many cases that are not the result of a degenerative condition, some of which are described just below, remain unexplained in our experience.
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Pontocerebellar Hypoplasias and Joubert Syndrome
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Aside from the congenital ataxia described above, there are several rare familial forms in which a failure of cerebellar development is associated with developmental delay. What has now come to be called Joubert syndrome was reported in a family in which the central feature is dysgenesis of the vermis; developmental delay; episodic hyperpnea; irregular, jerky eye movements; and unsteady gait in 4 of 6 siblings. In other reports, choroidal-retinal colobomas, polydactyly, cryptorchidism, and prognathism have been mentioned. Detailed examination of the cerebra of such individuals has been lacking but the MRI has a characteristic configuration of a "molar tooth sign" that reflects a deep invagination caused by vermian hypoplasia with a narrow cleft separating the cerebellar hemispheres and thickening of the superior cerebellar peduncles. Several genetic loci have been implicated, most acting as recessive traits.
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In the Gillespie syndrome, a combination of aniridia, cerebellar ataxia, and developmental delay is the denominating feature. In the Paine syndrome, a familial disorder with developmental delay and developmental delay, there is microcephaly, spasticity, optic hypoplasia, and myoclonic ataxia, the last presumably related to the cerebellar hypoplasia. These dysgeneses and the disequilibrium syndrome reported from Sweden are unified by the cerebellar ataxia; in the past, they were categorized as ataxic cerebral palsies. Imaging studies demonstrate the cerebellocerebral abnormality. Genetic factors are operative in some, but matters pertaining to etiology remain obscure (see the older monograph by Harding for details). One form of a pure nonprogressive congenital cerebellar hypoplasia has been mapped to a gene locus on chromosome Xq; it does not appear to be related to the fragile X syndrome, which may cause ataxia and tremor in adults as noted further on.
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Differential Diagnosis of the Congenital Ataxias
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The congenital ataxias must be distinguished from the progressive hereditary ataxias. The latter are likely to begin at a later age than the congenital ones. Some hereditary ataxias are intermittent or episodic, one of which is responsive to acetazolamide and is the result of an abnormality of the calcium channel as discussed in Chaps. 5 and 37.
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Also to be distinguished from the ataxias of congenital and neonatal origin is an acute cerebellar ataxia of childhood, which can usually be traced to a viral infection or postinfectious encephalitis, particularly after chickenpox. The opsoclonus-myoclonus ("dancing eyes") syndrome of Kinsbourne is another postinfectious disease peculiar to childhood (see Chaps. 14 and 39). The cerebellar ataxia in this disease may be overshadowed by polymyoclonus, which mars every attempted movement. With improvement, under the influence of corticosteroids, a cerebellar disorder of speech and movement becomes evident. A majority of the patients in which the disease became chronic (16 of the 26 cases followed by Marshall et al) were found later to be mentally slowed. The cause of the disease has never been established. An occult neuroblastoma or other tumor is uncovered occasionally. In the differential diagnosis of these acute forms of cerebellar ataxia, one must not overlook intoxication with phenytoin, barbiturates, or similar drugs.
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The Flaccid Paralyses and the "Floppy Infant" (Table 38-7; See also Chaps. 39 and 48)
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The rare cerebral form of generalized flaccidity, first described by Foerster and called cerebral atonic diplegia, has already been alluded to in the discussion of cerebral palsy. It can usually be distinguished from the paralysis of spinal and peripheral nerve origin and congenital muscular dystrophy by the retention of postural reflexes (flexion of the legs at the knees and hips when the infant is lifted by the axillae), preservation of tendon reflexes, and coincident failure of mental development. The Prader-Willi syndrome, discussed earlier in the chapter, also presents at first as a generalized hypotonia.
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The syndrome of infantile spinal muscular atrophy (Werdnig-Hoffmann disease) is the leading example of flaccid paralysis of lower motor neuron type. Perceptive mothers may be aware of a paucity of fetal movements in utero; in most cases the motor defect becomes evident soon after birth or the infant is born with arthrogrypotic deformities. Several other types of familial progressive muscular atrophies have been described in which the onset is in early or late childhood, adolescence, or early adult life. Weakness, atrophy, and reflex loss without sensory change are the main features and are discussed in detail in Chap. 39. A few patients suspected of having infantile or childhood muscular atrophy prove, with the passage of time, to be merely inactive "slack" children, whose motor development has proceeded at a slower rate than normal. Others may remain weak throughout life, with thin musculature. These and several other congenital myopathies—central core, rod-body, nemaline, mitochondrial, myotubular, and fiber-type disproportion and predominance—are described in Chap. 52. Unlike Werdnig-Hoffmann disease, the effects of many of them tend to diminish as the natural growth of muscle proceeds. Rarely, polymyositis and acute idiopathic polyneuritis manifest themselves as a syndrome of congenital hypotonia.
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Infantile muscular dystrophy and lipid and glycogen storage diseases may also produce a clinical picture of progressive atrophy and weakness of muscles. The diagnosis of glycogen storage disease (usually the Pompe form) should be suspected when progressive muscular atrophy is associated with enlargement of the tongue, heart, liver, or spleen. The motor disturbance in this condition may be related in some way to the abnormal deposits of glycogen in skeletal muscles, although it is more likely the result of degeneration of anterior horn cells that are also distended with glycogen and other substances. Certain forms of muscular dystrophy (myotonic dystrophy and several types of congenital dystrophy) may also be evident at birth or soon thereafter. The latter may have led to arthrogryposis and clubfoot (see Chap. 52 for an extensive discussion of the congenital neuromuscular disorders).
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Brachial plexus palsies, well-known complications of dystocia, usually result from forcible extraction of the fetus by traction on the shoulder in a breech presentation or from traction and tipping of the head in a shoulder presentation. The effects of such injuries are sometimes lifelong. Their neonatal onset is betrayed later by the small size and inadequate osseous development of the affected limb. Either the upper brachial plexus (fifth and sixth cervical roots) or the lower brachial plexus (seventh and eighth cervical and first thoracic roots) suffer the brunt of the injury. Upper plexus injuries (Erb palsy) are about 20 times more frequent than lower ones (Klumpke palsy). Sometimes the entire plexus is involved. Further details are found in Chap. 46.
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Facial paralysis, because of forceps injury to the facial nerve immediately distal to its exit from the stylomastoid foramen, is another common (usually unilateral) peripheral nerve affection in the newborn. Failure of one eye to close and difficulty in sucking make this condition easy to recognize. It must be distinguished from the congenital facial diplegia that is often associated with abducens palsy, that is, the Möbius syndrome discussed earlier in the chapter. In most cases of facial paralysis caused by physical injury, function is recovered after a few weeks; in some, the paralysis is permanent and may account for lifelong facial asymmetry.
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Once the motor features of cerebral palsy have been established, assistive devices, stretching therapy, and conventional orthopedic measures for joint stabilization and relief of spasticity are all useful. Injection of botulinum toxin for the relief of spasticity has gained wide favor and is now used early in the child's life to preempt deformities. Most published trials have been too small, however, to allow firm conclusions to be drawn about the durability of this treatment. Finally, hyperbaric oxygen treatment of children with cerebral palsy was ineffective in a randomized trial conducted by Collet and colleagues, despite periodic claims to the contrary.
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In summary, it can be said that all these forms of disabling motor abnormalities rank high as important issues in neuropediatrics. In attempts at prevention, steps have been taken in most hospitals to identify and eliminate risk factors. Indeed, better prenatal care, reduction in premature births, and control of respiratory problems in critical care wards have reduced their incidence and prevalence. Physical and mental therapeutic measures appear to be helpful, but many of the methods have been difficult to evaluate in a nervous system undergoing maturation and development. The neurologist can contribute most by segregating groups of cases of identical pattern and etiology and in differentiating the congenital groups of delayed expressivity from the treatable acquired diseases of this age period. Woefully lacking are critical neuropathologic studies.