Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 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. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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, 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.


Neurology_Adams

Neurology_Adams. Differential diagnosis of the congenital ataxias 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 Chap. 5.


Neurology_Adams

Neurology_Adams. 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 cognitively impaired. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The Flaccid Paralyses and the “Floppy Infant” (Table 37-7; See Also Chaps. 38 and 45) 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.


Neurology_Adams

Neurology_Adams. 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. 38. 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,


Neurology_Adams

Neurology_Adams. 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. 45. 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.


Neurology_Adams

Neurology_Adams. 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. 45 for discussion of the congenital neuromuscular disorders).


Neurology_Adams

Neurology_Adams. 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. 43.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Once the motor features of cerebral palsy have been established, assistive devices, physical 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 of either of these approaches have been too small, however, to allow firm conclusions to be drawn about the long-term durability of treatment. In experienced hands, selective and partial section of dorsal spinal roots has had a beneficial effect on regional spasticity. 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.


Neurology_Adams

Neurology_Adams. 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 has 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.


Neurology_Adams

Neurology_Adams. Throughout the intrauterine period the embryo and fetus are subject to particular infections. Because the infective agent must reach the fetus through the placenta, it is evident that the permeability of the latter at different stages of gestation and the immune status of the maternal organism are determinative. We include a discussion of these intrauterine infections here because some of them may lead to malformations or destructive lesions of the brain and, later in life, must be distinguished from developmental abnormalities.


Neurology_Adams

Neurology_Adams. Until the third to fourth month of gestation, the large microbial organisms—such as bacteria, spirochetes, protozoa, and fungi—cannot invade the embryo, even if the mother harbors the infection. Viruses, however, may do so, specifically rubella, CMV, HIV, and possibly others. The rubella virus enters embryonal tissues during the first trimester, Treponema pallidum in the fourth to fifth postconceptional months, and Toxoplasma after that period. Bacterial meningitis (except for that caused by Listeria monocytogenes, described below) is essentially a perinatal infection contracted during or immediately after parturition. Neonatal herpes simplex encephalitis, as a result of the type 2 (genital) virus, is also usually acquired by passage through an infected birth canal. Some cases of HIV infection may be acquired during delivery, but most are a result of transplacental transmission.


Neurology_Adams

Neurology_Adams. The main neonatal infections—toxoplasmosis, rubella, CMV, and herpes—have been commonly designated by the acronym TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex). With the persistence of Listeria, the rise of AIDS infections, and a marked reduction in rubella infections, the mnemonic LATCH, which includes Listeria and HIV, might be more appropriate. There has been recent interest in maternal Zika virus infection during the first trimester and microcephaly with developmental delay in infants, discussed below.


Neurology_Adams

Neurology_Adams. Infants with any of these infections share certain common features, such as low birth weight, prematurity, congenital heart disease, purpura, jaundice, anemia, microcephaly or hydrocephaly, cerebral calcifications, chorioretinitis, cataracts, microphthalmia, and pneumonitis; as a corollary, if any combination of these features is manifest, one should suspect one of these infectious agents and take measures to identify it. However, all these clinical manifestations are unlikely to be present in any one infant, and in the cases of rubella and CMV, only a small percentage of infected infants will show major systemic signs or symptoms. Nevertheless, on clinical grounds alone, certain infections can be identified and others excluded. For example, cerebral calcifications are present mainly in toxoplasmosis and CMV encephalopathy, being rare in rubella and absent in herpes simplex virus (HSV) encephalitis; the calcifications are widely disseminated in toxoplasmosis (Fig. 37-16) and have a


Neurology_Adams

Neurology_Adams. toxoplasmosis and CMV encephalopathy, being rare in rubella and absent in herpes simplex virus (HSV) encephalitis; the calcifications are widely disseminated in toxoplasmosis (Fig. 37-16) and have a periventricular distribution in CMV infection. Cardiac lesions are present only with rubella, and deafness occurs only with CMV and rubella. Thus, there are clinical signposts to guide the clinician in selecting the appropriate diagnostic tests. And importantly, in considering neonatal infections, one must also search for other, less-common infectious types (see Chaps. 31 and 32).


Neurology_Adams

Neurology_Adams. Added difficulty in the diagnosis of embryonal and fetal infections arises when the mother has been entirely asymptomatic. Isolation of the organism from fetal and neonatal tissues is possible, but usually they are inaccessible, and it may be impossible to demonstrate antibodies or other immune responses because of the early stage of the infection or limitations of the infant’s immune response.


Neurology_Adams

Neurology_Adams. Gregg, in 1941, first reported the association of maternal rubella and congenital cataracts in the neonate. His observations were quickly verified, and soon it became widely known that cataracts, deafness, congenital heart disease, and developmental delay constituted a kind of tetrad diagnostic of this disease. That a virus could affect so many tissues, causing in essence a noninflammatory developmental disorder of multiple organs, was a novel concept, and it raised the interesting prospect that other viruses might have similar effects. Surprisingly, however, only CMV and possibly HSV have been incriminated in embryonal-developmental neuropathology. A large number of other viruses (e.g., influenza, Epstein-Barr, hepatitis) have been implicated in human teratogenesis, but in none is the relationship beyond doubt.


Neurology_Adams

Neurology_Adams. It is now well established that most instances of congenital rubella infection occur in the first 10 weeks of gestation and that the earlier the infection occurs, the greater the risk to the fetus. However, there may be some risk beyond the first trimester, up to the twenty-fourth week, according to Hardy.


Neurology_Adams

Neurology_Adams. Following the experience of the massive rubella epidemics of 1964 and 1965, the congenital rubella syndrome has been expanded to include low birth weight; sensorineural deafness, sometimes unilateral (the most common complication); microphthalmia; pigmentary degeneration of the retina (salt-and-pepper chorioretinitis); glaucoma, cloudy corneas, and cataracts of special type (the latter two abnormalities usually cause visual impairment); hepatosplenomegaly, jaundice, and thrombocytopenic purpura; and patent ductus arteriosus or interventricular septal defect. There may be one, a few, or many of these abnormalities, in various combinations. The developmental delay is severe and may be accompanied by seizures and motor defects such as hemiplegia or spastic diplegia and rarely by seizures. Psychiatric symptoms, some resembling autism, are said to occur.


Neurology_Adams

Neurology_Adams. Infection of the fetus after the first trimester results in a less impressive neonatal syndrome. The infant may seem lethargic and fail to thrive. The cranium is abnormally small. Only a cardiac abnormality, deafness, or chorioretinitis may provide clues to the diagnosis. The CSF later may show an increase of mononuclear cells and an elevated protein. The infection may persist for a year or longer. Foci of calcification are rare, and CT and MRI are of little help in diagnosis. The maternal infection may be so mild that it is passed off as minor; but even when it is evident, the fetus is spared in approximately 50 percent of cases. Diagnosis can be verified in the neonate by demonstrating immunoglobulin (Ig) M antibodies to the virus or by the isolation of the virus from the throat, urine, stool, or CSF. Also, the virus has been obtained from cells in the amniotic fluid. In subsequent pregnancies, the fetus has been normal in our experience.


Neurology_Adams

Neurology_Adams. The neuropathology is of considerable interest. In the nervous system of fetuses exposed to maternal rubella in the first trimester, R.D. Adams found no visible lesions by light microscopy, even though the virus had been isolated from the brain by Enders (personal communications). At this period of development there is no inflammatory reaction because of the absence of polymorphonuclear leukocytes, lymphocytes, and other mononuclear cells in the fetus. At birth the brain is usually of normal size, and there may be no discernible lesions. There may be a mild meningeal infiltration of lymphocytes, and a few zones of necrosis and vasculitis with later calcification of vessels are seen, as are small hemorrhages, presumably related to the thrombocytopenia. Smallness of the brain and delay in myelination have been observed in children who died at 1 to 2 years of age. None of the brains in Adams’ series was malformed. Rubella virus continues to be recoverable from the CSF for at least 18


Neurology_Adams

Neurology_Adams. myelination have been observed in children who died at 1 to 2 years of age. None of the brains in Adams’ series was malformed. Rubella virus continues to be recoverable from the CSF for at least 18 months after birth. A form of delayed progressive rubella encephalitis in childhood is also known and is described in Chap. 32 under “Progressive Rubella Panencephalitis.” Because there is no treatment for the active infection, the obvious approach to the problem of congenital rubella infection is to make sure that every woman of childbearing age has been vaccinated against rubella or has antibodies as a result of infection prior to pregnancy. The widespread use of rubella vaccine has reduced the chance of major outbreaks, but sporadic infections continue to be seen, and outbreaks of epidemic proportions continue to occur in developing countries.


Neurology_Adams

Neurology_Adams. For many years it was known that there were swollen cells containing intranuclear and cytoplasmic inclusions in the tissues of some infants who died in the first weeks and months of life. This cytologic change seemed related to the fatalities. In 1956 and 1957, three different laboratories isolated what has come to be called the human cytomegalovirus (see Weller). This has proved to be the most frequent intrauterine viral infection, rivaled in the current era only by HIV.


Neurology_Adams

Neurology_Adams. CMV disease is widespread in the general population. Although cervicitis is common, the virus is probably transmitted to the fetus transplacentally. Infection of the fetus usually occurs in the first trimester of pregnancy, sometimes later, by way of an inapparent maternal viremia and infection of the placenta. The newborn can also be infected in the course of delivery or afterward by the mother’s milk or by transfusions. However, only a small proportion of women known to harbor the virus give birth to infants with active infection. The likelihood of the fetus being infected is much greater if the seronegative mother becomes infected for the first time during pregnancy. In one study, 18 percent of infants born to such mothers were symptomatic at birth, and 25 percent became blind, deaf, or cognitively impaired within a few years (Fowler et al). In mothers with recurrent CMV infection, the infants were asymptomatic at birth, and only a few developed serious sequelae. Evidently, the


Neurology_Adams

Neurology_Adams. or cognitively impaired within a few years (Fowler et al). In mothers with recurrent CMV infection, the infants were asymptomatic at birth, and only a few developed serious sequelae. Evidently, the presence of maternal antibodies before conception protects against congenital CMV infection.


Neurology_Adams

Neurology_Adams. Early infection of the fetus may result in a malformation of the brain; later, there is only inflammatory necrosis from encephalitis in parts of the normally formed brain. Disseminated inflammatory foci have been observed in the cerebrum, brainstem, and retinae. Here there were aggregates of lymphocytes, mononuclear cells, and plasma cells. The mononuclear histiocytes (microglia cells) contain inclusion bodies; some astrocytes are similarly affected. Granulomas form and later calcify, particularly in the periventricular regions. Often there is hydrocephalus. In the low-birth-weight or full-term infant, the clinical picture is one of jaundice, petechiae, hematemesis, melena, direct hyperbilirubinemia, thrombocytopenia, hepatosplenomegaly, microcephaly, mental defect, and convulsions. Cells in the urine may show cytomegalic changes. There is a pleocytosis and an increased protein in the CSF.


Neurology_Adams

Neurology_Adams. Congenital CMV infections pose a much greater problem than does rubella. There is no way of identifying the infected fetus prior to birth or to prevent inapparent infections in the pregnant woman. As indicated above, if the pregnant woman has measurable titers of antibodies to CMV at the time of conception, her infant is relatively protected. Moreover, some infected infants (with viruria) may appear normal at birth but develop neural deafness and developmental delay several years later. Viral replication in infected organs continues after the first year and health workers are at risk. A second child may be infected. There is no known treatment. The difficulties in prenatal diagnosis of maternal infection preclude planned abortion. Routine serologic testing should be done on every young woman of childbearing age. Until an effective vaccine becomes available, pregnancy should be avoided if a sexual partner is infected.


Neurology_Adams

Neurology_Adams. In the United States, approximately 10 percent of cases of AIDS have occurred in women, almost all of them of childbearing age, and the rate of new cases is increasing at a faster rate among them than among men. The numbers are higher in many developing countries. In children, practically all instances of AIDS come from an HIV-infected mother (“vertical transmission”). The infection may be acquired in utero, during delivery, or from breast-feeding. The relative importance of each of these modes of transmission has not been settled.


Neurology_Adams

Neurology_Adams. It is estimated that HIV infection and AIDS occur in 15 to 30 percent of infants born to HIV-seropositive mothers (see Prober and Gerson). Infected infants present special difficulties in diagnosis, and the infection runs a more accelerated course in them than in adults. In the perinatal period, infected and noninfected infants can only rarely be distinguished clinically, and laboratory diagnosis is hampered by the presence of maternally derived antibody to HIV. The initial clinical signs usually appear within a few months after birth; practically all infected infants become ill before their first birthday, and very few are asymptomatic beyond 3 years of age. Early signs consist of lymphadenopathy, splenomegaly, hepatomegaly, failure to thrive, oral candidiasis, and parotitis. In the European Collaborative Study, comprising 600 children born to HIV-infected mothers, 83 percent of infected children showed laboratory or clinical features of HIV infection by 6 months of age. By 12


Neurology_Adams

Neurology_Adams. European Collaborative Study, comprising 600 children born to HIV-infected mothers, 83 percent of infected children showed laboratory or clinical features of HIV infection by 6 months of age. By 12 months, 26 percent had clinical symptoms of AIDS and 17 percent had died of HIV-related diseases. Once AIDS is established in children, it does not differ materially from the syndrome in adults as described in Chap. 32.


Neurology_Adams

Neurology_Adams. There is often a delay in the attainment of psychomotor milestones. Or after a period of normal development, a psychomotor decline begins, with corticospinal or peripheral nerve signs, often with pleocytosis in the CSF. The typical giant cell AIDS encephalitis, neuritis, and myelitis are easily distinguished from CMV encephalitis and toxoplasmosis. Infected children are also subject to a variety of opportunistic infections, including bacterial meningitis, toxoplasmosis, CMV encephalitis, fungal infections (cryptococcosis, aspergillosis, candidiasis), herpes simplex, syphilis, zoster, and mycobacterial meningitis. There may also be vascular lesions, with infarction or hemorrhage and lymphoid neoplasia. These are discussed in Chaps. 31 and 32. Treatment of newborns exposed to HIV or who test positive for HIV is with antiretroviral drug therapy.


Neurology_Adams

Neurology_Adams. Infection with this flavivirus during the first trimester of pregnancy infection has been strongly linked to microcephaly and developmental delay, usually severe in degree. The frequency in various outbreaks and models has been from less than 1 percent to over 10 percent but the best estimates are in the lowest part of the range. Clinical infection, usually a mild febrile flu-like illness transmitted by mosquito, had been considered rare but serologic surveys have shown exposure rates of about 6 percent in some parts of the world.


Neurology_Adams

Neurology_Adams. It came as somewhat of a surprise that an outbreak occurred in Micronesia and French Polynesia and subsequently in parts of South America, particularly Brazil, and in parts of Africa several years ago and that offspring of infected mothers had severe microcephaly. There is viral transmission from infected mother to child and an estimated one-third of infants are affected by microcephaly. Viral genome is found in infant brains and the brain is extremely small with reduced gyration in the few autopsy studies available (Mlakar and colleagues). An association with Guillain-Barré syndrome has been established in adults.


Neurology_Adams

Neurology_Adams. This tiny protozoan Toxoplasma gondii, occurring freely or in pseudocyst form, is a frequent cause of meningoencephalitis in utero or in the perinatal period of life. The disease exists in all parts of the world but is more frequent in countries with hot, humid climates than it is in the United States. The mother is most often infected by exposure to cat feces, handling uncooked infected meat, or eating partially cooked meat, but she is nearly always asymptomatic or has only a mild fever and cervical lymphadenopathy.


Neurology_Adams

Neurology_Adams. The precise times of placental and fetal invasion are unknown, but presumably they occur late in the gestational period. The clinical syndrome usually becomes manifest in the first days and weeks of postnatal life, when seizures, impaired alertness, hypotonia, weakness of the extremities, progressive hydrocephalus, and chorioretinitis appear. The retinal lesions consist of large pale areas of destroyed retina surrounded by deposits of pigment. If the infection is severe, the maculae are destroyed; optic atrophy and microphthalmos follow. We have several times observed hemiplegias in older infants, first on one side and then on the other, followed by tension hydrocephalus. The latter is present in about one-third of the cases.


Neurology_Adams

Neurology_Adams. The CSF contains a moderate number of white blood cells, mostly lymphocytes and mononuclear cells, and the protein content is in the range of 100 to 400 mg/dL (i.e., a higher protein content than all other neonatal infections except bacterial meningitis). The glucose values are normal. Fewer than 10 percent of infected children recover; the others are developmentally delayed to varying degrees, with seizures and paralysis. In those without symptoms of infection at birth, the outcome is better.


Neurology_Adams

Neurology_Adams. Granulomatous masses and zones of inflammatory necrosis abut the ependyma and meninges. The organisms, 6 to 7 mm in length and 2 to 4 mm in width, are visible in and near the lesions. Microcysts may also be found, lying free in the tissues without surrounding inflammatory reaction. The necrotic lesions calcify rapidly and, after several weeks or months, are readily visible in plain films of the skull. These appear in periventricular and other regions of the brain as multiple nodular densities (see Fig. 37-16). In adults, often in association with HIV, the disease takes the form of a rapidly evolving meningitis and multifocal encephalitis in conjunction with myocarditis, hepatitis, and polymyositis.


Neurology_Adams

Neurology_Adams. In adults, often in association with HIV, the disease takes the form of a rapidly evolving meningitis and multifocal encephalitis in conjunction with myocarditis, hepatitis, and polymyositis. This syndrome is described in Chap. 31, as are the diagnostic tests and current treatment. In the infant, infections such as rubella, syphilis, CMV disease, and herpes simplex must be considered in the differential diagnosis. The most reliable means of diagnosis is the IgM indirect fluorescent antibody test, performed on umbilical cord blood. Passive transfer of IgG antibody from mother to fetus takes place, but its presence in the fetus is not proof of active infection. In women who develop antibodies in the first 2 or 3 months of pregnancy, treatment with spiramycin (Rovamycine) prevents fetal infection. Once the fetus is infected, pyrimethamine and sulfadiazine must be used. A later second pregnancy is not affected.


Neurology_Adams

Neurology_Adams. The clinical syndromes and pathologic reactions of congenital neurosyphilis of the newborn are similar to those of the adult, as described in Chap. 31. Such differences that exist are determined principally by the immaturity of the nervous system at the time of spirochetal invasion. The syphilitic infection may be transmitted to the fetus at any time from the fourth to the seventh months. The fetus may die, with resulting miscarriage or stillbirth, or may survive only to be born with florid manifestations of secondary syphilis. The dissemination of the spirochetes throughout the body, the time of appearance of the secondary manifestations, and the time of formation of antisyphilitic antibodies (reagin) in the blood are all governed by the same biologic principles that apply to adult syphilis.


Neurology_Adams

Neurology_Adams. At birth, the spirochetemia may not have had time to cause syphilitic antibodies to appear; hence a negative Venereal Disease Research Laboratory (VDRL) reaction in umbilical cord blood does not exclude congenital syphilis. In unselected groups of syphilitic mothers, 25 to 80 percent of fetuses have been infected, and in 20 to 40 percent of those infected, the CNS is invaded as judged by the finding of abnormal CSF. The types of congenital neurosyphilis (asymptomatic and symptomatic meningitis, meningovascular disease, hydrocephalus, general paresis, and tabes dorsalis) are the same as those in the adult except for the great rarity of tabes dorsalis. The classic Hutchinson triad (dental deformities, interstitial keratitis, and bilateral deafness) is infrequently observed in complete form.


Neurology_Adams

Neurology_Adams. The sequence of neurologic syndromes is also the same as in the adult, all stemming basically from chronic spirochetal meningitis. The infection may become symptomatic in the first weeks and months of postnatal life, meningovascular lesions and hydrocephalus reaching maximal frequency during the period from 9 months to 6 years. An early form of syphilitic meningoencephalitis may occur at 1 to 2 years and result in severe developmental delay. More often, a congenital paresis and tabes usually appear between the ninth and fifteenth years. The pathologic basis of the neurosyphilitic syndromes is discussed in Chap. 31.


Neurology_Adams

Neurology_Adams. Fewer cases of congenital neurosyphilis are being observed as the years pass, but there may be a recrudescence of the disease in HIV-infected patients. If the syphilitic mother is treated before the fourth month of pregnancy, the fetus will not be infected. The affected infant may be normal at birth or exhibit only mucocutaneous lesions, hepatosplenomegaly, lymphadenopathy, and anemia. In the neonatal period, there are no signs of meningeal invasion, or there may be only asymptomatic meningitis. If the latter is actively treated until the CSF is normal, vascular lesions of brain and spinal cord, hydrocephalus, general paresis, and tabes dorsalis will not develop.


Neurology_Adams

Neurology_Adams. Congenital syphilis must be considered a potential, albeit rare, cause of epilepsy and developmental delay. Once the syphilitic infection has been treated in early life and rendered inactive (acellular CSF, normal protein), the occurrence of a congenital infection can only be substantiated by an accurate history; the finding of the syphilitic stigmata in the eyes, teeth, and ears; or a positive serologic reaction in the CSF. Treatment of syphilis in the child follows along the same lines as treatment of the syphilitic adult (see Chap. 31), with appropriate adjustment of dosage in accordance with the child’s weight.


Neurology_Adams

Neurology_Adams. Several other infections of late fetal life or the neonatal period are only mentioned here, for to describe them all would be excessive and would elucidate no new neurologic principles. Meningitis as a result of the small gram-positive rod L. monocytogenes may be acquired in the usual way, at the time of passage through an infected birth canal or in utero, as a complication of maternal and fetal septicemia because of this organism. In the latter case, it causes abortion or premature delivery. Neonatal bacterial meningitis with this organism is a particularly devastating and often fatal type of bacterial infection, not easily diagnosed unless the pediatrician is alert to the possibility of a silent meningitis in every case of neonatal infection. Coxsackievirus B, polioviruses, other enteroviruses, and arboviruses (western equine) seem to be able to cross the placental barrier late in pregnancy and cause encephalitis or encephalomyelitis in the near-term fetus, which is


Neurology_Adams

Neurology_Adams. other enteroviruses, and arboviruses (western equine) seem to be able to cross the placental barrier late in pregnancy and cause encephalitis or encephalomyelitis in the near-term fetus, which is indistinguishable from the disease in the very young infant. Herpes zoster may occur in utero, leaving cutaneous scars and retarding development. Or zoster may appear soon after birth, the infection having been contracted from the mother. Only later in childhood can varicella induce an autoimmune perivenous demyelination and possibly a direct infection, affecting predominantly the cerebellum (see Chap. 32), or it may precede the now rare Reye syndrome.


Neurology_Adams

Neurology_Adams. Epstein-Barr virus is another frequent cause of meningoencephalitis. In some instances, it may present as aseptic meningitis or a Guillain-Barré type of acute polyneuritis. This infection tends to affect the nervous system of children rather than that of adults, but there are exceptions to this comment. It is estimated that approximately 2 percent of children and adolescents with this infection have some type of neurologic dysfunction; rarely will this be the only manifestation of the disease. Stupor, chorea, and aseptic meningitis were the main neurologic findings in the case reported by Friedland and Yahr, and acute cerebellar ataxia and deafness were observed in the case of Erzurum and associates (see also Chaps. 31 and 32).


Neurology_Adams

Neurology_Adams. The major types of seizure disorder have already been discussed in some detail in Chap. 15. In bringing them up here, attention is drawn to the fact that epilepsy is mainly a disease of infancy and childhood. Approximately 75 percent of epileptics fall into these age periods, and some of the most interesting and unique types of seizures are peculiar to these epochs of life. Epilepsies that are observed exclusively in infants and children are benign neonatal convulsions; benign myoclonic epilepsy of infancy; febrile seizures (both genetic and acquired); infantile spasms of West; absence seizures; the Lennox-Gastaut syndrome; rolandic and occipital paroxysms and other benign focal epilepsies; and the juvenile myoclonic epilepsies.


Neurology_Adams

Neurology_Adams. One principle that emerges is that the form taken by seizures in early life is in part age-linked. Neonatal seizures are predominantly partial or focal; infantile seizures take the form of myoclonic flexor (sometimes extensor) spasms; and the various forms of petit mal are essentially diseases of childhood (4 to 13 years). The motor phenomena of epilepsy in young children are often termed myoclonic, but this should not be confused with other, later-occurring epilepsies that are endowed with the same name. Furthermore, certain epileptic states tend to occur only during certain epochs of life—one type of febrile seizure from 6 months to 6 years, generalized or temporal spike-wave activity with benign motor and complex partial seizures from 6 to 16 years, and juvenile myoclonic epilepsy in the midand late-adolescent years. In general, idiopathic epilepsy, so called because the cause cannot be determined, is predominantly a pediatric neurologic problem. This is not to say that seizures of


Neurology_Adams

Neurology_Adams. midand late-adolescent years. In general, idiopathic epilepsy, so called because the cause cannot be determined, is predominantly a pediatric neurologic problem. This is not to say that seizures of unknown cause do not occur for the first time in adult life but rather that the onset of such seizures is far more frequent in childhood and tends to diminish once adulthood is reached.


Neurology_Adams

Neurology_Adams. The clinical characteristics of infantile and childhood seizures, including those of genetic origin, are fully described in Chap. 15.


Neurology_Adams

Neurology_Adams. Two clinical types can be recognized based on the adequacy of motor skills that are acquired in parallel with cognitive skills. In the first, the essential characteristic is that, almost from birth, the infant is delayed in all aspects of development. There is a tendency to sleep more, to be less demanding of nourishment, to move less than normal, and to suck poorly and regurgitate. Parents comment on how good their baby is, how little he troubles them by crying. As the months pass, every expected achievement is late. The baby is usually more hypotonic and turns over, sits unsupported, and walks later than the normal infant. Yet despite these obvious motor delays, there is later no sign of paralysis, ataxia, chorea, or athetosis. These babies do not smile at the usual time and take little notice of the mother or other persons or objects in their environment. They are less attentive to visual, and often to auditory, stimuli, to the point where questions may be raised about blindness or


Neurology_Adams

Neurology_Adams. notice of the mother or other persons or objects in their environment. They are less attentive to visual, and often to auditory, stimuli, to the point where questions may be raised about blindness or deafness. Certain phases of normal development, such as hand regard, may persist beyond the sixth month, when they are normally replaced by other activities. Mouthing (putting everything in the mouth) and slobbering, which should end by 1 year of age, also persist. There are only fleeting signs of interest in toys, and the impersistence of attention becomes increasingly prominent. Vocalizations are scant, often guttural, piercing, or high-pitched and feeble. Babbling is not replaced by attempts at word formation at the usual time.


Neurology_Adams

Neurology_Adams. In the second type, early motor milestones (supporting the head, rolling over, sitting, standing, and walking) are attained approximately at their normal times, yet the infant is inattentive and slow in learning the usual nursery tricks. It seems as though motor development had somehow escaped the process of developmental delay. There may, however, be aimless overactivity and persistence of rhythmic movements, grinding of the teeth (bruxism), and hypotonia.


Neurology_Adams

Neurology_Adams. Because the developmental sequence of motor function and speech may be normal, even to the point where the baby acquires a few words by the end of the first year, the examiner may be misled into thinking that the delayed infant was at first normal and had then deteriorated. In such infants it can even be shown that various test procedures yield lower scores with progressing age (from 3 years onward); this is not the result of a decline in ability but of the fact that the tests are not comparable at different times. In the early years, the tests are weighted toward sensorimotor functions and after that toward perception, memory, and concept formation. Interestingly, the development of language depends upon both groups of functions, needing a certain maturation of the auditory and motor apparatus at the start and highly specialized cognitive skills for continued development. These and other aspects of development of speech and language were considered earlier in this chapter and are


Neurology_Adams

Neurology_Adams. apparatus at the start and highly specialized cognitive skills for continued development. These and other aspects of development of speech and language were considered earlier in this chapter and are commented on further in Chaps. 22 and 27.


Neurology_Adams

Neurology_Adams. Members of both groups of these mildly delayed individuals exhibit a number of noteworthy features that have medical and social implications. Although not overtly dysmorphic and having a normal or low-normal head circumference, they have a high incidence of minor congenital anomalies of the eyes, face, mouth, ears, and hands; they tend to be sickly, and the more severely affected among them have poor physiques and are often undersized. Difficult behavior occurs frequently, most often taking the form of poor self-control and aggressiveness, especially pronounced in children with temporal lobe epilepsy. Other behavioral disturbances are restlessness, repetitive activity, explosive rage reactions and tantrums, stereotyped play, and the seeking of sensory experiences in unusual ways. Pica (the compulsive ingestion of nonnutritive substances) is a problem between ages 2 and 4 years of age, but is also seen in normal, neglected children.


Neurology_Adams

Neurology_Adams. An endless debate is centered on matters of causation—whether this category of mild delay is the product of genetic influence or of societal discrimination and lack of training and education coupled with the effects of malnutrition, infections, or other exogenous factors. Surely both factors are at work, with the genetic being dominant for the reasons discussed above, although the relative importance of each has proved difficult to determine.


Neurology_Adams

Neurology_Adams. A pathologic basis for most cases of mild developmental delay has not been established and new methodologies, perhaps relating to neuronal connectivity, will be needed if the brains of these individuals are to be differentiated from normal children. Differences might be expected in terms of the number of neurons in thalamic nuclei and cortex, in dendritic–axonal connectivity, or in synaptic surfaces, elements that are not being assayed by the conventional techniques of tissue neuropathology. The observations of Huttenlocher, who found a sparsity of dendritic arborization in Golgi-Cox preparations, and of Purpura, who found an absence of short, thick spines on dendrites of cortical neurons and other abnormalities of dendritic spines, are first steps in this direction but require confirmation. Genetic Aspects of Nonsyndromic


Neurology_Adams

Neurology_Adams. Sex linkage is a notable feature of some types of mild developmental delay. The fragile X syndrome, discussed later, is the most important of this group, predominating in males and accounting for approximately 10 percent of all cases of male developmental delay. These individuals may be physically normal except for large testicles. Renpenning and colleagues reported a series of 21 developmentally delayed males in three generations of a Canadian family, all free of any congenital malformations and with normal head size, and Turner and coworkers have described a similar Australian series. Other X-linked forms of developmental delay that have few or no dysmorphic features include the Partington, Lowe, Lesch-Nyhan, and Menkes syndromes and adrenoleukodystrophy, each with special characteristics in addition to developmental delay, as discussed in Chap. 36. Numerous other X-linked retardation syndromes with profound accompanying neurologic anomalies have been delineated; for example, the


Neurology_Adams

Neurology_Adams. in addition to developmental delay, as discussed in Chap. 36. Numerous other X-linked retardation syndromes with profound accompanying neurologic anomalies have been delineated; for example, the one caused by a mutation in the oligophrenin gene, in which there is epilepsy, and another involving cerebellar hypoplasia. The relationship of intelligence in general to the X chromosome is discussed in Chap. 20.


Neurology_Adams

Neurology_Adams. However, there is emerging information relating autosomal mutations, rather than X-linked ones, in genes that control synaptic function such as SYNGAP1, and non-dysmorphic developmental delay as detailed in the publication by Hamdan and coworkers. There are approximately 30 X-linked and 6 autosomal recessive genes associated with nonsyndromic developmental delay and more are sure to be found. Investigated from another perspective, de Ligt and colleagues sequenced the coding regions of over 21,000 genes in a series of 100 individuals with IQ below 50 and round that there were numerous de novo mutations that involved cerebral development of function. Together, all of the aforementioned genetic alterations, mutations, lesser polymorphisms and copy number variants, account for approximately 15 to 20 percent of cases of mild, moderate, and severe developmental delay and autism. Most are de novo mutations, making their discovery difficult. The challenge will be to elucidate the manner in


Neurology_Adams

Neurology_Adams. 15 to 20 percent of cases of mild, moderate, and severe developmental delay and autism. Most are de novo mutations, making their discovery difficult. The challenge will be to elucidate the manner in which they disrupt cerebral development on a synaptic or subcellular level.


Neurology_Adams

Neurology_Adams. Infants should be considered at risk for developmental delay when there is a family history of developmental delay, low birth weight in relation to the length of gestation (small-for-date babies), marked prematurity, maternal infection early in pregnancy (especially rubella), and toxemia of pregnancy. In the first few months of life, certain of the behavioral characteristics described above are of value in predicting developmental delay. Prechtl and associates have found that a low Apgar score (especially at 5 min after delivery, Table 27-3), flaccidity, underactivity, and asymmetrical neurologic signs are the earliest indices of subnormality in the infant. Slow habituation of orienting reactions to novel auditory and visual stimuli and the presence of “fine motor deficits” (as previously discussed under “Delays in Motor Development”) are other early warnings of developmental delay.


Neurology_Adams

Neurology_Adams. In the first year or two of life, suspicion of developmental delay is based largely on clinical impression, but it should always be validated by psychometric procedures. Most pediatric neurologists use some of the criteria laid down by Gesell and Amatruda or the Denver Developmental Screening Scale, from which a DQ is calculated.


Neurology_Adams

Neurology_Adams. For testing of preschool children, the Wechsler Preschool and Primary Scale of Intelligence is used, and for school-age children, the Wechsler Intelligence Scale for Children is preferred. IQ tests for preschoolers must be interpreted with caution, as they have had less predictive validity for school success than the tests that are used after 6 years of age. In general, however, normal scores for age on any of these tests essentially eliminate developmental delay as a cause of poor school achievement and learning disabilities; special cognitive defects may, however, be revealed by low scores on particular subtests. Developmentally delayed children not only have low scores but exhibit more scatter of subtest scores. Also, like demented adults, they generally achieve greater success with performance than with verbal items. It is essential that the physician know the conditions of testing, for poor scores may be due to fright, inadequate motivation, lapses in attention, dyslexia, or a


Neurology_Adams

Neurology_Adams. performance than with verbal items. It is essential that the physician know the conditions of testing, for poor scores may be due to fright, inadequate motivation, lapses in attention, dyslexia, or a subtle auditory or visual defect rather than a developmental lag.


Neurology_Adams

Neurology_Adams. The EEG, in addition to exposing asymptomatic seizure activity, shows a high incidence of other abnormalities in the developmentally delayed child. Presumably this is because of a greater degree of immaturity of the cerebrum at any given age. However, a normal EEG is not infrequent and of relatively little help. Moreover, CT and MRI have been unhelpful in revealing abnormalities in this group of children.


Neurology_Adams

Neurology_Adams. In the diagnosis of milder grades of developmental delay, the possible effects of severe malnutrition, neglect and deprivation, chronic systemic disease, iodine deficiency, impaired hearing and vision, and possibly childhood psychosis should be considered. Of particular importance is the differentiation of a group of patients who are normal for a variable period after birth and then manifest a progressive decline from disease of the nervous system. This type of disorder is representative of the group of hereditary metabolic and degenerative diseases discussed in Chap. 36. Seizure disorders (and antiepileptic medications) can impair cerebral function, and several special childhood seizure disorders are associated with a progressive decline in mental function in this group of patients (see Chap. 15). Management of Mild Developmental Delay


Neurology_Adams

Neurology_Adams. Management of Mild Developmental Delay Because there is little or no possibility of restoring function to a nervous system that is developmentally or structurally damaged, the medical objective is to assist in planning for the patient’s training, education, and social and occupational adjustments. As Voltaire remarked long ago, guidance is needed more than education. Early multidisciplinary intervention is recommended and the parents must be counseled in forming realistic attitudes and expectations. Psychiatric and social counseling may help the family to maintain gentle but firm support of the patient so that he can acquire, to the fullest extent possible, self-help skills, self-control, good work habits, and a congenial personality.


Neurology_Adams

Neurology_Adams. Most individuals with an IQ above 60 and no other handicaps can live an independent life. Special schooling enables such patients to realize their full potential. Social factors that contribute to underachievement must be eliminated if possible. Later, there is need for advice about possible occupational attainments. Great care must be exercised in deciding about institutionalization. Whereas severe degrees of cognitive impairment are all too apparent by the first or second year, less-severe degrees are difficult to recognize early. As stated above, psychologic tests alone are not trustworthy. The method of assessment suggested many years ago by Fernald still has a ring of soundness. It includes (1) physical examination, (2) family background, (3) developmental history, (4) school progress (grade achieved), (5) performance in schoolwork (tests of reading, arithmetic, etc.), (6) practical knowledge, (7) social behavior, (8) industrial efficiency, (9) moral reactions, and (10)


Neurology_Adams

Neurology_Adams. progress (grade achieved), (5) performance in schoolwork (tests of reading, arithmetic, etc.), (6) practical knowledge, (7) social behavior, (8) industrial efficiency, (9) moral reactions, and (10) intelligence as measured by psychologic tests. All these data except (5) and (10) can be obtained by a skillful physician during the initial medical and neurologic examination and are used to guide the family in its difficult decisions.


Neurology_Adams

Neurology_Adams. The subject of developmental delay was introduced in Chap. 27, where it was pointed out that two major categories of this disorder have been delineated. In one, and by far the more common group, the cognitive limitation is relatively mild, allowing the individual to succeed with therapy and education; it is often familial and is featured by a lack of definite neurologic abnormalities (except possibly a slightly higher incidence of seizures) and the absence of neuropathologic changes. A large part of this group, falling between 2 and 3 standard deviations below the normal mean IQ, probably are the lower end of the Gaussian curve of intelligence, the converse of which is genius. This group is, however, contaminated with a small number of defined diseases of the nervous system occurring in a less-severe form. In a second group, the degree of developmental delay is usually more severe (IQ of 50 to 70), and yet more so in the third group (IQ less than 50 or not measurable because of


Neurology_Adams

Neurology_Adams. in a less-severe form. In a second group, the degree of developmental delay is usually more severe (IQ of 50 to 70), and yet more so in the third group (IQ less than 50 or not measurable because of limitations of cooperation or physical impediments). Most of the cases in the second and third groups are nonfamilial, and a wide variety of neuropathologic changes are in evidence. The subdivisions are not absolute, for there are a few metabolic and developmental diseases in which developmental delay is profound yet with no somatic or neurologic abnormalities and, most importantly, well-defined neuropathologic changes are lacking. Here we refer to conditions such as Rett syndrome, autism, and the X-linked developmental delay syndromes (Renpenning and fragile X types). In this chapter, these major types of severe developmental delay are described.


Neurology_Adams

Neurology_Adams. The overall frequency of severe developmental delay cannot be stated precisely. Rough estimates place the figure at 0.2 to 0.4 percent of the general population and at approximately 10 percent of the general developmentally delayed segment of society. It is important to emphasize that in a large proportion of individuals with severe developmental delay, a particular congenital abnormality or anomaly of development cannot at present be traced to any of the disorders reviewed in the preceding pages. More precisely stated, when groups of such severely impaired patients are studied clinically, a reasonably accurate etiologic determination of the underlying brain disease can be made in only slightly more than half. According to Penrose, chromosomal abnormalities account for 15 percent, single-gene disorders for 7 percent, and environmental agents for 20 percent. More recent studies of the subtelomeric parts of chromosomes reportedly find abnormalities in another 7 percent of severely


Neurology_Adams

Neurology_Adams. disorders for 7 percent, and environmental agents for 20 percent. More recent studies of the subtelomeric parts of chromosomes reportedly find abnormalities in another 7 percent of severely retarded children (Knight et al). No cause is found for the remaining cases. Males outnumber females 3 to 1.


Neurology_Adams

Neurology_Adams. However, from the neuropathologic standpoint, the examination of the brains of the severely developmentally delayed by conventional histopathologic methods discloses lesions in approximately 90 percent, and in fully three-quarters of the entire group, an etiologic diagnosis can be determined or tentatively assigned. Many of the remaining 10 percent lack definite pathologic changes, but their brains are lighter in weight by 10 to 15 percent than age-matched normal brains. Interestingly, the proportion of vascular, hypoxic-ischemic, metabolic, and genetic lesions in this group of severely impaired individuals is much the same as is found in a group selected on the basis of “cerebral palsy.”


Neurology_Adams

Neurology_Adams. Here it is important to repeat a point made earlier and in Chap. 27: A few of the severely disabled and a large majority of the mildly affected do not have a recognizable cerebral pathology or exhibit any of the familiar and conventional signs of cerebral disease. Although the milder forms of developmental delay tend to be familial, this does not by itself separate them from the severe forms of developmental delay. There are several types of hereditary developmental delay, in which the cognitive impairment may be severe and in some of which there may be maldevelopment of the cerebral cortex. These are discussed further on. Clinical Characteristics of the Severely Developmentally Delayed


Neurology_Adams

Neurology_Adams. These cases can be broadly divided into four groups. In one large group, designated dysmorphic developmental delay, a variety of physical deformities, including microcephaly, is commonly present. In a second group, with multiple-system retardation, the developmental delay is linked to nonskeletal abnormalities (e.g., hepatosplenomegaly, hematologic and skin disorders), which provide reliable clues to the underlying somatic disease. In a third group, neurologic retardation, somatic abnormalities are lacking but a configuration of neurologic signs leads to the diagnosis. In the fourth group, and the most difficult one to clarify, that comprising uncomplicated retardation, there are no or minimal somatic, visceral, or neurologic abnormalities. One is then forced to turn to special features of the developmental delay itself for identification of the underlying disease. Table 37-8 elaborates a reasonable classification of the types of developmental delay.


Neurology_Adams

Neurology_Adams. The profoundly developmentally delayed infant with a virtually untestable IQ is identified early in life because he does not sit, stand, or walk. If any one of these motor activities is acquired, it appears late and is imperfectly performed. Language never develops; at most a few spoken words or phrases are understood and fewer are uttered, or the patient only vocalizes in a meaningless way. Such a person may not even indicate bodily needs for food, drink, excretion, and so on. Usually the patient is continuously idle and interacts little with people and objects. Only the most primitive emotional reactions are exhibited, often without connection to an appropriate stimulus. Physical growth is usually retarded, nutrition may be poor, and susceptibility to infections is increased. Sphincteric control may never be attained and, if attained, is precarious.


Neurology_Adams

Neurology_Adams. When the cognitive impairment is less severe than described above, falling into the IQ ranges of 20 to 45, or 45 to 70, there may be somatic neurologic abnormalities. If specific motor defects do not coexist, then sitting, standing, and walking are achieved but not at the expected times. The existence of a mental defect is most clearly evidenced by a delay in psychomotor development and a failure to speak by the second or third postnatal year. The patient does not acquire the usual household and play activities as well as other children. However, delay in speech development must not, by itself, be taken as a mark of developmental delay, for in some children a unique delay in speech can be an isolated abnormality as described in Chap. 27, with subsequent normal development of speech and mental ability. Toilet training may be difficult to accomplish in the developmentally delayed child, but, again, bedwetting may be a problem in an otherwise normal child. Also, the deaf child may have


Neurology_Adams

Neurology_Adams. ability. Toilet training may be difficult to accomplish in the developmentally delayed child, but, again, bedwetting may be a problem in an otherwise normal child. Also, the deaf child may have to be considered separately; here the problem becomes apparent by an indifference to noise and reduced vocalization (stereotypy of babbling).


Neurology_Adams

Neurology_Adams. More thorough analyses of cognitive functions in the moderately cognitively impaired child have been undertaken by O’Connor and Hermelin, Pulsifer, and others. These authors measured the efficiency of visual and auditory perception, adequacy of communication, relations between language development and thought, crossmodal sensory encoding, alertness, attention, and memory. It was concluded that none of these functions was specifically impaired. Instead, the child could not properly encode new information because the memory systems and the stock of past assimilated knowledge were insufficient to provide a framework of items and categories with which new information could be integrated. Some patients also seemed unable, perhaps on the basis of this encoding problem, to extract from perceived material selective features that could be interpreted. Furthermore, they were unable to deal with an array of sensory experiences like normal children. The complexity of these mental operations,


Neurology_Adams

Neurology_Adams. material selective features that could be interpreted. Furthermore, they were unable to deal with an array of sensory experiences like normal children. The complexity of these mental operations, which we would reduce to a global failure of the normal processes of apperception and integration, was called by Piaget a “failure of assimilation and accommodation.” However, within the spectrum of developmental delay, apart from cognitive impairments, there are curious differences in behavior and personality, even in those with more or less the same IQ. Some individuals with moderately severe retardation are pleasant and amiable and achieve a satisfactory social adjustment. This is particularly notable in patients with Down and Williams syndromes. At the opposite end of the behavioral scale are the syndromes of autism and that of Smith-Magenis and of DeLange, in which the individual fails to manifest normal interpersonal social contact, including communicative language. The phenylketonuric


Neurology_Adams

Neurology_Adams. the syndromes of autism and that of Smith-Magenis and of DeLange, in which the individual fails to manifest normal interpersonal social contact, including communicative language. The phenylketonuric child is usually irritable, unaffectionate, and implacable, and the same is said of certain other forms of retardation, discussed earlier in the section on retardation with dwarfism.


Neurology_Adams

Neurology_Adams. Regarding differences in motor activity levels, many developmentally delayed individuals are slow, clumsy, and relatively akinetic. Others, as many as half, display an incessant hyperactivity characterized by a restless, seemingly inquisitive searching of the environment. When thwarted, they may exhibit a low frustration tolerance. They may be destructive and recklessly fearless and impervious to the risk of injury. Some exhibit a peculiar anhedonia that renders them indifferent to both punishment and reward. Other aberrant types of behaviors, such as violent aggressiveness and self-mutilation, are common.


Neurology_Adams

Neurology_Adams. Rhythmic rocking, head-banging, incessant arm movements—so-called rhythmias or movement stereotypies—are observed in the majority of those who are severely and moderately severely impaired. These movements are maintained hour after hour without fatigue and may be accompanied by breathing sounds, squeals, and other exclamations. A number of them tend to be particularly common in certain forms of developmental delay: hand-flapping in autism, handwringing in Rett syndrome, and hand-waving in Down syndrome and other disorders. Self-stimulation, even hurtful—such as striking the forehead or ears or biting the fingers and forearms—seems to be compulsive or perhaps to provide some sort of satisfaction. It is not that these rhythmias are by themselves abnormal, for some of them occur for brief periods in normal babies, but that they persist. Nevertheless, many moderately delayed persons, when assigned to a simple task such as putting envelopes in a box, can continue this activity under


Neurology_Adams

Neurology_Adams. periods in normal babies, but that they persist. Nevertheless, many moderately delayed persons, when assigned to a simple task such as putting envelopes in a box, can continue this activity under supervision for several hours.


Neurology_Adams

Neurology_Adams. In the least-severe types of retardation, all the mental activities are intact but subnormal. The point to be made is that all aspects of intellectual life, personality, and deportment are affected in slightly differing degrees and that these effects have a neurologic basis. There is more than a hint that in particular diseases, because of their anatomy, the cognitive experience, affective life, and behavior are affected in special ways. The group of moderately delayed, like the severely affected ones, is divisible into groups with somatic systemic and neurologic abnormalities, although the proportions are not the same. There are fewer of the dysmorphic type and more of the nondysmorphic, nonneurologic group. Etiology of Severe Developmental Delay


Neurology_Adams

Neurology_Adams. Etiology of Severe Developmental Delay From Table 37-1 it is obvious that many diseases can blight the development and maturation of the brain. Some of these are acquired and some are congenital and hereditary. Some affect all parts of the organism, giving rise to associated dermal, skeletal, and visceral abnormalities, while others affect only the nervous system in particular patterns. With respect especially to the milder degrees of developmental delay, in all populations thus far studied, infants of extremely low birth weight are more likely to have disabilities, brain abnormalities, and poorer language development and scholastic achievement (see Chap. 27). Mild developmental delay also tends to correlate with lower social status, which must relate in some manner to biological factors, as pointed out in the Scottish Low-Birthweight Study. Viral and spirochetal infections and parturitional accidents are other common causes. They act acutely and are theoretically preventable.


Neurology_Adams

Neurology_Adams. The factor of malnutrition during the fetal or infantile period of life as a cause of severe developmental delay has received considerable attention because it is a worldwide problem. Animal experiments by Winick and others demonstrated that severe undernutrition in early life leads to behavioral abnormalities and biochemical and morphologic changes in the brain, which may be permanent (see Chap. 40). Galler studied a group of infants in Barbados who were severely malnourished during the first year of life and then given an adequate diet. These children were followed to adulthood and compared with normally nourished siblings. No effect was observed on physical growth, but there were persistent attention deficits in 60 percent of the undernourished group and in only 15 percent of controls. The IQ scores of the former were also lower. Unfortunately, genetic factors could not be completely controlled for. In general, it may be said that the data showing developmental delay to be caused


Neurology_Adams

Neurology_Adams. The IQ scores of the former were also lower. Unfortunately, genetic factors could not be completely controlled for. In general, it may be said that the data showing developmental delay to be caused by malnutrition, while suggestive, are far from convincing.


Neurology_Adams

Neurology_Adams. Severe protein-calorie malnutrition in the first 8 months of life, which induces kwashiorkor, has been reported to retard mental development. However, such patients are said to regain mental function when fed. The authors have been impressed with the ability of the nervous system to withstand the effects of nutritional deficiency, perhaps better than any other organ.


Neurology_Adams

Neurology_Adams. The action of exogenous toxins during pregnancy is another factor to be considered. Severe maternal alcoholism has been linked to a dysmorphic syndrome and developmental delay, but the findings of several studies have not been consistent (see Chap. 41); a similar problem attaches maternal exposure to anticonvulsant medications (see Chap. 15). Surprisingly, maternal addiction to opiates, while causing an opiate withdrawal in infants for weeks or even months (Wilson et al), seems not to result in permanent injury to the nervous system. The importance of exposure to extremely small amounts of environmental lead is also controversial.


Neurology_Adams

Neurology_Adams. The effect of psychologic deprivation on cognitive development has been of interest. Following the observations that complete isolation of young female monkeys had a devastating effect on their later sexual and nurturing behavior, the idea became popular that such deprivation might cause faulty mental development in humans. Orphaned and neglected babies were found to be inactive and apathetic in comparison with those who were constantly stimulated by caring mothers. But surprisingly, when nurtured properly at a later time, these babies soon caught up with their peers. This general idea of psychologic deprivation has been the basis of many interesting educational programs for neglected children. To this day, however, it has not been proven that sensory, emotional, and psychologic deprivations of a degree observed in humans are the causes of severe developmental delay or repeated scholastic failure. The controversies regarding the effects of prematurity, maternal hypertension, and


Neurology_Adams

Neurology_Adams. of a degree observed in humans are the causes of severe developmental delay or repeated scholastic failure. The controversies regarding the effects of prematurity, maternal hypertension, and eclampsia, which are often associated with neonatal cerebral pathology and slowed psychomotor development, have been mentioned earlier in this chapter. The problem is complex and the arguments pro and con have been elaborated by Haywood and Wachs.


Neurology_Adams

Neurology_Adams. A Clinical Approach to Developmental Delay As a particular guide to the pediatrician and neurologist who assume responsibility for the diagnosis and management of children harboring a wide array of diseases and maldevelopments of the nervous system, the following clinical approach is suggested. First, as already described, there is an advantage in setting aside as one large group those who are only mildly developmentally delayed from those who have been severely delayed in psychomotor development since early life. With regard to the former group, having no obvious neurologic signs or physical stigmata, one should nevertheless initiate a search for the common metabolic, chromosomal, and infective diseases. In this large group, one must be sure that their deficit is a general one and not one of hearing, poor sight, or the special isolated language and attention deficits.


Neurology_Adams

Neurology_Adams. For patients with moderately severe and very severe cognitive deficits, one begins with a careful physical examination, searching specifically for somatic stigmata and neurologic signs, as summarized by Vasudevan and Suri. Abnormalities of eyes, nose, lips, ears, fingers, and toes are particularly important, as are head circumference and a variety of neurologic abnormalities, as outlined in Table 37-8. Data so obtained allow classification into one of three categories, as follows:


Neurology_Adams

Neurology_Adams. Table 37-8. Data so obtained allow classification into one of three categories, as follows: In those with somatic abnormalities (with or without obvious neurologic signs), one assumes the presence of a maldevelopment of the brain, possibly caused by a chromosomal abnormality. The psychomotor retardation is usually severe and often nongenetic and, as a rule, has a well-defined neuropathology. Diagnosis is determined by the gestalt of physical signs. The possible maldevelopments are numerous and diverse and are summarized in Tables 37-1 and 37-8; some of the main ones are described earlier in the chapter. Inevitably, one turns to the several atlases to denominate the syndromes (Holmes et al; Jones).


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Neurology_Adams. In the group in which the abnormalities are confined to the nervous system, attention is focused on a larger number of diseases, many caused by exogenous factors such as perinatal hypoxia-ischemia, preor postnatal infections, trauma, and so on. There are usually conspicuous neurologic signs. The degree of developmental delay is variable, depending on the location and extent of a demonstrable neuropathology. Usually the family history is negative, but careful questioning of parents regarding the pregnancy, delivery, and early postnatal period and examination of hospital records from birth may disclose the nature of the neurologic insult.


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Neurology_Adams. The third category is one in which neither somatic anomalies nor focal neurologic signs are present, or if present, they are minimal. The more severely delayed in cognitive development of this special group are represented by the following disease states: autism (Asperger-Kanner syndrome), the Rett and Williams syndromes, and the fragile X and Renpenning syndromes. All of these but autism are now known to have a genetic basis as noted earlier in the chapter and are described together below.


Neurology_Adams

Neurology_Adams. The practical importance of this clinical approach is that it directs the intelligent use of laboratory procedures for confirmation of the diagnosis. CT and MRI are useful in clarifying maldevelopment and neurologic diseases but are seldom helpful in the third group of cases. EEG confirms seizure discharges when there is uncertainty as to the nature of episodic neural dysfunction. Karyotyping and genetic studies are useful in group 1 (somatic abnormalities with or without obvious neurologic signs) and rarely in group 2 (abnormalities confined to the nervous system). An algorithmic approach to genetic testing for evaluation of a patient with intellectual disability is provided by Mefford and colleagues.


Neurology_Adams

Neurology_Adams. Mefford and colleagues. A major pitfall in this clinical approach is in mistaking a hereditary metabolic disease for a developmental one. Here one is helped by the fact that manifestations of the metabolic diseases are not usually present in the first days of life; they appear later and are progressive and often associated with specific visceral abnormalities. However, some metabolic diseases are of such slow progression that they appear almost stable, especially the late-onset ones, such as one type of metachromatic leukodystrophy, late-onset Krabbe leukodystrophy, adult adrenoleukodystrophy, and adult hexosaminidase deficiency (see Chap. 36).


Neurology_Adams

Neurology_Adams. There has been great interest in this syndrome, which some geneticists hold accountable at least in part for the preponderance of developmentally delayed males in whom an etiology could not be previously established. A large kindred in whom developmental delay was inherited in an X-linked pattern was first reported by Martin and Bell in 1943. It was in such a family, with X-linked developmental delay, that Lubs, in 1969, discovered a fragile site at the distal end of the long arm of the X chromosome; subsequently, it was established that there is an unstable inherited CGG repeating sequence at this site, which leads to breakage, as discussed previously. At first, it was assumed that the fragile X syndrome was only an example of the Renpenning syndrome (an X-linked hereditary developmental delay in males; see below) until it was pointed out that in this latter condition, stature was reduced, as was the cranial circumference, and further that the X chromosomes of the Renpenning patients


Neurology_Adams

Neurology_Adams. delay in males; see below) until it was pointed out that in this latter condition, stature was reduced, as was the cranial circumference, and further that the X chromosomes of the Renpenning patients were normal. The nature of chromosomal breakage that can be attributed to an expanded trinucleotide repeat sequence of the FMR1 gene and a resultant loss of protein function were discussed earlier in “Other Chromosomal Dysgeneses.”


Neurology_Adams

Neurology_Adams. In some series, fully 10 percent of developmentally delayed males have this fragile X chromosomal abnormality, although 2 to 4 percent is more accurate according to other series. Females are sometimes affected, but their cognitive function is only slightly reduced. Affected males have only mild dysmorphic features (large ears, broad forehead, elongated face, and enlarged testes) that may not become obvious until puberty. Others are somatically normal. Behavioral problems of one sort or another are almost universal. Pulsifer, whose review of the neuropsychologic aspects of developmental delay is recommended, lists self-injurious, hyperactive, and impulsive behaviors as the most common. The hand-flapping that is more characteristic of autism may be seen.


Neurology_Adams

Neurology_Adams. Fragile X premutation syndrome of adults As discussed in Chap. 5, a curious form of progressive adult onset ataxia and tremor, previously thought to be of a degenerative type, has been discovered to be caused by a “premutation” of the fragile X gene (50 to 200 trinucleotide repeats). Some of these patients have characteristic symmetrical MRI signal changes in the middle cerebellar peduncles in the T2 sequence. Other unusual late presentations have been described, including a spastic paraparesis without ataxia or tremor (Cellini et al). A report by Grigsby and coworkers suggests that cognitive function may be diminished in these men, but only when adjusted for their level of education and not compared to normative data; the observation requires confirmation and any suggestions that a fragile X premutation is responsible for dementia in adults should be accepted cautiously. The permutation expansion may be manifest in women as premature ovarian failure. In contrast to the mutation that


Neurology_Adams

Neurology_Adams. X premutation is responsible for dementia in adults should be accepted cautiously. The permutation expansion may be manifest in women as premature ovarian failure. In contrast to the mutation that causes developmental delay, this disorder is thought to be related in some way to an excess of messenger RNA. Several papers suggest that the premutation may also be the cause of some cases of mild retardation and autistic-like behavior.


Neurology_Adams

Neurology_Adams. This is yet another hereditary form of developmental delay, but one that affects girls. None of the cases in the extensive studies of Hagberg and coworkers (1983) was male. The responsible spontaneous mutation was shown to relate to a defect at chromosomal site Xq28, making it one of the X-linked developmental delays. A fatal outcome in boys because of a severe neonatal encephalopathy explains the expression of the disease only in girls, who are mosaics for the mutation. The involved gene, MECP2, is responsible for suppressing various other genes at critical stages of development (see Dunn and MacLeod). It has this effect by binding to methylated DNA. Defective function of the gene leads to an alteration in synaptogenesis and neural connectivity (Neul and Zoghbi). Severe inactivation of gene expression causes classic Rett syndrome, but it has become apparent that incomplete expression and mosaicism lead to a number of partial syndromes, including nonspecific developmental delay,


Neurology_Adams

Neurology_Adams. of gene expression causes classic Rett syndrome, but it has become apparent that incomplete expression and mosaicism lead to a number of partial syndromes, including nonspecific developmental delay, tremor, psychiatric disturbances, and autism-like presentations.


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Neurology_Adams. Prevalence studies from Sweden indicate an occurrence of 1 per 10,000 girls; thus Rett syndrome is more common than phenylketonuria. Although most cases appear to be sporadic, there is a high familial incidence and concordance in monozygotic twins. The syndrome is usually marked by withdrawn behavior that simulates autism, dementia, ataxia, loss of purposeful hand movements, and respiratory irregularities. Highly characteristic is a period of 6 to 18 months of normal development followed by the rapid appearance and progression of all these signs, and then by relative stability for decades. Spasticity, muscle wasting, scoliosis, and lower limb deformities may become evident in the late stages of the illness. Handwringing and similar stereotypes are very typical features (and are different in subtle ways from the hand-flapping of autistic children).


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Neurology_Adams. Armstrong and also Naidu, who have reviewed the neuropathology of Rett syndrome, have drawn attention to a number of subtle cortical abnormalities, most of which are consistent with disruption of the postnatal integrative phase of cerebral development; however, not all cases showed these abnormalities. There is generally a decrease in brain size, most marked frontally. Dendritic branching is reduced in several areas. MRI studies have shown reduced volume in dorsal parietal gray matter with preserved occipital volume, and reduction of anterior frontal lobe volume that correlates with symptom severity.


Neurology_Adams

Neurology_Adams. This is yet another X-linked type of developmental delay, which in its fully expressed form is associated with prominent dystonia of the hands and sometimes of the feet, or ataxia. Like Rett syndrome, discussed above, variations in gene expression appear to cause other syndromes including myoclonic epilepsy, West syndrome, autism, and nonspecific retardation, as well as lissencephaly. The mutated gene, termed Aristaless-related homeobox (ARX), is involved with regulation of protein-DNA interactions. The subject is reviewed by Sherr.


Neurology_Adams

Neurology_Adams. A similar type of hereditary, male-sex-linked developmental delay was described by Renpenning and associates (and subsequently associated with Renpenning’s name). The originally described family comprised 21 males in 2 generations of Mennonites in western Canada whose IQs ranged from 30 to 40. It has now been described in at least 60 individuals from 15 families. As with the fragile X syndrome, female siblings may show slight degrees of retardation. Affected members were small in stature and slightly microcephalic but otherwise free of somatic and neurologic abnormalities. The mutated gene responsible is PQBP1, the polyglutamine binding protein of which produces the syndrome through unknown means.


Neurology_Adams

Neurology_Adams. This inherited form of developmental delay is manifest in both males and females and was mentioned earlier. It is characterized by mild and variable developmental delay but with sometimes striking retention and even precocity or superiority of musical aptitude and social amiability. In some instances, a retained facility for writing permits the production of long, written descriptions; yet at the same time, these subjects are barely able to draw simple objects. The child is physically slow and has minor but distinctive somatic changes (wide mouth, almond-shaped eyes, short upturned nose, flat nasal bridge, long philtrum, delicate chin, and small pointed ears), together imparting an “elfin appearance” that is nonetheless variable and not as apparent in adulthood as the facial features coarsen. There is often an unusual sensitivity to auditory stimuli. The delay in acquisition of communicative speech and defects in visual, spatial, and motor skills make these children seem more


Neurology_Adams

Neurology_Adams. coarsen. There is often an unusual sensitivity to auditory stimuli. The delay in acquisition of communicative speech and defects in visual, spatial, and motor skills make these children seem more deficient than they actually are. Striking sociability and empathy set them apart; they represent virtually the converse of autism in this respect. Memory for musical scores—such as memorizing parts of a complete symphony after one hearing—may be prodigious.


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Neurology_Adams. By the use of high-resolution cytogenetics, the disease was traced in over 90 percent of cases to a deletion on chromosome 7 in the ELN gene that controls the production of elastin (Nickerson et al). This is of interest because one index feature of these cases is supravalvular aortic stenosis and variations (but not necessarily deletions) in the same gene account for cases of familial supravalvular stenosis without developmental delay. This cardiovascular disease is the main cause of death in these individuals.


Neurology_Adams

Neurology_Adams. It is not known whether there is a characteristic brain pathology, but one 35-year-old patient examined by Golden and associates showed no cerebral abnormalities except for Alzheimer changes, mainly plaque formation in the entorhinal cortex and amygdala. The laboratory diagnosis can be established by the use of ELN-specific probes or other techniques that show only one allele of the gene. A most interesting related finding by Somerville and colleagues is that duplication at the same site on chromosome 7 implicated in Williams syndrome can cause a delay in the acquisition of expressive speech. The reader is referred to an extremely thorough clinical and genetic review of the syndrome by Pober.


Neurology_Adams

Neurology_Adams. Among the disorders of cerebral sulcation, lissencephaly and the related disorder of subcortical band heterotopia are usually associated with severe defects in mental development. However, in female carriers, other mutations in the doublecortin gene (DCX) on the X chromosome have given rise to mild nondysmorphic developmental delay and cryptogenic epilepsy (see Guerrini and colleagues). Thus this disorder joins the group of X-linked developmental delays with minimal dysmorphic features and has implications for the understanding of X-chromosome inactivation in female carriers.


Neurology_Adams

Neurology_Adams. This condition was described almost simultaneously by Kanner in Baltimore (in 1943) and Asperger in Vienna (in 1944). The latter’s name is now under scrutiny as denominating the syndrome as a result of the exposure of Nazi collaboration (in addition to which, his descriptions were poor and of only a few children). The British psychiatrist Lorna Wing brought Aperger’s paper to the attention of the medical community and championed the idea of a spectrum of disorders in this category. Among a large group of developmentally delayed children, Kanner observed exceptional ones who appeared to be asocial, lacking in communicative skills both verbal and nonverbal, and committed to repetitive ritualistic behaviors. At the same time certain intellectual capacities—such as focused attention, retentive memory, skilled sensory and motor aptitudes, and capacity for visuospatial perception—were often retained or overly developed. In other words, the disorder pervaded only certain aspects of mental


Neurology_Adams

Neurology_Adams. memory, skilled sensory and motor aptitudes, and capacity for visuospatial perception—were often retained or overly developed. In other words, the disorder pervaded only certain aspects of mental development.


Neurology_Adams

Neurology_Adams. It is the gestalt of negative and positive aptitudes that sets this syndrome apart from other types of delay. Kanner incorrectly ascribed the condition to psychosocial factors—such as a cold, aloof parent—and regarded it as a psychopathy. The implication that these children are literally “autistic”—that is, that they have a rich inner psychic life or dream world out of relation to reality—is an assumption wholly without foundation. Asperger, whose observations included somewhat older children who were less completely disabled, later ascribed the retardation (also incorrectly) to a metabolic disease, possibly related to hyperammonemia. Opinion varied as to the relationship between the severe Kanner syndrome and the less-severe Asperger syndrome. The authors have taken the more modern view that these forms of autism represent a single syndrome of varying severity, with similar pathologic underpinnings but possibly of multiple etiologies, including genetic. Some 1 percent of autistic


Neurology_Adams

Neurology_Adams. that these forms of autism represent a single syndrome of varying severity, with similar pathologic underpinnings but possibly of multiple etiologies, including genetic. Some 1 percent of autistic children are of normal or superior intelligence.


Neurology_Adams

Neurology_Adams. In our opinion, the overarching issues in classification have become (1) the existence or embedding of autistic traits in a vast number of syndromes that are characterized by developmental delay; examples of this confluence include processes as divergent as fragile X syndrome, phenylketonuria, and tuberous sclerosis; and (2) the extent and margins of the diagnosis of “autistic spectrum disorder.” If most socially awkward children are included, the disease begins to encroach on the spectrum personality structure and presents serious problems in diagnosis and the allocation of resources. With regard to the first issue of autistic elements that are part of another well-defined disease, it has become all too easy to ascribe genetic findings to that feature of the syndrome, confusing the problem of sorting out the true etiologies of a clearly identifiable clinical syndrome of autism alone. Baker takes another perspective in an article on the history of the definitions of the disorder that


Neurology_Adams

Neurology_Adams. of sorting out the true etiologies of a clearly identifiable clinical syndrome of autism alone. Baker takes another perspective in an article on the history of the definitions of the disorder that also comments on the DSM classification.


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Neurology_Adams. Despite many claims to the contrary, there is no evidence of a psychogenesis. However, as Rapin points out, behavioral modification and special education are beneficial for less-severely affected children.


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Neurology_Adams. The overall prevalence of the autistic state has been calculated at 4.5 to 20 per 10,000. Although there was said in the past to be no familial tendency, this is almost certainly incorrect; we have seen the disease in both identical twins and in brothers, and small familial subgroups are known to exist. Autistic traits, without the full syndrome, are being found with increasing frequency in sibs and other family members, suggesting a polygenic inheritance. DeMyer found that 4 of 11 monozygotic twins were concordant for autism and that siblings have a 50 times greater risk of developing the disorder than normal children. Bailey and associates and also LeCouteur and associates have reported a concordance rate in monozygotic twins of 71 percent for the autistic spectrum disorder (as defined below) and 92 percent for an even broader phenotype of disordered social communication and stereotypic or obsessive behaviors. DeLong has found an increased incidence of bipolar disease in the


Neurology_Adams

Neurology_Adams. below) and 92 percent for an even broader phenotype of disordered social communication and stereotypic or obsessive behaviors. DeLong has found an increased incidence of bipolar disease in the families of one group of autistic children and superior mathematical aptitudes in other family members.


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Neurology_Adams. The elucidation of microdeletions and microduplications within chromosome 16p by Weiss and colleagues, working with the Autism Consortium was the first hint of a genetic locus for susceptibility to autism. Despite a high degree of penetrance in individuals with these changes, the importance of these findings is as a biologic direction for research as it explains no more than 1 percent of cases. Furthermore, certain polymorphisms, particularly in the SHANK3 gene may explain a small number of cases. Shank proteins serve as scaffolds on the post-synaptic membranes of glutamatergic synapses, and are highly expressed in the striatum. This gene has variants that appear disproportionately often in schizophrenia as well, leading to speculation on common biologic processes.


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Neurology_Adams. The autistic child is ostensibly normal at birth and may continue to be normal in achieving early behavioral sequences until 18 to 24 months of age. Then an alarming regression occurs, sometimes fairly abruptly. In some instances, the abnormality appears even before the first birthday and the child is identified as different in some way by the mother; or, if there had been a previously autistic child, she recognizes the early behavioral characteristics of the disorder. The level of activity is reduced or increased. There may be less crying and an apparent indifference to surroundings. Toys are ignored or held tenaciously. Spinning toys or running water may hold a strange fascination for the child. Cuddling may be resisted. Motor developments, on the other hand, proceed normally and may even be precocious. Later there may be an unusual sensitivity to all modes of sensory stimulation. Occasionally the onset appears to have a relationship to an injury or an upsetting experience.