Neurology_Adams

Neurology_Adams. On the trunk, the diagnostic lesion is the “shagreen patch” (in reality a plaque of subepidermal fibrosis) found most often in the lumbosacral region. It appears as a flat, slightly elevated, flesh-colored area of skin 1 to 10 cm in diameter, with a “pigskin,” “elephant hide,” or “orange peel” appearance (Fig. 37-6). Another common site of fibromatous involvement is the nail bed; subungual fibromas usually appear at puberty and continue to develop with age. Other common skin changes, not in themselves diagnostic, include fibroepithelial tags (soft fibromas), café-au-lait spots, and port-wine hemangiomas.


Neurology_Adams

Neurology_Adams. The brain exhibits a number of diagnostic anomalies. Broadening, unnatural whiteness, and firmness of parts of some of the cerebral convolutions are simulated by no other disease. These are the tubers after which the disease is named. On the surface of the brain, they range in width from 5 mm to 2 or 3 cm. Their cut surface reveals a lack of demarcation from cortex and white matter and the presence of white flecks of calcium; these, which are readily seen on CT and MRI, are called brain stones (see below and Fig. 37-7). The walls of the lateral ventricles may be encrusted with white or pink-white masses resembling candle gutterings. When calcified, they appear in radiographs as curvilinear opacities that follow the outline of the ventricle. Rarely, nodules of abnormal tissue are observed in the basal ganglia, thalamus, cerebellum, brainstem, and spinal cord.


Neurology_Adams

Neurology_Adams. Under the microscope the tubers are seen to be composed of interlacing rows of plump, fibrous astrocytes (much like an astrocytoma, though lacking in glial fibrillar protein). In the cerebral cortex and ganglionic structures, derangements of architecture result from the presence of abnormal-appearing cells: greatly enlarged “monstrous,” or “balloon” neurons and glia cells—often difficult to distinguish from one another. Also, displaced normal-sized neurons contribute to the chaotic histologic appearance. Gliomatous deposits may obstruct the foramina of Monro or the aqueduct or floor of the fourth ventricle, causing hydrocephalus. Neoplastic transformation of abnormal glia cells, a not infrequent occurrence, usually takes the form of a large-cell astrocytoma, less often of a glioblastoma or meningioma. Recently, certain relationships have been drawn between the balloon cells of this disease and similar cells in focal cortical dysplasias (see Crino for details).


Neurology_Adams

Neurology_Adams. The phakomas of the retina are also composed mainly of neuronal and glial components, but occasionally there is an admixture of fibrous tissue.


Neurology_Adams

Neurology_Adams. When the full combination of seizures and mental and dermal abnormalities is conjoined, the diagnosis is self-evident. It is the early stage of the disease and the formes frustes that give trouble, and here the experienced dermatologist can be of great help. Epilepsy—that is, flexion spasms in infancy—and delay in psychomotor development are by no means diagnostic of tuberous sclerosis, as they occur in many diseases. It is in these cases, and also in every sizable population of the epileptic or developmentally delayed, especially when the family history is unrevealing, that a search for the dermal equivalents of the disease—the hypomelanotic ash-leaf spots, adenoma sebaceum, collagenous skin patch, phakoma of the retina, or subungual or gingival fibromas—is so rewarding. The finding of any one of these lesions provides confirmation of the partial and atypical case. Adenoma sebaceum may occasionally occur alone and is easily confused with acne vulgaris in the adolescent. The history


Neurology_Adams

Neurology_Adams. any one of these lesions provides confirmation of the partial and atypical case. Adenoma sebaceum may occasionally occur alone and is easily confused with acne vulgaris in the adolescent. The history of epilepsy or demonstration of developmental delay is helpful but neither is a requisite for the diagnosis of tuberous sclerosis (see the monograph by Gomez).


Neurology_Adams

Neurology_Adams. The most useful laboratory measures for corroborating the disease are CT and MRI (see Fig. 37-7). The calcific tuber lesions tend to be periventricular and are particularly well shown on CT, whereas MRI is more sensitive in detecting the hamartomatous giant cell subependymal and subcortical lesions. There is an absence of edema in the surrounding tissue. Roach and colleagues have indicated that an increasing number of cortical lesions demonstrated with MRI appear to correlate with an increased impairment of neurologic function. Clinics that treat large numbers of these patients recommend imaging of the kidneys and lungs and, in children, echocardiography. Serial examinations to detect enlargement of the subependymal tumors is advised annually for those younger than age 21 years and every 2 to 3 years thereafter, but the best course of action if a glioma emerges has not been clearly established.


Neurology_Adams

Neurology_Adams. Nothing can be offered in the way of prevention other than genetic counseling. Antiepileptic therapy of the standard type suppresses the convulsive tendency more or less effectively and should be applied. Adrenocorticotropic hormone (ACTH) suppresses the flexor spasms in infancy and tends to normalize the EEG for a time.


Neurology_Adams

Neurology_Adams. Tumor excision is generally not undertaken, especially in severely affected individuals (with the exception of renal hamartomas that impair kidney function). However, sirolimus, which suppresses the mTOR signaling pathway, causes slight regression of the bodily angiolipomas (Bissler et al) and, of greater interest to the neurologist and neurosurgeon, the similar drug rapamycin has been shown in a report by Franz and colleagues to shrink subependymal giant cell astrocytomas in some patients, and its efficacy has been supported by more recent studies. Everolimus, another mTOR inhibitor has been found to be useful in the same way and in suppressing the status epilepticus associated with some cases of tuberous sclerosis (Krueger et al).


Neurology_Adams

Neurology_Adams. Some patients undergo dermabrasion of the facial lesions for cosmetic reasons, with the knowledge that these slowly regrow. To an increasing degree, neurosurgeons are excising single epileptogenic cortical tubers in otherwise relatively normal children. There are about 15 specialized centers in the United States, and several abroad, that are expert at caring for these patients and establishing a regimen of radiologic surveillance. (See http://www.tsalliance .org as well as the International Tuberous Sclerosis Complex Consensus Group for further information including guidelines for testing, surveillance, and management.)


Neurology_Adams

Neurology_Adams. Complex Consensus Group for further information including guidelines for testing, surveillance, and management.) In general, the disease advances so slowly that years must elapse before one can be sure of progression. Of the severe cases, approximately 30 percent die before the fifth year, and 50 to 75 percent before attaining adult age. Worsening is mainly in the cognitive sphere. Status epilepticus accounted for many deaths in the past, but improved medication therapy has reduced this hazard. Neoplasias take their toll; the authors have had several such patients who died of malignant gliomas arising in striatothalamic regions. Neurofibromatosis of von Recklinghausen


Neurology_Adams

Neurology_Adams. Neurofibromatosis of von Recklinghausen Neurofibromatosis (NF) is a comparatively common hereditary disease in which the skin, nervous system, bones, endocrine glands, and sometimes other organs are the sites of a variety of congenital abnormalities, often taking the form of benign tumors. The typical clinical picture, usually identifiable at a glance, consists of multiple circumscribed areas of increased skin pigmentation accompanied by dermal and neural tumors of various types.


Neurology_Adams

Neurology_Adams. The condition known as multiple idiopathic neuromas was the subject of a monograph by R.W. Smith in 1849; even at that time, he referred to examples recorded by other writers. It was von Recklinghausen, however, who, in 1882, gave the definitive account of its clinical and pathologic features. The subsequent studies of the disease by Yakovlev and Guthrie; Lichtenstein; Riccardi; and Martuza and Eldridge; and more recently by Créange and colleagues; and the comprehensive monographs of Crowe and colleagues and of Riccardi and Mulvihill are informative references that provide a complete analysis of the clinical, pathologic, and genetic data pertaining to the disease.


Neurology_Adams

Neurology_Adams. Epidemiology Crowe and associates calculated the prevalence of the disease to be 30 to 40 per 100,000, with the expectancy of 1 case in every 2,500 to 3,300 births over 50 years ago and these rates pertain in the all series from the current era. Approximately half of their cases had affected relatives, and in all instances the distribution of cases within a family was consistent with an autosomal dominant mode of inheritance. The disease has been observed in all races in different parts of the world, and males and females are about equally affected.


Neurology_Adams

Neurology_Adams. Cause and pathogenesis The hereditary nature of NF has been appreciated for a century. More recently, it has been established that NF comprises two distinct disorders, the genes for which are located on different chromosomes. Both are inherited in an autosomal dominant pattern with a high degree of penetrance, but half the cases are a result of spontaneous mutations. The classic form of the disease with multiple neurofibromas, described below, is caused by a mutation located near the centromere on chromosome 17 in a gene called neurofibromin (Barker et al). The second type, in which the main feature is bilateral acoustic nerve neuromas, described further on, is caused by a mutation in the merlin gene (also called schwannomin). These two forms of NF have been loosely referred to as peripheral and central, respectively, but the terms neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are less confusing (Martuza and Eldridge) and are used in the following discussion.


Neurology_Adams

Neurology_Adams. The large size of the NF1 gene (60 exons) and the widely scattered mutations has made genetic testing complex but such testing is available. Virtually all families manifest different mutations and there have been no clear associations between specific mutations and phenotypic characteristics except that the rare complete deletion leads to early onset multiple neurofibromas, developmental delay, and facial dysmorphism.


Neurology_Adams

Neurology_Adams. The pathogenesis is less obscure now that the genes implicated in both diseases have been identified. Both involve tumor suppression. As with tuberous sclerosis, there is a suggestion of a disorder that allows low-grade ectodermal cell proliferation without tumor transformation. Cellular elements derived from the neural crest (i.e., Schwann cells, melanocytes, and endoneurial fibroblasts, the natural components of skin and nerves) proliferate excessively in multiple foci, and the melanocytes function abnormally. The hormones and growth factors involved in this proliferative process and the mechanism by which it occurs are as obscure as they are in tuberous sclerosis. It is known, however, that most of the numerous mutations in the NF1 gene lead to premature termination of protein synthesis and a consequent “loss of function.” This is in keeping with the tumor suppressor characteristics of the gene and the emergence of neoplasms in the presence of homozygous mutations.


Neurology_Adams

Neurology_Adams. Neurofibromatosis Type 1 (Classic, or Peripheral, NF) (Table 37-6)


Neurology_Adams

Neurology_Adams. In the majority of patients, spots of hyperpigmentation (café-au-lait lesions) and cutaneous and subcutaneous neurofibromatous tumors are the basis of clinical diagnosis. Pigmentary changes in the skin are nearly always present at birth, but neurofibromas are infrequent at that age. Both lesions increase in number and size during late childhood and adolescence. There may be a spurt of new lesions at puberty or during pregnancy. Exceptionally, a neurofibroma of a cranial nerve or a spinal root (sometimes with compression of the cord), disclosed during imaging of the spine or a neurosurgical intervention, may be the initial manifestation of the disease. In a large series of patients with neurofibromatosis (Crowe et al), approximately one-third were found to have only the cutaneous manifestations that were noted while being examined for symptoms of some other disease; that is to say, the NF was asymptomatic. Usually these are the patients with the slightest degree of cutaneous


Neurology_Adams

Neurology_Adams. manifestations that were noted while being examined for symptoms of some other disease; that is to say, the NF was asymptomatic. Usually these are the patients with the slightest degree of cutaneous abnormality. Of the remaining two-thirds, most consulted a physician because of the disfigurement produced by the skin tumors or because some of the neurofibromas were producing neurologic symptoms.


Neurology_Adams

Neurology_Adams. The patches of cutaneous pigmentation, appearing shortly after birth and occurring anywhere on the body, constitute the most obvious clinical expression of the disease. They are approximately oval in shape and vary in size from a 1 to 2 mm to many centimeters, and in color from a light to dark brown (the term café-au-lait is applied) and are rarely associated with any other pathologic state (Fig. 37-8).


Neurology_Adams

Neurology_Adams. They do not appear to change in number as the patient ages, but they do enlarge during puberty and become more pigmented. In a survey of pigmented spots in the skin, Crowe and associates found that 10 percent of the normal population had one or more spots of this type; however, anyone with more than 6 such spots, some exceeding 1.5 cm in diameter in postpubertal individuals (bigger than 0.5 mm in prepubertal ones), nearly always proved to have neurofibromatosis. Of their 223 patients with NF, 95 percent had at least 1 spot and 78 percent had more than 6 large spots. Freckle-like or diffuse pigmentation of the axillae and other intertriginous areas (groin, under breast) and small, round, whitish spots are characteristic, as pointed out by Crowe; when coupled with café-au-lait patches, they are virtually pathognomonic of the disease.


Neurology_Adams

Neurology_Adams. The appearance of multiple cutaneous and subcutaneous tumors in late childhood or early adolescence is the other principal feature of the disease. The cutaneous tumors are situated in the dermis and form discrete soft or firm papules varying in size from a few millimeters to a centimeter or more (molluscum fibrosum; Fig. 37-9). They assume many shapes—flattened, sessile, pedunculated, conical, lobulated, and so on. They are flesh-colored or violaceous and often topped with a comedo. When pressed, the soft tumors tend to invaginate through a small opening in the skin, giving the feeling of a seedless raisin or a scrotum without a testicle. This phenomenon, spoken of as “buttonholing,” is useful in distinguishing the lesions of this disease from other skin tumors, for example, multiple lipomas. A patient may have anywhere from a few of these dermal tumors to hundreds.


Neurology_Adams

Neurology_Adams. The subcutaneous neural tumors, which are also multiple, take two forms: (1) firm, discrete nodules attached to a nerve or (2) an overgrowth of subcutaneous tissue, sometimes reaching enormous size. The latter, which are called plexiform neuromas (also pachydermatocele, elephantiasis neuromatosis, la tumeur royale), occur most often in the face, scalp, neck, and chest, and may cause severe disfigurement. When palpated, they feel like a bag of worms or strings; the bone underlying the tumor may thicken. Neurofibromas are easily distinguished from lipomas, which are soft, unattached to the skin or nerve, and not accompanied by any neurologic disorder. An exception to this last statement is the rare disease of multiple symmetrical lipomatosis with axonal polyneuropathy (Launois-Bensaude disease). As a rule, congenital neurofibromas tend to be highly vascular and invasive and are especially prominent in the orbital, periorbital, and cervical regions. They may be accompanied by hypertrophy


Neurology_Adams

Neurology_Adams. As a rule, congenital neurofibromas tend to be highly vascular and invasive and are especially prominent in the orbital, periorbital, and cervical regions. They may be accompanied by hypertrophy of a segment of the body (a sign also seen in the arteriovenous malformation of Klippel-Trenaunay-Weber syndrome). When the hyperpigmentation lesion overlies a plexiform neurofibroma and extends to the midline, one should suspect an intraspinal neurofibroma tumor at that level.


Neurology_Adams

Neurology_Adams. Another unique finding is the Lisch nodule. This is a small whitish spot (actually a hamartoma) in the iris that was present in 94 percent of Riccardi’s type 1 cases, but was not found in patients with NF2 or in normal individuals (Fig. 37-10 and below). Headache, hydrocephalus, and tumors involving the optic pathways, meningiomas, gliomas, and malignant peripheral nerve tumors are common, even among adults, according to the survey of 158 patients by Créange and colleagues; also, pain was a common symptom in adults and often related to a malignant peripheral nerve sheath tumor.


Neurology_Adams

Neurology_Adams. Other abnormalities associated less consistently with type 1 (peripheral) NF include bone cysts, pathologic fractures (pseudoarthrosis), cranial bone defects with pulsating exophthalmos (sphenoid bone dysgenesis), bone hypertrophy, precocious puberty, pheochromocytoma, scoliosis, syringomyelia, nodules of abnormal glia cells in brain and spinal cord, and macrocephaly, rarely with obstructive hydrocephalus as a result of overgrowth of glial tissue around the sylvian aqueduct and fourth ventricle. Some degree of intellectual impairment is common; it was found in 40 percent of Riccardi’s series of 133 patients. But in our experience, the figure is much lower and the impairment is usually not profound. Learning difficulty, developmental disorder, and hyperactivity have been more frequent abnormalities, occurring in almost 40 percent of patients. Rosman and Pearce have ascribed developmental delay in NF to congenital malformation of the cerebral cortex (cortical dysgenesis). The incidence


Neurology_Adams

Neurology_Adams. occurring in almost 40 percent of patients. Rosman and Pearce have ascribed developmental delay in NF to congenital malformation of the cerebral cortex (cortical dysgenesis). The incidence of seizures is about 20 times higher than that in the general population, but these tend not to be a very frequent or intractable problem.


Neurology_Adams

Neurology_Adams. Exceptionally, NF is associated with peroneal muscular atrophy, congenital deafness, and partial albinism (Bradley et al). In childhood, progressive blindness is a particularly dire complication from a tumor mass composed mainly of astrocytes (optic glioma). The tumor may involve one or both optic nerves. The diagnosis comes to mind at once in a child with any of the cutaneous manifestations of NF and this tumor. Uncertainty as to its nature arises from the fact that the neuropathologist may be unable to decide between a benign hamartoma and a grade 1 astrocytoma. Progressive enlargement in a succession of MRI scans may be needed to affirm its nature. It needs to be stated that neurofibromas of the spinal roots occur regularly in patients without NF (see Chaps. 42 and 43). Whether multiple such lesions implicate NF is not clear. Neurofibromatosis Type 2 (Acoustic, or Central, NF)


Neurology_Adams

Neurology_Adams. Neurofibromatosis Type 2 (Acoustic, or Central, NF) This condition is considerably less frequent than NF1. Here there is an absence or paucity of cutaneous lesions. Progressive deafness and the demonstration by enhanced CT or MRI of bilateral acoustic neuromas afford accurate diagnosis (see Fig. 30-18). Also, an acoustic neuroma developing before age 30 years is suspect as being caused by NF2. Other cranial or spinal neurofibromas, meningioma (sometimes multiple), and glioma may be added to the syndrome of deafness or may occur prior to its emergence. Juvenile cataracts of the subcortical or capsular variety are seen in some affected patients. Analysis for the NF2 gene is available and the genetics and affected protein (merlin or schwannomin) are discussed in “Cause and Pathogenesis” above.


Neurology_Adams

Neurology_Adams. Analysis for the NF2 gene is available and the genetics and affected protein (merlin or schwannomin) are discussed in “Cause and Pathogenesis” above. As commented in Chap. 30 in the discussion of acoustic neuroma, it is now apparent that the propensity to develop multiple schwannomas can also be inherited as a dominant trait, without the vestibular tumors characteristic of NF2. This trait maps to a genetic locus on chromosome 22 that is distinct from the one for NF2. It has been estimated that 2 to 5 percent of schwannomas requiring resection are from this disease. The diagnostic criteria are based on the presence of two of more schwannomas without vestibular nerve tumors in an individual older than age 18 years, as summarized in a thorough review by MacCollin and colleagues, and more recently by Plotkin and colleagues. Pain is the dominant problem. Pathology of NF1 and NF2


Neurology_Adams

Neurology_Adams. Pathology of NF1 and NF2 The cutaneous tumors are characterized by a rather thin epidermis whose basal layer may or may not be pigmented. The collagen and elastin of the dermis is replaced by a loose arrangement of elongated connective tissue cells. The lack of compactness of the normal dermal collagen allows the palpable opening in the skin. The pigmented (café-au-lait) lesions contain only the normal numbers of melanocytes; the dark color of the skin is instead the result of an excess of melanosomes in the melanocytes. Some of the abnormally large melanosomes measure up to several microns in diameter.


Neurology_Adams

Neurology_Adams. The nerve tumors are composed of a mixture of fibroblasts and Schwann cells (except the optic nerve tumors, which contain a combination of astrocytes and fibroblasts). Predominance of one or the other of these cells in the nerve is the basis of the diagnosis of neurofibroma or schwannoma. Palisading of nuclei and sometimes encircling arrangements of cells (Verocay bodies) are features of both (see Chap. 30). Occasionally, along spinal roots or sympathetic chains, one may find a tumor made up of partially or completely differentiated nerve cells, a typical ganglioneuroma. Clusters of abnormal glia cells may be found in the brain and spinal cord, and, according to Bielschowsky, they imply a link with tuberous sclerosis that has never been proved. Clinically and genetically, the two diseases are quite independent. Malignant degeneration of the tumors is found in 2 to 5 percent of cases; peripherally they become sarcomas and centrally, astrocytomas or glioblastomas (Fig. 37-11).


Neurology_Adams

Neurology_Adams. If skin tumors and café-au-lait spots are numerous and Lisch nodules are present in the iris, the identification of the disease as type 1 neurofibromatosis offers no difficulty. A history of the illness in antecedent and collateral family members makes diagnosis even more certain. Doubt arises most frequently in patients with bilateral acoustic neuromas or other cranial or spinal neurofibromas or schwannomas with no skin lesions or only a few random ones. The tendency for these forms of NF to have few skin lesions is well known, but differentiation of type 1 from type 2 may be uncertain unless genetic studies are undertaken. Plexiform neuromas with muscle weakness because of nerve involvement and abnormalities of underlying bone may be confused with other tumors, especially in young children, who tend to have few café-au-lait spots and few cutaneous tumors. Hypertrophy of a limb requires differentiation from other developmental anomalies including Klippel-Trenaunay-Weber syndrome.


Neurology_Adams

Neurology_Adams. As already mentioned, Crowe and coworkers expressed the view that 80 percent of patients with von Recklinghausen disease can be diagnosed by the presence of more than 6 café-au-lait spots. Of the remaining 20 percent, those older than 21 years of age will be found to have multiple cutaneous tumors, axillary freckling, and a few pigmented spots; in those younger than 21 years of age with no dermal tumors and only a few café-au-lait patches, a positive family history and radiographic demonstration of bone cysts will be helpful in some instances. Café-au-lait spots and cutaneous tumors should always be sought, for they may help the neurologist diagnose an otherwise obscure progressive spinal syndrome, a cerebellopontine angle syndrome, bilateral deafness, progressive blindness, and an occasional case of precocious puberty, hydrocephalus, or developmental delay.


Neurology_Adams

Neurology_Adams. Because of the many potentially dangerous conditions that accompany classic NF, the initial clinical evaluation should be supplemented by a number of ancillary examinations that may include measurement of IQ, EEG, slit-lamp examination of irides, visual and auditory evoked responses, and CT or MRI of the cranium and, sometimes, of the spine and mediastinum. In the series reported by Duffner and colleagues, 74 percent of cases had abnormal signals in T2-weighted images of the basal ganglia, thalamus, hypothalamus, brainstem, and cerebellum. The EEG was abnormal in 25 percent. If there is suspicion of a pheochromocytoma, 24-h urine should be tested for metabolites of epinephrine. Each of these tests not only is an aid to diagnosis but also is essential to the effective management of the illness.


Neurology_Adams

Neurology_Adams. The skin tumors should not be excised unless they are cosmetically objectionable or show an increase in size, suggesting malignant change. The effects of radiotherapy on these lesions are so insignificant that they do not justify the risk of exposure. Plexiform neuromas about the face pose especially difficult problems. Here one must resort to plastic surgery, but the results are not always satisfactory because the growths may encompass distal branches of cranial nerves (with risk of greater paralysis after surgical excision) or alter the underlying bone, the latter being either eroded from pressure or hypertrophied from increased blood supply. Cranial and spinal neurofibromas are amenable to excision, and the gliomas and meningiomas usually demand surgical measures as well. Here the differentiation of hamartomas from gliomas of structures such as the optic nerves, hypothalamus, or pons may be difficult. Bilateral optic nerve gliomas are usually treated with radiation; unilateral ones


Neurology_Adams

Neurology_Adams. of hamartomas from gliomas of structures such as the optic nerves, hypothalamus, or pons may be difficult. Bilateral optic nerve gliomas are usually treated with radiation; unilateral ones are excised. Peripheral nerve tumors that have undergone malignant (sarcomatous) degeneration pose special surgical problems.


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Neurology_Adams. Affected individuals should be referred for genetic counseling. Fertility, especially in males, seems to be reduced by the disease. Prognosis varies with the grade of severity, being most favorable in those with only a few lesions. But the disease is always progressive, and the patient should remain under surveillance. Other Cutaneous Angiomatoses With Abnormalities of the Central Nervous System


Neurology_Adams

Neurology_Adams. There are at least 7 additional diseases in which a cutaneous or ocular vascular anomaly is associated with an abnormality of the nervous system: (1) meningoor encephalofacial (encephalotrigeminal) angiomatosis with cerebral calcification (Sturge-Weber syndrome); (2) dermatomal hemangiomas and spinal vascular malformations (sometimes with limb hypertrophy, as also occurs in Klippel-Trenaunay-Weber syndrome and in neurofibromatosis); (3) the epidermal nevus (linear sebaceous nevus) syndrome; (4) familial telangiectasia (Osler-Rendu-Weber disease); (5) hemangioblastoma of cerebellum and retina (von Hippel-Lindau disease); (6) ataxia-telangiectasia (Louis-Bar disease); and (7) angiokeratosis corporis diffusum (Fabry disease). The last three disorders are considered elsewhere: ataxia-telangiectasia and Fabry disease with the inherited metabolic disorders in Chap. 36, and von Hippel-Lindau disease below and with hemangioblastoma in Chap. 30.


Neurology_Adams

Neurology_Adams. This condition has been referred to as the Sturge-Weber syndrome, as it was W. Allen Sturge who, in 1879, described a child with sensorimotor seizures contralateral to a facial “port-wine mark,” and Weber and Parkes, who gave the first radiographic demonstration of the atrophy and calcification of the cerebral hemisphere ipsilateral to the skin lesion. This eponym overlooks the important intervening contributions of Kalischer (1897, 1901), who first described the meningeal angioma in conjunction with the facial one; of Volland, who demonstrated the intracortical calcific deposits; and of Dimitri, who in 1923 described the characteristic double-contoured radiographic shadows. Krabbe showed conclusively that the calcification lay not in the blood vessels (as Dimitri and many others had concluded), but in the second and third layers of the cortex (see Wohlwill and Yakovlev for historical review and bibliography).


Neurology_Adams

Neurology_Adams. A vascular nevus is observed at birth to cover a large part of the face and cranium on one side (in the territory of the ophthalmic division of the trigeminal nerve). In one-quarter of the cases the nevus is bilateral. The lesions vary in extent, the most limited being an involvement of only the upper eyelid and forehead, and the most extensive being the entire head and even other parts of the body. The skin lesion is deep red (port-wine nevus) and its margins may be flat or raised; soft or firm papules, evidently composed of vessels, cause surface elevations and irregularities. Orbital tissue, especially the upper eyelid, is almost invariably involved; congenital buphthalmos may enlarge the eye before birth and glaucoma may develop later in that eye, causing blindness. The choroid is implicated in some cases. The increased cutaneous vascularity may result in an overgrowth of connective tissue and underlying bone, giving rise to a deformity like that of the Klippel-Trenaunay-Weber


Neurology_Adams

Neurology_Adams. implicated in some cases. The increased cutaneous vascularity may result in an overgrowth of connective tissue and underlying bone, giving rise to a deformity like that of the Klippel-Trenaunay-Weber syndrome. Indications of cerebral disease appear as early as the first year of life or later in childhood; the most frequent clinical manifestations are unilateral seizures followed by increasing degrees of spastic hemiparesis with smallness of the arm and leg, hemisensory defect, and homonymous hemianopia, all on the side contralateral to the trigeminal nevus. Skull films (usually normal just after birth) taken after the second year reveal a characteristic “tramline” calcification, which outlines the involved convolutions of the parietooccipital cortex. CT and MRI show the abnormalities of the involved cortex at an earlier age (Fig. 37-12) and in greater detail.


Neurology_Adams

Neurology_Adams. It is not the case that all cranial hemangiomas affect the cerebrum; the common facial nevi, especially the flat midline ones and the elevated strawberry nevi, are of no neurologic significance. And a cerebral–meningeal angiomatosis may be present without skin lesions. The involvement of the upper eyelid is of greatest importance since nearly all such cases are associated with cerebral lesions (Barlow). There seems to be a close correlation between the persistence or maldevelopment of the embryonic vascular plexus of the eyelid and forehead and that of the occipitoparietal parts of the brain. When the nevus lies entirely below the upper eyelid or high on the scalp, a cerebral lesion is usually absent, although in a few instances such an angioma has been associated with a vascular malformation of the meninges overlying the brainstem and cerebellum. In angiograms, the abnormal meningeal vessels, which are largely veins, are not well seen; thus they can be distinguished from true


Neurology_Adams

Neurology_Adams. of the meninges overlying the brainstem and cerebellum. In angiograms, the abnormal meningeal vessels, which are largely veins, are not well seen; thus they can be distinguished from true arteriovenous malformations. These purely meningeal venous nevi are rarely the source of subarachnoid or cerebral hemorrhage and they do not enlarge to form a mass. The cortical lesion is, however, destructive of cortical tissue, which is replaced by glial tissue that calcifies. One explanation holds that diversion of blood to the meninges during seizures causes progressive ischemia of the cerebral cortex. Barlow has stated that the seizures themselves are responsible for the progressive neurologic deficits and that a special effort should be made to prevent them by carefully regulated medical therapy. Occasionally surgical excision of intractable discharging foci may be necessary, but often this may not be feasible in view of the magnitude of the cerebral lesion. Radiotherapy in the past was


Neurology_Adams

Neurology_Adams. Occasionally surgical excision of intractable discharging foci may be necessary, but often this may not be feasible in view of the magnitude of the cerebral lesion. Radiotherapy in the past was unsuccessful in reducing the skin blemish, though has shown promise in small studies in treating ocular choroidal hemangiomas and preserving vision. Instead, various laser techniques have been employed for the skin lesion with moderate cosmetic success. There is little literature on treating the brain vascular malformation with endovascular techniques.


Neurology_Adams

Neurology_Adams. Although a heredofamilial trait has long been known, it was only relatively recently that Shirley and colleagues found a polymorphism in the responsible gene, GNAQ, in almost 90 percent of individuals with the trait and in a similar number of patients with non-syndromic port-wine stains on the cranium. The variant may be of a mosaic type, being present only in affected tissues. This substitution in the gene activates extracellular signal-regulated kinase. Similar SNPs have been known to participate in other conditions that feature abnormal skin pigmentation.


Neurology_Adams

Neurology_Adams. A hemangioma of the spinal cord may rarely be accompanied by a vascular nevus in the corresponding dermatome, as was first pointed out by Cobb. Such nevi are most frequent on the arm and trunk. When the cutaneous lesion involves an arm or leg, there may be enlargement of the entire limb or fingers in combination with underdevelopment of certain other parts (Klippel-Trenaunay-Weber syndrome). Some of these angiomatous syndromes combine a spinal or retinal-diencephalic arteriovenous malformation (AVM) with a nevus of the trunk or face, respectively. Such cases provide a link to the common AVMs described in Chap. 33.


Neurology_Adams

Neurology_Adams. This is a closely related congenital neurocutaneous disorder in which a specific skin lesion (epidermal nevus or linear sebaceous nevus) is associated with a variety of hemicranial and neurologic abnormalities. The skull and brain abnormalities are ipsilateral to the nevus. One-sided thickening of the bones of the skull is characteristic. Developmental delay, seizures, and hemiparesis are the usual neurologic manifestations and have their basis in a wide variety of cerebral lesions—unilateral cerebral atrophy, porencephalic cyst, leptomeningeal hemangioma, arteriovenous malformation, and atresia of cerebral arteries and veins. The somatic and neurologic abnormalities of this syndrome have been comprehensively reviewed by Solomon and Esterley and by Baker and associates.


Neurology_Adams

Neurology_Adams. Solomon and Esterley and by Baker and associates. This vascular anomaly is transmitted as an autosomal dominant trait. To date, two mutant genes have been identified as causes of this disease: endoglin and novel kinase. The small arteriovenous malformations affect the skin, mucous membranes, gastrointestinal and genitourinary tracts, lungs, and occasionally the nervous system. The basic lesion is probably a defect in the vessel wall, and the main complication, bleeding, is thought to be a result of the mechanical fragility of the vessel. Located sparsely in the skin of any part of the body, these vascular lesions first appear during childhood, enlarge during adolescence, and may assume spidery forms, resembling the cutaneous telangiectases of cirrhosis in late adult life. The lesions range from the size of a pinhead to 3 mm or more, are bright red or violaceous, and blanch under pressure.


Neurology_Adams

Neurology_Adams. The significance of the lesions lies in their hemorrhagic tendency. During adult years they may give rise to severe and repeated epistaxis or gastric, intestinal, or urinary tract bleeding and result in an iron-deficiency anemia. Pulmonary fistulas constitute another important feature of the generalized vascular dysplasia; patients with such lesions are particularly subject to brain abscesses and less so to bland embolic strokes. The angiomas of this disease may infrequently form in either the spinal cord or brain, where they can produce acute hemorrhage, or as in one of our patients, there may be an intermittently progressive focal thalamic syndrome resulting from enlargement of the vascular lesions or possibly from a succession of small hemorrhages. Repeated unexplained gastrointestinal, genitourinary, intracranial, or intraspinal hemorrhages warrant a search for small cutaneous lesions, which are easily overlooked. Satellite lesions tend to form after obliteration of an angioma.


Neurology_Adams

Neurology_Adams. There are five genetic types with hundreds of mutations known. A mutation in the gene coding for endoglin (ENG) accounts for most cases with a smaller proportion due to a mutation in the gene for activin (ACVRL1), both proteins involved in angiogenesis but the actual mechanism of formation of the main feature, vascular malformations, is not completely understood.


Neurology_Adams

Neurology_Adams. This is a genetic disease of multiple neoplasms, specifically by the presence of a hemangioblastoma, sometimes multiple (these are discussed with other cerebral tumors in Chap. 30). The tumor is situated in the cerebellum in most cases, but may also arise in the brainstem or spinal cord. In addition to the characteristic cerebellar tumor with its nodule within a cyst, half of these patients have retinal hemangioblastomas and somewhat fewer develop renal cell cancer; an even smaller number have a pheochromocytoma, pancreatic tumors or cysts, or cystadenomas. Polycythemia vera is an interesting feature in a few cases. We have encountered rare cases that presented as subarachnoid hemorrhage.


Neurology_Adams

Neurology_Adams. The cerebellar hemangioblastoma typically develops in the fourth decade and causes symptoms of ataxia and headache. On imaging studies, the lesions have a striking appearance of a cyst with a nodule contained in its wall, and angiography demonstrates the highly vascular nature of the nodule, which represents the actual neoplasm (see Fig. 30-13). The other identifying features of the disease, retinal hemangiomas, are smaller but indistinguishable histologically from the craniospinal ones. They are multiple and bilateral, usually appearing earlier than the cerebellar lesions but remaining asymptomatic until they become extensive (retinal detachment is one feature). Their diagnosis is made by funduscopy, by which a large feeding vessel leading to an irregularly shaped ovoid tumor in the retina can usually be appreciated. Imaging studies of the cranium that use dye enhancement will reveal them as well.


Neurology_Adams

Neurology_Adams. Inheritance is autosomal dominant with variable but high penetrance by older age. The causative mutation is in the VHL gene located on chromosome 3. This is a tumor suppressor gene that is inactivated by the mutation and may induce oncogenesis by increasing the expression of vascular mitogenic factors such as vascular endothelial growth factor (VEGF) but the precise mechanisms are not known. Renal cell cancer is a serious component of the disease, occurring in up to 60 percent of cases, but the tumors, although multiple, tend initially to be small and of low grade. Nonetheless, renal cancer accounts for one-third of deaths from the disease, the remainder being largely the result of complications of the cerebellar neoplasm. An extensive review of the subject was written by Losner and colleagues.


Neurology_Adams

Neurology_Adams. Mentioned here is the cerebellar gangliocytoma of Lhermitte-Duclos disease. There are no cutaneous malformations but small vascular anomalies in the brain and elsewhere may accompany the cerebellar tumor as discussed in Chap. 30 (see Fig. 30-15). This disease, also referred to as the Louis-Bar syndrome, was first described by Sylaba and Henner in 1926, before Louis-Bar’s report in 1941. It combines a progressive ataxia with humoral immune deficiency and telangiectasias. Like xeroderma pigmentosum and the Cockayne syndrome, ataxia-telangiectasia has been attributed to defective repair of DNA. The inheritance pattern is autosomal recessive and the clinical presentation is somewhat heterogeneous, with certain features predominating in a particular child and his siblings, as summarized by Boder and Sedgwick. An adult form may show few of the characteristic telangiectasias.


Neurology_Adams

Neurology_Adams. The disorder first presents as an ataxic-dyskinetic syndrome in children who appear to have been normal in the first few years of life. The onset of the disease coincides more or less with the acquisition of walking, which is awkward and unsteady. Later, by the age of 4 to 5 years, the limbs become ataxic, and choreoathetosis, grimacing, and dysarthric speech are added. The eye movements become jerky, with slow and long-latency saccades, and there is also apraxia for voluntary gaze (the patient turns the head but not the eyes on attempting to look to the side). This movement of the head and eyes in tandem is the most specific feature of the process. Optokinetic nystagmus is lost and reading becomes all but impossible. Severe cognitive developmental delay is infrequent, affecting perhaps 10 percent of children but in those affected, it is apparent by the age of 9 to 10 years; slight intellectual limitation is more common. Signs of mild polyneuropathy are evident at this age as well,


Neurology_Adams

Neurology_Adams. 10 percent of children but in those affected, it is apparent by the age of 9 to 10 years; slight intellectual limitation is more common. Signs of mild polyneuropathy are evident at this age as well, appearing similarly the Charcot-Marie-Tooth phenotype. Seizures are not part of the syndrome.


Neurology_Adams

Neurology_Adams. Muscle power is reduced little if at all until late in the illness, but tendon reflexes may disappear. The characteristic telangiectatic lesions, which are mainly transversely oriented subpapillary venous plexuses, appear at 3 to 5 years of age or later (they are not apparent in some patients until approximately age 7) and are most apparent in the outer parts of the bulbar conjunctivae (Fig. 37-13), over the ears, on exposed parts of the neck, on the bridge of the nose and cheeks in a butterfly pattern, and in the flexor creases of the forearms. Vitiligo, café-au lait spots, loss of subcutaneous fat, and premature graying of hair are observed in some older patients. Many of the patients have endocrine alterations (absence of secondary sexual development, glucose intolerance). The disease is progressive, and death may occur in the second decade from intercurrent bronchopulmonary infection or neoplasia—usually lymphoma, less often glioma, that develop in fewer one-third of patients.


Neurology_Adams

Neurology_Adams. As mentioned, the adult form of ataxia-telangiectasia, in which some of the deficient enzyme activity is retained (see below), manifests few telangiectasias but may be identified by an extrapyramidal syndrome in childhood and only later, with mild ataxia as summarized by Verhagen and colleagues; there may be a family history of cancers.


Neurology_Adams

Neurology_Adams. The significant abnormalities in the CNS are severe degeneration in the cerebellar cortex (visible on MRI); loss of myelinated fibers in the posterior columns, spinocerebellar tracts, and peripheral nerves; degenerative changes in the posterior roots and cells of the sympathetic ganglia; and loss of anterior horn cells at all levels of the spinal cord. In a few cases, vascular abnormalities, like the mucocutaneous ones, have been found scattered diffusely in the white matter of the brain and spinal cord, but they are of questionable significance. Also, there may be a loss of pigmented cells in the substantia nigra and locus ceruleus (a feature shared with PKU), and cytoplasmic inclusions (Lewy bodies) in the cells that remain (Agamanolis and Greenstein). During early development there are abnormalities of Purkinje cell migration and variations in nuclear size. Intranuclear inclusions and bizarre nuclear formations have also been found in the satellite cells (amphicytes) of dorsal root


Neurology_Adams

Neurology_Adams. abnormalities of Purkinje cell migration and variations in nuclear size. Intranuclear inclusions and bizarre nuclear formations have also been found in the satellite cells (amphicytes) of dorsal root ganglion neurons (Strich).


Neurology_Adams

Neurology_Adams. There is an absence or decrease in several immunoglobulins—IgA, IgE and isotypes, IgG2, IgG4—in practically every patient. These deficiencies, shown by McFarlin and associates to be a result of decreased synthesis, are associated with hypoplasia of the thymus, loss of follicles in lymph nodes, failure of delayed hypersensitivity reactions, and lymphopenia. This immunodeficient state accounts for the striking susceptibility of these patients to recurrent pulmonary infections and bronchiectasis. Transplantation of normal thymus tissue into the patient and administration of thymus extracts have been of no therapeutic value.


Neurology_Adams

Neurology_Adams. The defective gene (ATM) is a kinase that is a transducer in the pathway for DNA repair that halts the cell cycle after DNA damage. For this reason, there is faulty repair of DNA after radiation and a greatly increased risk of lymphomas, leukemias, and other tumors as well as certain specific susceptibilities to the effects of cancer treatment. The protein is normally expressed ubiquitously and 90 percent of patients have no ATM protein, usually because of a stop codon in the mutated gene. The only therapy centers on the control of infections. Free radical scavengers such as vitamin E have been recommended without proof of their effectiveness. Because of radiation sensitivity, even conventional diagnostic tests (dental, chest radiography) should be avoided unless there is a compelling reason for them.


Neurology_Adams

Neurology_Adams. In the course of clinical practice, one encounters a remarkable number of restricted disorders of the nervous system, many of which are transmitted from generation to generation as a mendelian, usually dominant, trait. Of the more severe ones, only a few of the more striking examples are described here. Milder and more restricted conditions, such as stuttering and dyslexia, that are pervasive in the population are described in Chap. 27. The reader may turn to books on genetics or teratology for an account of such oddities as hereditary unilateral ptosis, hereditary Horner syndrome, pupillary inequalities, jaw winking, and absence of a particular skeletal muscle.


Neurology_Adams

Neurology_Adams. The syndrome of congenital facial diplegia with convergent strabismus is referred to as Möbius syndrome, although Von Graefe had described it earlier. Its presence at birth is disclosed by the lack of facial movements and of full eye closure. A review of the subject in the English literature was written by Henderson, and a more recent analysis of 37 affected individuals was written by Harriëtte and colleagues. In Henderson’s study of 61 cases of the congenital facial diplegia syndrome, there were 45 instances of associated abducens palsy, 15 of complete external ophthalmoplegia, 18 of lingual palsy, 17 of clubfeet, 13 of a brachial disorder, 6 of mental defect, and 8 of an absent pectoral muscle. Thus the overlap with other neuromuscular and CNS abnormalities is evident. Moreover, at least two configurations of brainstem dysfunction have been proposed, one because of a lack of the facial nerve nucleus and the other in the nerve, perhaps acquired in type, based on electrophysiologic


Neurology_Adams

Neurology_Adams. two configurations of brainstem dysfunction have been proposed, one because of a lack of the facial nerve nucleus and the other in the nerve, perhaps acquired in type, based on electrophysiologic studies, but we have no basis to judge the validity of this. Harriëtte and coworkers emphasize the frequency of hypoplastic or dysplastic tongue, palatal involvement, and general motor clumsiness. They suggest that the disorder represents a widespread form of brainstem maldevelopment.


Neurology_Adams

Neurology_Adams. Early in life the mouth hangs open, the lower lip is everted, and there is difficulty in sucking. Usually this syndrome can be distinguished from the facial palsy of forceps or birth injury by its bilaterality and the other associated weaknesses. Occasionally, more than one family member is affected (usually in a pattern suggesting autosomal dominant inheritance). The cause of this peculiar condition is not known. The few adequate pathologic studies have shown a paucity of nerve cells in the motor nuclei of the brainstem, changes that also characterize the Fazio-Londe type of muscular dystrophy discussed in Chap. 45. Rarely, there may be an aplasia of facial muscles. The Möbius syndrome is also referred to in Chap. 44 in relation to restricted palsies of myopathic and nuclear origin.


Neurology_Adams

Neurology_Adams. Partial paralysis of facial muscles that dates from birth and cannot be attributed to obstetric trauma is not infrequent. In a common type, the lower lip on one side remains immobile when the child smiles or cries; the lip on the unaffected side is drawn downward and outward, resulting in a prominent asymmetry of the lower face. Often it is not appreciated that the side that droops during crying is the normal side (Hoefnagel and Penry). Congenital Lack of Lateral Gaze


Neurology_Adams

Neurology_Adams. Children with this congenital defect are unable to turn their eyes to either side volitionally or on command. Attempting to look to the right, the child turns the head to the right (there is no associated apraxia of head turning), but the eyes lag and turn to the left. As a result, the patient has to overshoot the mark with the head in order to attain ocular fixation. Once the eyes fixate, the head returns to the primary position. To compensate for the deficiency of eye movements, the patient develops jerky thrusting movements of the head, which characterize all attempts at voluntary gaze. Caloric stimulation of the labyrinth causes tonic movement of the eyes but not nystagmus, as in the normal person. Also, optokinetic nystagmus cannot be induced. Vertical eye movements are normal. A similar ocular condition may occur in conjunction with ataxia-telangiectasia and in Gaucher disease. Children with oculomotor apraxia are slow to walk; Ford observed one such child whose sibling had an


Neurology_Adams

Neurology_Adams. ocular condition may occur in conjunction with ataxia-telangiectasia and in Gaucher disease. Children with oculomotor apraxia are slow to walk; Ford observed one such child whose sibling had an absence of the vermis of the cerebellum. Aside from this observation, the anatomic basis of the condition has not been studied.


Neurology_Adams

Neurology_Adams. In this group of congenital disorders, a major disturbance of motor function, usually nonprogressive, has been present since infancy or early childhood. The popular terms for these conditions have been infantile cerebral paralysis (Freud) and cerebral palsy. The latter name is neither appropriate nor useful from the physician’s viewpoint, collocating as it does diseases of widely differing etiologic and anatomic types, wherein the hereditary and acquired and the intrauterine, natal, and postnatal diseases lose their identity. But the name has been adopted as a slogan by fund-raising societies and for rehabilitation clinics throughout the United States, hence it will not soon disappear from medical terminology. The term, often abbreviated CP, is still being used indiscriminately to designate every conceivable cognitive and motor disorder of corticospinal, extrapyramidal, cerebellar, and even neuromuscular type in infants and children.


Neurology_Adams

Neurology_Adams. Etiology of the Congenital Cerebral Motor Disorders


Neurology_Adams

Neurology_Adams. Motor abnormalities that have had their onset early in life are numerous and diverse in their clinical manifestations. Marked prematurity is an associated factor in a large proportion of cases. Each year, approximately 50,000 infants weighing less than 1,500 g are born in the United States; approximately 85 percent survive. Of these, 5 to 15 percent have a motor disorder of cerebral origin and 25 to 30 percent are found to be mentally impaired at school age (Volpe, 1995; also Hack et al). It is helpful to categorize a given case according to the extent and nature of the motor abnormality. A careful history of prenatal, perinatal, or postnatal insults to the developing nervous system must be sought; certain correlations of these factors with the resulting pattern of neurologic deficit are outlined below. Most patients with these motor abnormalities reach adult years. Many but not all have epilepsy in addition to the motor abnormalities and there is an unavoidable overlap in considering


Neurology_Adams

Neurology_Adams. below. Most patients with these motor abnormalities reach adult years. Many but not all have epilepsy in addition to the motor abnormalities and there is an unavoidable overlap in considering the causes and mechanisms of these three clinical states.


Neurology_Adams

Neurology_Adams. The following discussion is given from the perspective of the three major etiologic syndromes: matrix hemorrhages in the immature infant, hypoxic-ischemic encephalopathy, and certain other developmental motor abnormalities including those due to intrauterine stroke.


Neurology_Adams

Neurology_Adams. In low-weight and premature immature infants (20 to 35 weeks’ gestational age), there sometimes occurs, within a few days after birth, a catastrophic decline in cerebral function, usually preceded by respiratory distress (hyaline membrane disease) with spells of cyanosis and apnea. Also evident are deficiencies of brainstem automatisms (sucking and swallowing), bulging of the fontanels, and sanguineous CSF. If the infant becomes completely unresponsive, death usually ensues within a few days. Autopsy discloses a small lake of blood in each cerebral hemisphere (often asymmetrically distributed), occupying the highly cellular (subependymal) germinal matrix zone, near the caudate nucleus at the level of the foramen of Monro. This region is supplied by the lenticulostriate, choroidal, and Heubner recurrent arteries and is drained by deep veins, which enter the vein of Galen. In approximately 25 percent of cases, the blood remains loculated in the matrix zone, while in the majority it


Neurology_Adams

Neurology_Adams. Heubner recurrent arteries and is drained by deep veins, which enter the vein of Galen. In approximately 25 percent of cases, the blood remains loculated in the matrix zone, while in the majority it ruptures into the lateral ventricle or adjacent brain tissue. In a series of 914 consecutive autopsies in newborns, subependymal hemorrhage was found in 284 (31 percent); practically all of these neonates were of low birth weight, according to Banker and Bruce-Gregorios.


Neurology_Adams

Neurology_Adams. Lesser degrees of this cerebral hemorrhage are now being identified by ultrasonography (Fig. 37-14) and CT, and it is apparent that many infants with smaller hemorrhages survive. Some rapidly develop an obstructive hydrocephalus and require a ventricular shunt. In others, the hydrocephalus stabilizes and there is clinical improvement. Several series of surviving cases have now been followed for many years. Those in whom the hemorrhage was more extensive are often left with motor and intellectual handicaps.


Neurology_Adams

Neurology_Adams. Viewed from the perspective of cerebral palsy, just over half of the patients in the Swedish series of Hagberg and Hagberg with spastic diplegia had matrix hemorrhages, leukomalacia (see further on), or both. Congenital hemiplegia or quadriplegia was observed at a lower frequency. In another series of 20 cases of posthemorrhagic hydro-cephalus (Chaplin et al), 40 percent had significant motor deficits and more than 60 percent had IQ scores of less than 85. In an experience with 12 less severely affected surviving cases (mean birth weight 1.8 kg and gestational age of 32.3 weeks), R.D. Adams noted that only 1 had a residual spastic diplegia and 9 had IQs in the low-normal or normal range (personal communication).


Neurology_Adams

Neurology_Adams. The cause of matrix hemorrhage is not entirely clear. In all probability it is related to greatly increased pressure in the thin-walled veins of the germinal matrix coupled with a lack of adequate supporting tissue in these zones. During periods of unstable arterial or venous blood pressure that occur with the pulmonary disorders of immature infants, these thin-walled vessels rupture. These infants are also prone to the development of another characteristic lesion of the cerebral white matter (periventricular leukomalacia; see below), and the neurologic deficits resulting from these two lesions may be additive.


Neurology_Adams

Neurology_Adams. Treatment Control of the respiratory distress of prematurity may reduce the incidence of matrix hemorrhages and periventricular leukomalacia. Claims have been made that the administration of indomethacin ethamsylate, a drug that reduces capillary bleeding, and the intramuscular injection of vitamin E for the first 3 days after birth and possibly the use of betamethasone or other corticosteroids appears to be of value in reducing the incidence of periventricular hemorrhage (Benson et al; Sinha et al; see also Volpe [1989] for discussion of control of cerebral hemodynamics and effects of medications in the neonatal period). Acetazolamide and furosemide, which reduce the formation of spinal fluid, have been widely used in the treatment of posthemorrhagic hydrocephalus. However, in a large-scale controlled study, the effects were negligible and shunt placement was required to control worsening hydrocephalus (see International PHVD Drug Trial Group in the references).


Neurology_Adams

Neurology_Adams. These are zones of necrosis of white matter in the deep territories of cortical and central arteries. They lie lateral and posterolateral to the lateral ventricles, in a position to involve the occipital radiations and the sensorimotor fibers in the corona radiata (first described by Banker and Larroche; see also Shuman and Selednik). The white matter lesions occur in about one-third of cases of subependymal hemorrhage as mentioned, but they may develop independently in both premature and full-term infants who have suffered hypotension and apnea. In a study of 753 preterm infants, those born at 28 weeks’ gestation or less were at highest risk of this complication; the combination of intrauterine infection and premature rupture of membranes carried a 22 percent risk (Zupan et al). Survivors often manifest cerebral hemiplegia or diplegia and variable degrees of cognitive impairment. The motor disorder is usually more severe than the cognitive and language impairment. Increasingly, small


Neurology_Adams

Neurology_Adams. often manifest cerebral hemiplegia or diplegia and variable degrees of cognitive impairment. The motor disorder is usually more severe than the cognitive and language impairment. Increasingly, small lesions of this nature are being identified in term infants by cerebral imaging including ultrasound.


Neurology_Adams

Neurology_Adams. The mechanism of this type of periventricular infarction has been debated, and the terminology and clinical features, insofar as they overlap with germinal matrix hemorrhage, have been confusing. In recent years, most theories and experimental evidence converge on the notion that these represent regions of venous ischemia and infarction.


Neurology_Adams

Neurology_Adams. It has been estimated that in the range of 1 to 6 of every 1,000 live births manifests a neonatal encephalopathy (as quoted in the review by Ferriero). The seriousness of the condition is further emphasized by the associated mortality rate of 20 percent in the newborn period and the 25 percent rate of neurodevelopmental disability in survivors. Little’s conception of the hypoxic-ischemic form of “birth injury,” enunciated in 1862, has been reconsidered over the years. Although it is evident that many newborns suffer some degree of perinatal asphyxia, relatively few seem to manifest brain damage. Moreover, many, if not most, infants with a variety of cerebral motor syndromes appear to have passed the parturitional (perinatal) period without mishap, indicating the greater importance of other prenatal and postnatal causative factors. Nonetheless, severe neonatal asphyxia of term or preterm babies can be an important cause of spastic, dystonic and ataxic syndromes, often accompanied by


Neurology_Adams

Neurology_Adams. prenatal and postnatal causative factors. Nonetheless, severe neonatal asphyxia of term or preterm babies can be an important cause of spastic, dystonic and ataxic syndromes, often accompanied by seizures and mental delay in development.


Neurology_Adams

Neurology_Adams. This field has been sullied by an unprecedented rise in malpractice litigation, spawned in part by the belief that early detection of asphyxia and rapid delivery would have prevented the motor, epileptic, and cognitive problems of birth injury. The fallacy of this assumption is highlighted both by the below comments and by the observation that the incidence of cerebral palsy has not changed in term infants over the past few decades, despite the institution of fetal monitoring and more frequent cesarean sections.


Neurology_Adams

Neurology_Adams. One has the impression that the brain tolerates hypoxia and reduced blood flow in the immediate postnatal period better than at any other time in life. Indeed, animal experimentation supports this view. Not until the arterial oxygen tension is reduced dramatically to 10 to 15 percent of normal does brain damage occur, and even then the impaired function of other organs contributes to the damage. It is probably correct to think of the encephalopathy in terms of both hypoxia and ischemia, both of which usually occur in utero and are expressed postnatally by recognizable clinical syndromes.


Neurology_Adams

Neurology_Adams. Fenichel (1990), following the original work of Sarnat and Sarnat and of Levene and colleagues, has found it helpful to divide the encephalopathies that follow a complicated birth into three purely descriptive groups according to their severity, each having a prognostic value beyond that of the Apgar score: (1) In newborns with mild hypoxic-ischemic encephalopathy, the symptoms are maximal in the first 24 h and take the form of hyperalertness and tremulousness of the limbs and jaw (the “jittery baby”) and a low threshold of the Moro reaction. The tone of the limbs is normal except for a mild increase in head lag during traction. The reflexes are brisk and there may be ankle clonus. The anterior fontanel is soft. The EEG is normal. Recovery is usually complete and the risk of handicap is low. (2) Newborns with moderate hypoxic-ischemic encephalopathy are lethargic, obtunded, and hypotonic, with normal movements. After 48 to 72 h, the neonate may improve (having passed through a jittery


Neurology_Adams

Neurology_Adams. (2) Newborns with moderate hypoxic-ischemic encephalopathy are lethargic, obtunded, and hypotonic, with normal movements. After 48 to 72 h, the neonate may improve (having passed through a jittery hyperactive phase) or worsen, becoming less responsive in association with convulsions, cerebral edema, hyponatremia, and hyperammonemia from liver damage. The EEG is abnormal. Fenichel associates epileptiform activity and voltage suppression with an unfavorable outcome. Abnormal visual and auditory evoked potentials are other poor prognostic signs. (3) In neonates with severe hypoxic-ischemic encephalopathy, stupor or coma is present from birth; respirations are irregular, requiring mechanical ventilation. There are usually convulsions within the first 12 h. The limbs are hypotonic and motionless even during attempts to elicit the Moro response. Sucking and swallowing are depressed or absent, but pupillary reactions and eye movements may at first be retained, only to be lost as the coma


Neurology_Adams

Neurology_Adams. even during attempts to elicit the Moro response. Sucking and swallowing are depressed or absent, but pupillary reactions and eye movements may at first be retained, only to be lost as the coma deepens.


Neurology_Adams

Neurology_Adams. It is in the second and third categories, that is, the states of moderate to severe encephalopathy, where correction of the respiratory insufficiency and the metabolic abnormalities permits survival, that a number of motor abnormalities (corticospinal, extrapyramidal, and cerebellar) and developmental delay eventually emerge. Included in the category of severe hypoxic-ischemic encephalopathy are also newborns with a variety of developmental anomalies of the brain and other organs. However, clouding the issue of causality is the absence of perinatal complications in a large number of children with cerebral palsy and the large number of normal babies who are born after complicated deliveries. Notably, only a few cases result from often blamed intrapartum factors such as forceps delivery, breech presentation, cord prolapse, abruptio placentae, and maternal fever.


Neurology_Adams

Neurology_Adams. In addition, such infants may have been exposed to certain prenatal risk factors (toxemia of pregnancy, antepartum uterine hemorrhage, maternal hypotension, and certain epidemiologic associations such as hypothyroidism or fertility treatment), or their growth may have been abnormal (small-for-date babies). Some of these babies are born at term; others are premature, and the birth process may or may not have been abnormal. One must then consider the possibility, originally pointed out by Sigmund Freud, that the abnormality of the birth process, instead of being causal, was actually the consequence of prenatal pathology. The latter might include preterm intrauterine hypoxia-ischemia.


Neurology_Adams

Neurology_Adams. Other evidence of multifactorial etiology in the “causation” of cerebral palsy has been provided by Nelson and Ellenberg, who found that maternal developmental delay, birth weight below 2,000 g, and fetal malformation were among the leading predictors. Breech presentation was another factor, and one-third of these cases also had some noncerebral malformation. Twenty-one percent of the 189 children in their series had also suffered some degree of asphyxia. Additional determinants were maternal seizures, a motor deficit in an older sibling, two or more prior fetal deaths, hyperthyroidism in the mother, preeclampsia, and eclampsia. In children with cerebral diplegia born at term, likely contributory factors that were operative in nearly half included toxemia of pregnancy, low birth weight for age, placental infarction, and intrauterine asphyxia.


Neurology_Adams

Neurology_Adams. The factors enumerated above are involved to different degrees in the outcome of pregnancies but are informative because they bring to light the significant proportion of cases of cerebral birth injury in which hypoxia-ischemia, matrix hemorrhages, and leukomalacia were not operative. In this group, can be included the symmetrical porencephalies and hydranencephalies.


Neurology_Adams

Neurology_Adams. Thus the complexity of assigning a cause for cerebral palsy is evident. In respect to the motor disorders discussed below, hypoxic-ischemic perinatal injury is still the most commonly specified cause of neonatal encephalopathy but is often unrelated to a permanent defect of cerebral palsy. This statement has been amply confirmed by a large and often cited study from Western Australia that detected neonatal encephalopathy in 3.8 of 1,000 live term births but was able to identify causative intrapartum factors alone in only 5 percent (Badawi et al). Furthermore, only 10 percent of all the infants with neonatal encephalopathy developed spastic quadriplegia, according to Evans and colleagues.


Neurology_Adams

Neurology_Adams. Imaging studies of cerebral palsy have increasingly appeared and it has even been suggested, perhaps with excessive enthusiasm, that all such children undergo scanning. Cowan and colleagues (2003) used MRI to determine the proportion of infants with a neonatal encephalopathy who had antenatal brain injury. Excluding those with major congenital malformations or obvious chromosomal abnormalities, 80 percent of cases had no established lesion or brain atrophy. In contrast, those with only seizures and no neonatal encephalopathy in 69 percent of cases had evidence of antenatal damage on MRI; infarctions because of thrombophilic disorders were most common. An MRI–clinical correlative study of children with cerebral palsy by Bax and colleagues in The European Cerebral Palsy Study came to similar conclusions but found that periventricular leukomalacia of prematurity was the most common MRI change, present in 42 percent of infants, followed in frequency by basal ganglionic damage (13


Neurology_Adams

Neurology_Adams. similar conclusions but found that periventricular leukomalacia of prematurity was the most common MRI change, present in 42 percent of infants, followed in frequency by basal ganglionic damage (13 percent), cortical-subcortical lesions (9 percent), malformations (9 percent), and focal infarcts (7 percent). These authors found a correspondence between the clinical and MRI findings. These studies demonstrate the utility of MRI in identifying neonatal forms of encephalopathy and indicate that few are the result of obstetric accidents. Added difficulty is caused by the fact that the clinical signs of perinatal injury may emerge only when the maturational process of the nervous system exposes them at a later period of life. Woodward and coworkers suggested that the MRI pattern is predictive of developmental outcome in preterm infants, but this requires corroboration.


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Neurology_Adams. Treatment Much of the resources of neonatal intensive care is devoted to sustaining oxygenation and blood pressure, and reducing hyperbilirubinemia in premature and full-term but ill infants. Techniques such as the predelivery administration of corticosteroids in premature births to promote lung maturity, attempting to bring early births to 34 to 36 weeks’ gestation, and the treatment of maternal infection have all contributed to improved outcomes in children. The American Academy of Pediatrics, based on a systematic review of randomized clinical trials (e.g, Azzopardi et al and Shankaran et al), has given guidance that hypothermia is an effective therapy for improving neurologic outcome in neonatal encephalopathy. Criteria for patient enrollment that simulate those used in clinical trials of this intervention must be followed to achieve an effect, including early institution of treatment (see


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Neurology_Adams. Committee on Fetus and Newborn in references). It must be acknowledged that clinical trials have given conflicting advice, have had short follow-up, and small differences between treated and untreated groups. Trials of cooling have generally excluded infants with major malformations, which are present in approximately one-third of children with cerebral palsy, as alluded to above. The avoidance of the ostensible causes of cerebral palsy has been discussed in previous sections. None of the usually assigned causes of birth injury, particularly perinatal hypoxia-ischemia, explains most cases. Clinical Syndromes of Congenital Spastic


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Neurology_Adams. Clinical Syndromes of Congenital Spastic The most frequent motor disorder evolving from the four major categories of neonatal cerebral disease—matrix hemorrhage, periventricular leukomalacia, hypoxic-ischemic encephalopathy, kernicterus (discussed further on)—is spastic diplegia; that is, a motor disturbance that is severe in the lower limbs and mild in the upper, as discussed below. In addition, hypoxic-ischemic injury occurring in the term or preterm infant may take the form of a hemiplegia, double hemiplegia (quadriplegia), or a mixed pyramidal–extrapyramidal or spastic–ataxic syndrome.


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Neurology_Adams. A second form of motor disorder is characterized by the development of severe spastic quadriplegia and developmental delay. The major insult is usually intrapartum asphyxia and attendant fetal distress. Usually such infants will have required resuscitation and will have had low 5-min Apgar scores and seizures, which have important predictive value in this circumstance. The pathologic lesions of the brain in this second group consist of hypoxic-ischemic infarction in distal fields of arterial flow, primarily in the cortex and white matter of parietal and posterior frontal lobes, leaving an ulegyric sclerotic cortex.


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Neurology_Adams. A third group, discussed below, is characterized mainly by extrapyramidal abnormalities, combining athetosis, dystonia, and ataxia in various proportions. After reviewing the results of several large series of congenital and neonatal motor disorders, we have concluded that spastic diplegia occurs in 10 to 33 percent of cases, spastic quadriplegia in 19 to 43 percent, extrapyramidal forms in 10 to 22 percent, and mixed forms in 9 to 20 percent. Spastic diplegia (“Little disease”) The pattern of paralysis is more variable than the term spastic diplegia implies; actually, several subtypes may be distinguished: paraplegic, diplegic, quadriplegic, pseudobulbar, and generalized. Pure paraplegic and pseudobulbar types are relatively rare. The eponymic “Little disease” has been applied mainly to the spastic diplegic type, but it also has been attached to all forms of motor cerebral palsy in some older writings.


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Neurology_Adams. Usually all four extremities are affected, but the legs much more than the arms, which is the real meaning of diplegia. Hypotonia—with retained tendon reflexes and hypoactivity—is usually present initially. Only after the first few months will evident weakness and spasticity appear, first in the adductors of the legs. The plantar reflexes, which often take on ambiguous direction in the normal infant, here are clearly extensor, a finding that is pathologic at any later age. Also, stiff, awkward movements of the legs, which are maintained in an extended, adducted posture when the infant is lifted by the axillae, often do not attract attention until several weeks or months have passed. Seizures occur in approximately one-third of the cases, and it is not uncommon to observe a delay in all developmental sequences, especially those that depend on the motor system.


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Neurology_Adams. Once walking is attempted, usually at a much later date than usual, the characteristic stance and gait become manifest. The slightly flexed legs are advanced stiffly in short steps, each describing part of an arc of a circle; adduction of the thighs is often so strong that the legs may actually cross (scissors gait); the feet are flexed and turned in with the heels not touching the floor. In the adolescent and adult, the legs tend to be short and small, but the muscles are not markedly atrophic, as they are in spinal muscular atrophy. Passive manipulation of the limbs reveals spasticity in the extensors and adductors and slight shortening of the calf muscles. The arms may be affected only slightly or not at all, but there may be awkwardness and stiffness of the fingers and, in a few, pronounced weakness and spasticity. In reaching for an object, the hand may overpronate and a grasp may be difficult to release. Speech may be well articulated or noticeably slurred, and in some instances


Neurology_Adams

Neurology_Adams. weakness and spasticity. In reaching for an object, the hand may overpronate and a grasp may be difficult to release. Speech may be well articulated or noticeably slurred, and in some instances the face is set in a spastic smile. Scoliosis is frequent and may secondarily give rise to root compression and impaired respiratory function. As a rule, there is no disturbance of sphincteric function, although delay in acquiring voluntary bowel and bladder control is usual. Athetotic postures and movements of the face, tongue, and hands are present in some patients and may actually conceal the spastic weakness.


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Neurology_Adams. One subtype of spastic diplegia is associated with a relatively slight diminution in head size and of intelligence. As indicated above, there is no unifying neuropathology; the condition occurs independently of matrix hemorrhages and periventricular leukomalacia as well as with them. The frequency of cerebral spastic diplegia, which is closely related to the degree of prematurity, has declined significantly since the introduction of neonatal intensive care facilities, and there is reason to believe that genetic factors are of more importance.


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Neurology_Adams. Infantile hemiplegia and quadriplegia Hemiplegia is a common condition of infancy and early childhood. The functional difference between the two sides may be noticed soon after birth, but more often it is not perceived by the mother until after the first 4 to 6 months of life. In a second group, the child is in excellent health for a year or longer before the abrupt onset of hemiplegia (see below). In hemiplegia that dates from earliest infancy—that is, congenital hemiplegia—the parents first notice that movements of prehension and exploration are carried out with only one arm. A manifest hand preference at an early age should always raise the suspicion of a unilateral motor defect. The affection of the leg is usually recognized later, that is, during the first attempts to stand and walk. Sitting and walking are usually delayed by a few months. In the older child, there is evident hyperactivity of tendon reflexes and usually a Babinski sign. The arm is held flexed, adducted, and


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Neurology_Adams. walk. Sitting and walking are usually delayed by a few months. In the older child, there is evident hyperactivity of tendon reflexes and usually a Babinski sign. The arm is held flexed, adducted, and pronated, and the foot assumes an equinovarus posture. Sensory and visual field defects can be detected in some patients. Cognitive slowing may be associated with infantile hemiplegia but is less common and lesser in degree than with cerebral diplegia. There may also be speech delay, regardless of the side of the lesion; when this is present, there is usually developmental delay and bilaterality of motor abnormality. Convulsions occur in 35 to 50 percent of children with congenital hemiplegia, and these may persist throughout life. They may be generalized but are frequently unilateral and limited to the hemiplegic side (or the contralateral side if the hemiplegia is severe). After a series of seizures, the weakness on the affected side will be increased for several hours or longer (Todd


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Neurology_Adams. to the hemiplegic side (or the contralateral side if the hemiplegia is severe). After a series of seizures, the weakness on the affected side will be increased for several hours or longer (Todd paralysis). Gastaut and associates have described a hemiconvulsive–hemiplegic syndrome in which progressive paralysis and cerebral atrophy are attributed to the convulsions. As months and years pass, the osseous and muscular growth of the hemiplegic limbs is impeded, leading to an obvious hemiatrophy of the body.


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Neurology_Adams. With respect to the causation of congenital hemiplegia, it is generally agreed that perinatal asphyxia is only one of the possibilities. In the series of 681 children with “cerebral palsy” collected by Hagberg and Hagberg, there were 244 with hemiplegia of whom 189 were full-term babies and 55 were preterm. Prenatal risk factors were identified in only 45 percent, and mostly in the infants born prematurely. In nearly half of the cases, there was no clue as to the time in the intrauterine period when the cerebral lesion occurred.


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Neurology_Adams. In another group—acquired infantile hemiplegia—a normal infant or young child, usually between the ages of 3 and 18 months, develops a massive hemiplegia, with or without aphasia, within hours. The disorder often begins with seizures, and the hemiplegia may not be recognized until the seizures have subsided. In Banker’s series of autopsy cases, there was arterial or venous thrombosis in some cases, but instances without vascular occlusions were found. Some of the latter cases, in which arteriography had been normal, may have been embolic, possibly of cardiac origin. In the recent era, imaging has shown a large area of cerebral infarction, consistent with a stroke in the territory of the middle cerebral artery (Fig. 37-15). If the stroke occurs at an early age, the recovery of speech may be complete, though reduced scholastic capacity remains. The degree of recovery of motor function varies. Often, as the deficit recedes, the arm becomes involved by athetotic, tremulous, or ataxic


Neurology_Adams

Neurology_Adams. be complete, though reduced scholastic capacity remains. The degree of recovery of motor function varies. Often, as the deficit recedes, the arm becomes involved by athetotic, tremulous, or ataxic movements; there may be an interval of months or years between the hemiplegia and the athetosis.


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Neurology_Adams. Destructive lesions underlie most of the cases of infantile hemiplegia and some cases of bilateral hemiplegia (as well as many cases of seizures in the first few days of life). The pathologic change is essentially that of ischemic necrosis. In many cases, the lesions must have been acquired in utero. Precipitant delivery, fetal distress, and prepartum uterine hemorrhage may have been indications, more so than causes, of the process. What is most notable is that the ischemia tends to affect the tissues lying in arterial cortical border zones; there may also be venous stasis with congestion and hemorrhage occurring particularly in the deep central structures such as the basal ganglia and periventricular matrix zones. If they are purely hypoxic, the lesions should be bilateral. Myers has reproduced such lesions in the neonatal monkey by reducing the maternal circulation for several hours. As the lesions heal, the monkeys develop the same gliotic changes in the cortex and white matter of


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Neurology_Adams. such lesions in the neonatal monkey by reducing the maternal circulation for several hours. As the lesions heal, the monkeys develop the same gliotic changes in the cortex and white matter of the cerebrum (lobar sclerosis) and the “marbling” (état marbré) that characterizes the brains of patients with spastic diplegia and double athetosis (see below).


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Neurology_Adams. The quadriplegic state differs from bilateral hemiplegias in that the bulbar musculature is often involved in the latter and developmental delay is more severe. The condition is relatively rare and is usually a result of a bilateral cerebral lesion. However, one should also be alert to the possibility of a high cervical cord lesion. In the infant, this is usually the result of a fracture dislocation of the cervical spine incurred during a difficult breech delivery. Similarly, in paraplegia, with weakness or paralysis limited to the legs, the lesion may be either a cerebral or a spinal one. Sphincteric disturbances and a loss of somatic sensation below a certain level on the trunk always point to a spinal localization. Congenital cysts, tumors, and diastematomyelia are more frequently causes of paraplegia than of quadriplegia. Another recognized cause of infantile paraplegia is spinal cord infarction from thrombotic complications of umbilical artery catheterization.


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Neurology_Adams. This is a complex subject that has not been fully elucidated clinically or genetically. The concern is that persistently low levels of glucose will produce neuronal damage, as it has in experimental models. Its mildest form is a transient postpartum condition that occurs in premature and small for gestational age newborns and usually clears within hours. It is detected by a heel stick blood sample taken at birth and, if the glucose concentration is not below 45 mg/dL, often requires a repeat sample and confirmation by whole blood testing. Persistently low levels of glucose may be manifest as seizures or jitteriness.


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Neurology_Adams. A related form lasts days and may require treatment with intravenous glucose before it stabilizes. A few infants, some of diabetic mothers but most usually below about 2500 gm birth weight, continue to be hypoglycemic for days or weeks and are generally treated with intravenous glucose or glucagon if the situation is severe, and monitored in a neonatal intensive care unit. A proportion of these infants will have hypoglycemia that persists for only weeks or months and clears without explanation. This condition is due to congenital hyperinsulinism. The latter may be manifest as near normal insulin levels when the glucose drops below approximately 50 mg/dL. They can be treated with oral diazoxide, a drug formerly used intravenously for the control of severe acute hypertension but in oral form blocks insulin release, or with octreotide. The appropriate threshold for treatment of hypoglycemia has been a matter of debate.


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Neurology_Adams. When the condition is persistent or unresponsive to diazoxide, there is either a genetic defect in one of a number of channels responsible for releasing insulin or detecting low serum glucose levels, or tot a proliferation of beta-islet cells is often the cause, more in accord with the original term (now outdated) nesidioblastosis, signifying this excess of pancreatic cells. For the latter, almost total pancreatectomy has been performed but there is subsequent diabetes mellitus.


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Neurology_Adams. Many textbooks paint a bleak picture of developmental outcomes for persistent neonatal hypoglycemia based on studies from half a century ago but there have been few critical examinations of outcomes and, as mentioned, the threshold value that represents a risk has not been established. The cohort reported by McKinlay and colleagues reported on a cohort who were mostly under 2500 gm in birth weight, in whom glucose could be maintained above 47 mg/dL. They had no developmental delay at 2 years of age. Furthermore, continuous interstitial tissue monitoring of glucose revealed that many transient episodes of hypoglycemia were undetected by intermittent monitoring and the number or severity of these episodes also did not predict for developmental delay, at least at 2 years of age. Paradoxically, those with rapid correction of glucose and large amounts of time with higher glucose had more developmental delay than those in the low or normal range; this requires confirmation. Some


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Neurology_Adams. those with rapid correction of glucose and large amounts of time with higher glucose had more developmental delay than those in the low or normal range; this requires confirmation. Some observations have suggested that visuospatial difficulties are a form of deficit attributable to hypoglycemia and that appropriately placed occipital lesions are visible on MRI.


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Neurology_Adams. The spastic cerebral diplegias discussed above shade almost imperceptibly into the congenital extrapyramidal syndromes. These children are found in every cerebral palsy clinic, and, ultimately, they reach adult neurology clinics. Corticospinal tract signs may be absent and the student, familiar only with the syndrome of pure spastic diplegia, is always puzzled as to their classification. Some cases of extrapyramidal type are undoubtedly attributable to severe perinatal hypoxia and others to diseases such as erythroblastosis fetalis with kernicterus. To state the probable pathologic basis and future course of these illnesses, it is useful to separate the extrapyramidal syndromes of prenatal-natal origin (which usually become manifest during the first year of life) from the acquired or hereditary postnatal syndromes, such as familial athetosis, Wilson disease, dystonia musculorum deformans, and the hereditary cerebellar ataxias, which become manifest later.


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Neurology_Adams. Double athetosis This is probably the most frequent of the congenital extrapyramidal disorders. Two types stand out—one that is caused by hyperbilirubinemia or Rh incompatibility (kernicterus; see below) and hypoxic-ischemic encephalopathy. With control of neonatal hyperbilirubinemia (by use of anti-Rh immune globulin, exchange transfusions, and phototherapy), kernicterus has almost disappeared, whereas the severe hypoxic-ischemic form regularly continues to be seen. Rarely, a congenital, nonhemolytic icterus or a glucose-6-phosphate dehydrogenase deficiency produces the same syndrome.


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Neurology_Adams. Like the spastic states, double athetosis may not be recognized at birth but only after several months or a year has elapsed. In some cases, the appearance of choreoathetosis is for unexplained reasons delayed for several years; it may seem to progress during adolescence and even early adult life. It must then be differentiated from some of the inherited metabolic and degenerative extrapyramidal diseases. Chorea and athetosis dominate the clinical picture, but bewildering combinations of involuntary movements—including dystonia, ataxic tremor, myoclonus, and even hemiballismus—may be found in a single case. At times, we have been unable to classify the movement disorder because of its complexity. It should be noted that practically all instances of double athetosis are also associated with a defect in voluntary movement.


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Neurology_Adams. Choreoathetosis in infants and children varies greatly in severity. In some, the abnormal movements are so mild as to be misinterpreted as restlessness or “the fidgets”; in others, every attempted voluntary act provokes violent involuntary spasms, leaving the patient nearly helpless. The clinical features of choreoathetosis and other involuntary movements are discussed in Chap. 4.


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Neurology_Adams. Early hypotonia, followed by delayed motor development, is the rule in these cases. Erect posture and walking may not occur until the age of 3 to 5 years and may never be attained in some patients. Tonic neck reflexes or fragments thereof tend to persist well beyond their usual time of disappearance. The plantar reflexes are usually flexor, although they may be difficult to interpret because of the continuous flexion and extension of the toes. Sensory abnormalities are not found. Because of the motor and speech impairment, patients are often erroneously thought to be cognitively impaired. In some, this conclusion is doubtless correct, but cognitive function may be unaffected in many others.


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Neurology_Adams. A variety of rehabilitative measures have been tried: physiotherapy, surgery, sensory integrative therapy, progressive patterned movement, and various undocumented forms of neuromuscular facilitation. We agree with Hur, who has critically reviewed this subject, that properly controlled studies provide no proof of the success of any of them. Surely, with growth and development, new postures and motor capacities are acquired. The less-severely affected patients make successful occupational adjustments. The more-severely affected children rarely achieve a degree of motor control that permits them to live independently. One sees some of these unfortunate persons bobbing and twisting laboriously as they make their way in public places.


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Neurology_Adams. Imaging studies are seldom of diagnostic value. Mild cerebral atrophy and loss of volume of the basal ganglia are seen in some cases, and cavitary lesions are present in some of the severe anoxic encephalopathies. The EEG is rarely helpful unless there are seizures. The most frequent pathologic finding in the brain has been a whitish, marble-like appearance of the putamen, thalamus, and border zones of the cerebral cortex. These whitish strands represent foci of nerve cell loss and gliosis with condensation of bands of transversing myelinated fibers—so-called status marmoratus (état marbré). This lesion does not develop if the insult occurs after infancy, that is, after myelination has completed its early developmental cycle.


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Neurology_Adams. Kernicterus This is now a rare cause of extrapyramidal motor disorder in children and adults. Such cases are the neurologic sequelae of erythroblastosis fetalis secondary to Rh and ABO blood incompatibilities or to a deficiency of the hepatic enzyme glucuronosyltransferase. The symptoms of kernicterus appear in the jaundiced neonate on the second or third postnatal day. The infant becomes listless, sucks poorly, develops respiratory difficulties as well as opisthotonos (head retraction), and becomes stuporous as jaundice intensifies. The serum bilirubin is usually greater than 25 mg/dL. In acidotic and hypoxic infants (e.g., those with low birth weight and hyaline membrane disease), the kernicteric lesions develop with much lower levels of serum bilirubin.


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Neurology_Adams. A proportion of infants with this disease die within the first week or two of life. Many of those who survive are developmentally delayed, deaf, hypotonic, and totally unable to sit, stand, or walk. There are exceptional patients, however, who are mentally normal or at most only slightly limited. They develop a variety of persistent neurologic sequelae—choreoathetosis, dystonia, and rigidity of the limbs—a picture not too different from that of cerebral spastic diplegia with involuntary movements. Kernicterus should always be suspected if an extrapyramidal syndrome is accompanied by bilateral deafness and paralysis of upward gaze. Later, in childhood there may be a greenish pigmentation of the dental enamel.


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Neurology_Adams. Neonates who die in the acute postnatal stage of kernicterus show a unique yellow staining (icterus) of nuclear masses at one time was called the “Kern nuclei” and gave the disease its name in the basal ganglia, brainstem, and cerebellum. In those surviving this postnatal insult, the pathologic changes consist of a symmetrically distributed nerve cell loss and gliosis in the subthalamic nucleus, the globus pallidus, the thalamus, and the oculomotor and cochlear nuclei; these lesions are the result of the hyperbilirubinemia. In more than 30 cases examined by R.D. Adams, the immature cerebral cortex including the hippocampus was spared. In the newborn, unconjugated bilirubin can pass through the poorly developed blood–brain barrier into these nuclei, where it is assumed to be directly toxic. Acidosis and hypoxia exacerbate the effect. Also in the newborn, the development of hyperbilirubinemia is enhanced by a transient deficiency of the enzyme glucuronosyltransferase, essential for the


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Neurology_Adams. Acidosis and hypoxia exacerbate the effect. Also in the newborn, the development of hyperbilirubinemia is enhanced by a transient deficiency of the enzyme glucuronosyltransferase, essential for the conjugation of bilirubin. Hereditary hyperbilirubinemia, caused by lack of this enzyme (Crigler-Najjar syndrome), may exhibit the same effects on the nervous system at a later period of infancy or childhood as hyperbilirubinemia because of Rh incompatibility.


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Neurology_Adams. Immunization, phototherapy, and exchange transfusions designed to prevent high levels of unconjugated serum bilirubin have been shown to protect the nervous system from the toxic effects of erythroblastosis fetalis. If the blood bilirubin level can be held to less than 20 mg/dL (10 mg/dL in premature infants), the nervous system may escape perinatal damage. The effective use of these measures has practically eradicated this disease. Both kernicterus and ischemic état marbré must be differentiated clinically from hereditary choreoathetosis, the Lesch-Nyhan syndrome, and—later in life, from ataxia-telangiectasia and Friedreich ataxia.