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Rett and Angelman’s syndromes: models of arrested development
Rett and Angelman’s Syndromes: Models of Arrested Development Michel Philippart, MD Rett and Angelman’s syndromes have emerged slowly from their initial classifications as degenerative disorders and static encephalopathies; the terms development and developmental arrest have been used for 200 years. An attempt has been made to trace the genesis and the various contexts of these seminal concepts. Both disorders give frozen-framed expression of developmental levels not easily appreciated in normal children who progress from day to day. Although close in developmental level, about 9 and 15 months with a scatter of a few months, these disorders may actually overlap in a few instances. These syndromes illustrate how a slightly more advanced brain function may appear to be a big gap and how difficult it is to differentiate between a failure to progress further, which is easily confused with regression, and an apparent loss of skills actually never acquired. Learning to see the infant brain behind the aging body and how it adjusts within the constraints of its fixed low level of neural organization is the best basis for diagnosis and treatment. Identifying shortcomings and special risks is more rewarding than ill-conceived attempts to modify anatomic destiny. © 2001 by Elsevier Science Inc. All rights reserved. Philippart M. Rett and Angelman’s syndromes: Models of arrested development. Pediatr Neurol 2001;25:288-294.
Introduction Knowledge expansion mandates frequent reorganization and sometimes rejection of traditional concepts that have become obsolete and distort the order of nature. Linear thinking is tempting, and it is difficult to reject appearances even when knowing they are wrong. It is still easier to see the sun going round the earth despite Copernicus and Galileo’s long-resisted demonstrations that such common sense is a fallacy. In the forest of
From the Brain Research Institute; UCLA; Los Angeles, CA.
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accumulating new leaves, how is it possible to find trees and paths leading to them? Like barnacles on an old clipper, old knowledge may become a burden. Will the metaphysics of water molecules be elaborated to explain their path down a mountain or will simple laws of least resistance and gravity that effectively dictate their behavior be identified? In this vein, Rett and Angelman’s syndromes first were classified as neurodegenerative or static encephalopathies and were often blamed on birth anoxia despite tenuous evidence of it, if any. Both disorders result from genetic mutations blocking further differentiation of the nascent brain organization, which depends on the turning on of genes still to be identified. The concept of lack or arrest of brain development provides a powerful framework to facilitate diagnosis and treatment. Adopting new concepts is a difficult task when dealing with acquired knowledge that we long for to be permanent. Going back to the roots and following the genesis of new ideas allows a sorting out and ordering the entangled mass of new data. A comprehensive historic review would require an encyclopedia where the grain gets lost in the chaff. This review focuses on the history of important concepts with immediate implications for simplifying the process of diagnosis and appropriate treatment. The word development has many meanings and is used rather blindly, with scant attention to its intimate significance. The word has been used within varying contexts in embryology, evolution, and psychology. Its most simple meaning is equivalent to growth, or “getting bigger.” The association between a small brain and mental retardation (“a Fool from his birth”) was first reported by Thomas Willis [1]. The notion of developmental arrest was introduced by Geoffroy St. Hilaire [2], a pioneer in embryology. The term was first defined in the context of mental retardation by Georget [3], who separated “idiocy” from insanity, which was a distinction that was later elaborated by Esquirol [4]. The concept of development in increasing complexity can be traced to Parmenides: “. . . the highest
Communications should be addressed to: Dr. Philippart; 300 UCLA Medical Plaza; Suite 1247; Los Angeles, CA 90095-6967. Received October 23, 2000; accepted April 3, 2001.
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degree of organization gives the highest degree of thought” [5]. In his developmental hypothesis, Spencer [6] defined evolution as a structure of increasing complexity and dissolution as its opposite. In Draper’s treatise [7] the term development implies growth, the increase in size of a structure and conjointly differentiation, which involves modification of fabric and the assumption of new function. The concept of dissolution was elaborated on by Jackson [8], who described the regression of the mature central nervous system (CNS) from a higher to lower level of organization. Since then neurology has focused on the damage to adult structures from neurodegenerative disease, infection, vascular compromises, tumors, and similar processes. The idea of damage had a powerful influence on pediatric neurology, and the view persisted that anoxia/ischemia was the almost exclusive etiology of cerebral palsy and, more recently, of autism. The study of simple animals at early stages of development was exploited in Cajal’s work [9], which identified pathways that become hard to trace amid the complexity of the adult CNS. Immature nerve cells grow connections through a dendritic tree, building the skeleton of the nascent CNS functions. Cajal’s masterful accomplishment, however, had little detectable impact on neurologists or developmentalists at the time. The implications of his work, based on the Golgi technique, have not been used fully by pathologists, who often complain of the unreliability of the method. Neurologists not trained in pediatrics do not appreciate that brain growth is more an increase in complexity than an increase in size. Huttenlocher [10] revived the studies of developmental processes and documented the burst of synaptic formation after birth in the human, followed by considerable elimination. Positron-emission tomography (PET) studies with fluoro-deoxy-glucose illustrated this process in vivo [11] and also demonstrated that the bulk of energy consumption takes place at the synapse [12], which is the basis for the enormous blood flow the brain needs. Brain development in neonates requires the presence of thyroid hormones. The concept of a therapeutic window allowing limited time to provide the necessary stimulus to dendrite growth and to prevent developmental arrest was slow to be accepted [13]. Remodeling cortical connections through usage underlies reflex conditioning. Fixed connections limit the freedom of movements and thought involved in the highest level of brain maturation. This balance was appreciated by Jackson [14], who noted that the highest levels were less organized and less automatic than the lower ones, and the most simple levels were more strongly organized from birth. Vital functions, such as respiration, blood pressure, heart rate, deglutition, and sympathetic controls illustrate the sophisticated organization of the brainstem in the human newborn. Automatic newborn walking requires a high level of basic limb connections, which are hidden under terms like reflex or automatic level. Elementary emotions, such as pain and
pleasure, are recognizable in early infancy; the “gastric smile” of the newborn is an example [15]. The complexity of early behavior that results from preprogrammed wiring, with augmentation and suppression of primitive reflexes, has often been attributed to mental activities that will only appear much later in human development. Because higher mental functions develop alongside motor functions, it is hard not to associate a complex motor behavior with mental functions that are difficult to test objectively. The increasingly intricate motor development of the growing child should not be confused with intellectual development. Conscious utilization of motor skills involves higher cortical functions, which are modulated by emotions. This type of events explains the irresistible conviction there is a “mind” lurking behind these phenomena. Of course, the mind grows with the brain [16], which is a fact that has met opposition since Aristotle fostered the concept of an immaterial spirit causing matter to live. The acquisition of purposeful movements and posture is discontinuous; it is characterized by periods of slow and rapid development. Infants have periods of aimless movements followed by intentional movements that are coordinated and progress in a regular fashion, which are often repeated for a long time in exactly the same way [17]. This natural method of learning is often misconstrued to be stereotyped activity or self-stimulation. Gesell [16] recognized that development is not a linear process, comparing it with a braiding pattern, shuttling back and forth. Psychomotor development, which he called behavior, is directly related to brain maturation. He designed simple tests to document objectively developing infant functions. Confusing steps of motor organization with “intelligence,” and using the developmental quotient to illustrate deviations from the norm rather than emphasizing the actual developmental/functional age has subsequently distorted the objective value of his work. A remarkable grasp of the developmental process was achieved by McGraw [18], who examined normal infants monthly and graphically documented discrete phases in the maturation of motor systems, such as posture, hand use, and ambulation. Vygotsky [19] stressed the interdependency between intellectual and emotional defects in mentally retarded children. Coghill [20] noted the early appearance of generalized movements in the embryo. A remarkable example of the intimate process of CNS development was achieved in studying how the visual system is prewired and remodeled by nascent function [21]. The nonlinear nature of brain development, with gains of skills and temporary regressions, reflects stages of reorganization [22]. Children with developmental disabilities are frequently arrested at a given stage from which they do not proceed to a higher level [3,23]. This is quite different from regression to a more elementary level in the Jacksonian sense. Degenerative diseases or insults to the grown brain have no relation to the normal developmental process with remodeling and emerging functional organization taking
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two decades to achieve. Higher functions require more neurons and connections, and are, therefore, more vulnerable to various insults. Regression is not a mirror image of normal brain growth. Damage in multiple areas of a rat brain causes a “mentally retarded rat” [24], illustrating how an intact organization is necessary for complex functions. The training of neurologists has remained influenced by the concepts of strong personalities, such as Osler and Gowers, who did not have the clinical background to recognize that children are not miniature adults. Adults forget that the mind is weaved woof and warp before the patches became unrecognizable in the final tapestry. Until the 1930s the biology of the phenomena underlying development was largely unknown and Cajal’s pioneering work was ignored. Failure to focus on the underlying anatomic structure building exposes can make idle speculations on unsupported assumptions. For Democritus, atoms dictate the structure of the world. Molecular arrangements and contacts determine self-organization, the basis for biology from bacteria to brain. Fairly stable arrangements make contacts of increasing complexity and hierarchized structures, like stair-steps leading to a higher level through multiple forks or loops. Some steps lead to a dead-end, others may be backwards. Representations of the structures remain conjectural. A visual integration may be considered, like Pribram’s holograms [25], or an auditory one, like musical notes arranged haphazardly in a cacophony or harmoniously in a symphony. Fairly stable is the key concept, which was pointed out by Freeman [26], because small variations, linked to the low rate of errors in transcribing DNA information, allow the appearance of new combinations. These will be selected when advantageous in a given endogenous and exogenous environment. The more simple arrangements, illustrated by bacteria that have been maintained unchanged for billions of years, are inherently more stable. The price for higher complexity, which allows more flexibility in adapting to the environment, is less tolerance for mistakes. This is the human predicament of possessing a complex nervous system requiring 20 years to build. Errors, dysfunctions, and failures are part of the molecular fabric of the biology, the entropy of the system. The time arrow is unidirectional in the sequential construction of the CNS scaffolding. The master plan is encoded in the genome. The homeobox [27] is the blueprint, which determines the architecture of the body plan in three dimensions, cephalocaudal, anteriorposterior, and lateral (left, right). The actual sequences are just starting to be deciphered. Precise timing in some way is also encoded; it is crucial in coordinating the construction of the inverted pyramid of development. Data on the molecular mechanisms of this process are rapidly accumulating. Primogenitor brain cells migrate, differentiate into various neuron colonies and glial cells, and establish connections with other CNS colonies. Many growth factors, neurotransmitters, cytokines, matrix molecules, and chaperones
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participate to the orchestration of the whole process. Much remodeling takes place to remove, reorganize, connect and disconnect, or reconnect the different neuron colonies. Use and function are an intimate part of the process, starting early during the fetal development [20]. Cell death is part of the fabric of biology at all stages and ages. Peculiar epileptic syndromes so common in the first year of life may be an expression of remodeling gone awry. Like a defective gearbox, it may prevent the moving up to a higher level of organization and sometimes disturb the functional level already achieved. Membranes are the strategic site of cell functions, controlling import and export through specific receptors and transporters. Synapses are specialized areas of the dendritic spines where a complex machinery [28] has been developed to allow growth and function of the neuronal assemblies. Connections are reinforced through constant use at a more and more elaborate level, or eliminated. A great deal of redundancy is found at many levels from the homeobox [27] to codes for receptors and neurotransmitters [28], striking examples of the process by which evolutionary tinkering may achieve more elaborate functions, by trial and error rather than rational design. A misstep may cause functional failure in the remodeling of developing neuronal systems or seldom may originate a new type of interaction with the molecules from the neuronal milieu. The concept of developmental arrest still needs to receive proper recognition, while facing the fact that it goes against the zeitgeist that expects imminent cures through gene therapy. Two diseases, Rett syndrome and Angelman’s syndrome, can be used as paradigms of genetically determined developmental arrest. They offer an opportunity to study stages of development that are normally too fleeting to be appreciated. Rett Syndrome Most Rett syndrome children have an unremarkable prenatal and perinatal history. They are probably hypotonic, judging from the number suspected of a lower motor neuron or Prader-Willi syndrome. Muscle biopsies are negative. They are quiet, feeding well and raising no concern. The first objective sign is the falling off of the head circumference to lower percentiles. After 3 months of age the lack of motor progress becomes apparent. Children clasp their hands in the middle but never transfer or grasp with full finger flexion. Milestones for sitting, standing, and cruising may remain normal or may never take place. Independent walking is a little late or never fully matures, the elbows remain flexed at 90 degrees or more, and the arms do not swing. The ability to blow saliva between pursed lips is a not well-known milestone of around 9 months of age; it is barely noted in normal children because it is immediately repressed. The ability to imitate gestures and mimic facial expression and sounds are key steps that never develop. The patient may move and make
sounds, thus giving the impression of apparent normality, except for the prelanguage skills of a 9-month-old infant throwing a tantrum to communicate all its needs and feelings in bulk fashion. They never learn differentiated patterns, which causes them to be regarded as capricious and searching for attention, rather than immature. There is a tendency to misunderstand developmental events that appear by small steps [18]. One is dealing with delay, which may be extreme, but is not associated with abnormal motor signs, such as spasticity. Social skills, one of their assets, may be ignored or sadly neglected, sometimes by professionals who mistake their impaired ocular pursuit for autistic features, or even hallucinations. These children are either regarded as quite normal or very deviant when focusing on their increasing delay. By 1 year of age, head circumference has fallen below the second pecentile and will generally remain around the fifth percentile after 2 years old, and the brain weight and structure is arrested at the 9-month-old level according to postmortem examinations of patients 2-35 years of age [29]. The developmental level is so low that a number of genetic or acquired conditions, including tuberous sclerosis, brain malformations, meningitis, or even prematurity, cannot be differentiated functionally. Two camps have handled the difficulty differently, one claims that all retarded children behave similarly, and the other claims that Rett syndrome children are distinctive because they have no identifiable etiologies. This is partially true but needlessly restricted now that a genetic mutation has been identified [30]. Separating “formes frustes” misses the fact that genes seldom breed true in a complex genetic organism. One striking event, which is actually exceptional, is a sudden dramatic change described as “stage 2” or acute regression when Rett syndrome was thought to be a degenerative disease. After an identified event, such as immunization or viral illness with high fever, children lose their hand skills. The need to rationalize is atavistic, and the search for a causal factor exerts a great fascination, which was cogently analyzed by David Hume’s classic discussion of causality [31]. Such events may be coincidences or may represent the shock of recognition when forcefully faced with more or less latent abnormalities, which can no longer be ignored. Many Rett syndrome children never present such sudden changes. Observations need to focus on underlying developmental process, such as synapse remodeling, “changing gears,” and reorganizing the loops controlling movements, for example, to proceed to a higher stage of function illustrated by McGraw [18]. Handwringing, which is a developmental step at 3-4 months old [32], is the most distinctive, but by no means pathognomonic sign, generally manifested at the end of the second year, sometimes in association with a regression in hand skills. The so-called loss of hand use has been widely accepted in the field, despite lack of evidence for “normal” hand skills at any age. The hand function, requiring a large cortical area, second only to
language, has received little attention from most professionals, as attested by indexes in textbooks. Handwringing, often associated with bruxism and hyperventilation, is a normal human expression of anxiety, fear, and frustration [32]. Its compulsive character in Rett syndrome, often mislabeled self-stimulation, reflects the immaturity of the underlying synaptic organization, unable to learn from experience, and repeating the same motor pattern, like a gramophone needle unable to move to the next groove. Stretching the elbow to an angle of at least 90 degrees will abolish it in a few seconds, and the use of elbows splints [33] to ensure sustained relaxation, is a simple effective method, whereas psychotropic medications, sedatives, and behavior conditioning are rather useless. Hand use permanently remains at a 3-month age level. Children may learn to grasp a spoon with a wide handle and feed themselves by using their biceps, never able to control the appropriate degree of pronation/supination. Some learn to swing their arms properly extended, or on command lift the arms using the deltoid or the legs using the psoas. They may rub their ears or vulva, or blow saliva between their pursed lips, a normal 9-month-old milestone. They may imitate smiling or laughing, not sounds or gestures. One of their best skills, communications through facial expression, is narrow. Epilepsy occurs in approximately two of three Rett syndrome patients. It can present with early onset and unusual severity, often leading to Lennox-Gastaut syndrome, but this is rare, except in the combination tuberous sclerosis and Rett syndrome [34], which presents an interesting equation to solve. Epilepsy is widely overdiagnosed and overmedicated in children with abnormal or excessive movements. Video-telemetry illustrates a lack of correlation between events called seizures by the parents and documented electrical seizures [35]. Gastrointestinal dysfunctions are the leading problem from infancy to old age. Patients enjoy eating, which is expected at their developmental age, which leads caretakers to ignore a grossly inadequate caloric intake that is difficult to demonstrate in a clinical setting. Swallowing difficulties, occult or not so occult, and gastroesophageal reflux (GER), in combination with impaired digestive transit, aerophagia, and excessive salivation, cause chronic malnutrition, repeated pneumonia, and sometimes premature death (a relatively rare event). Extensive gastrointestinal evaluation is generally unrevealing unless it documents GER and delayed gastric emptying, which are best treated with pyloromyotomy and Nissen fundoplication, although percutaneous gastrostomy (PEG) sometimes is effective. Ambulation is the best motor milestone, although some will not even achieve independent sitting. It may be extremely delayed, for instance 21 years in two personal reports. Some will tiptoe, which leads to heel cord lengthening on the basis of assumed cerebral palsy. Muscles do not develop normally, which should not be confused with atrophy. It may cause body imbalance and sometimes loss
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of ambulation when the necessary adjustments to increased height and weight cannot occur properly. Indeed, the appearance of the skinny legs kept akimbo with foot dorsiflexion and curling down of the toes may suggest the diagnosis in adult patients. Muscle biopsies in Rett syndrome children with severe hypotonia illustrate minor abnormalities, fiber disproportion, or small fibers without fetal character. Nerve biopsies also reveal minor abnormalities with no evidence of progressive neuropathy. Muscle stretch reflexes are generally brisk, like in anxious subjects. Magnetic stimulation depicts normal conduction in the pyramidal tract but less elaborate responses than in normal subjects of the same age [36]. Angelman’s Syndrome The early appellation happy puppet was a masterstroke of clinical acumen and concision. A personal patient correctly diagnosed on the basis of the original report [37] shortly after its publication did not make it in the official registry, which kept the favored “birth anoxia” until the chromosome 15q11 deletion was demonstrated 35 years later. Objective information on the early infantile development is not available because everybody was convinced it is normal. The sociable easy-to-content nature of the patient, appropriate for their developmental level, endears them so much that little attention is paid to the stagnation of their progress and clumsy motor skills. They are probably not as markedly hypotonic as Prader-Willi or Rett syndrome patients, many of whom undergo muscle biopsies. Walking is delayed but achieved by most. Parents become concerned by the failure of acquiring speech by 2-4 years of age. Some develop brief absences or may fall more often without evidence of loss of consciousness. Like Prader-Willi syndrome patients they may become overweight, a feature not mentioned in the literature. Many present a peculiar stereotyped tremor, distinct from classic myoclonus. It may be constant and suggests essential tremor, but is usually brief, associated with movements, not striking amid their general clumsiness but noted by parents when queried about it. This is commonly confused with epilepsy but not necessarily associated with it. Routine electroencephalograms may be normal or demonstrate trains of high voltage 4-6 Hz activity, which are highly characteristic but whose significance is frequently overlooked. A minority develops severe epileptic syndromes, including hypsarrhythmia and LennoxGastaut syndrome. A few have associated myoclonus [38]. Developmental testing characterizes low age level, around 12 months, with strong social skills, fair gross motor, low fine motor, and low daily living skills. For those who have been regularly tested for up to 40 years old, the age level remains constant, demonstrating developmental arrest and the reliability of Gesell techniques used by many psychologists. Some Angelman’s syndrome patients, nevertheless, may be diagnosed as autistic, their happy laughs being mistaken for a psychiatric disorder [39]. The patient’s
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tongue may protrude and, like Rett syndrome patients, they may suck on their fingers and drool profusely. Many have dysmorphic features with prognathism, fullness of the face, and flat occiput. This may not become obvious before adulthood. The patient’s gait is that of a toddler, often described as ataxic but without cerebellar features, they have a low incidence of fractures, and an amazing ability to avoid expected falls. Some develop a simple language, which is a feature shared with some Rett syndrome patients [40], may include a few parrot-like phrases, and may have an apparent pertinacy. A few with intractable seizures may never exhibit a happy nature or acquire ambulation. Thus, they may be indistinguishable from Rett syndrome until the proper genetic tests are performed. They never present severe scoliosis or failureto-thrive, which is the rule in nonambulatory Rett syndrome. They may present gastrointestinal problems in adulthood, but seldom require gastrostomy or fundoplication. Intractable seizures may persist into middle age. The myoclonus responds to clonazepam, which causes excessive muscle relaxation in these hypotonic, uncoordinated subjects. Valproate is frequently used but is best avoided in young children with a tendency to become overweight. Topiramate is becoming the most promising of the new antiepileptic drugs, but monotherapy may not always be successful. Carbamazepine has been reported to be contraindicated, but that assumption cannot be generalized. Older patients in their 50s may develop dystonia or Parkinsonism, another similarity to Rett syndrome, however, these patients present such problems in their 20s and suffer a severe form by their 40s. General Remarks on Treatment The impossibility of cure or treatment was the immediate consequence of Georget [3] and Esquirol’s [4] concept of mental retardation as a congenital developmental defect. When Se´ guin [41] took up Itard’s challenge in educating the wild male of the Aveyron he elicited bitter animosities from the French medical establishment. His emigration to the United States after the 1848 revolution gave him the opportunity to develop a comprehensive program of education for the mentally retarded in a sheltered environment. Se´ guin delineated a complete training of the motor, sensory and communication skills, including the construction of special equipment for the purpose if necessary [42]. Rather than normalizing the mentally retarded, Se´ guin realized that the world around these patients needed to be tailored to their needs and limitations. He nurtured their skills in the spirit of our current Individual Educational Plan without the mindless bureaucracy. Recognizing the developmental arrest and accepting it is difficult, especially for the patient’s parents, until they see the value of treatment appropriate to the developmental needs and peculiar risks, that is, dying from malnutrition and not from intractable epilepsy. Neither parents nor society will ever accept that nothing
can be done, defeating the traditional neurologist urge to stress the lack of cure or treatment. Children are naturally motivated to gain as much independence as they can, first crawling and then walking or pushing the wheel of their chair. They enjoy food and social interaction. Behaviorists have popularized concepts of attention deficit, lack of motivation, laziness, hyperactivity, self-stimulation, and indifference to pain, which misunderstands the emotional responses of children lost in a world with which they cannot properly connect but learn to fear as exhibited by their intense look on the face of approaching strangers. Multidisciplinary teams can be extremely effective [33] but often function like cogwheels that never connect. Simple goals and techniques go a long way. Growth curves including the head circumference are being increasingly neglected after the first year of age. Deviations from the original percentile are more valuable than serial neuroimaging. A plateau in height gain may point to scoliosis more effectively than serial spine x-rays. Failure to gain weight is the leading problem in Rett syndrome patients between 5 and 20 years of age. They have small muscles, the main site of carnitine storage, and lowplasma carnitine. Carnitine and medium-chain triglyceride (MCT) oil promotes weight gain in one third of the patients. The oil softens stools, preventing constipation, which is the nemesis of a child with limited mobility. Keeping Rett syndrome patients on their legs effectively prevents scoliosis. Spine fusion is popular, but its alleged value in preventing pulmonary and feeding difficulties still awaits validation. Patients in severe failure to thrive a decade after a spinal fusion may gain from one third to one half of their weight 1 or 2 years after a percutaneous gastrostomy or a fundoplication with pyloromyotomy. The proper time to proceed with surgery is difficult to determine in children who do not present with pneumonia or demonstrable reflux. Failure to reach 50-60 pounds at 14 years may well be a sufficient criterion. Epilepsy is seldom a major problem. For Lennox-Gastaut the ketogenic diet, always difficult to implement in a grossly underweight child, may be remarkably effective. Topiramate, among the new antiepileptic drugs, is the most promising for Rett syndrome and Angleman syndrome patients with intractable epilepsy, but weight loss may prevent monotherapy. Valproate, often in combination with clonazepam, is popular but both have undesirable side effects, including sedation, insomnia, muscle relaxation, bloating, and carnitine deficiency. Carbamazepine is the drug of choice for most, helping with emotional lability, anxiety, sleep, weight, and seizure control. In patients in whom carbamazepine is not effective, lamotrigine is promising. Phenobarbital still has a place. Trihexyphenidyl is useful for controlling drooling, and also reduces respiratory congestion. Large amounts may be necessary, up to 15-20 mg three times daily, and well tolerated by patients less than 20 years old. Children with Rett syndrome or Angelman’s syndrome, being normal although permanently immature, do well
with each other or with normal very young children who communicate with them and do not threaten them or bully them like older normal children generally do. They can enjoy a life free of competition or domination.
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[34] Philippart M. Rett syndrome associated with tuberous sclerosis in a male and in a female: Evidence for arrested motor and mental development. Am J Med Genet 1993;48:229-30. [35] Cooper RA, Kerr AM, Amos PM. Rett syndrome: Critical examination of clinical features, serial EEG and video-monitoring in understanding and management. Eur J Paediatr Neurol 1998;2:127-35. [36] Eyre JA, Kerr AM, Miller S, O’Sullivan MC, Ramesh V. Neurophysiological observations on corticospinal projections to the upper limb in subjects with Rett syndrome. J Neurol Neurosurg Psychiat 1990;53:874-9. [37] Angelman H. Puppet children. Dev Med Child Neurol 1965;7: 681-8. [38] Guerrini R, De Lorey TM, Bonanni P, et al. Cortical myoclonus in Angelman syndrome. Ann Neurol 1996;40:39-48. [39] Steffenburg S, Gilberg CL, Steffenburg U, Kyllerman M. Autism in Angelman syndrome. A population-based study. Pediatr Neurol 1996;14:131-6. [40] Zappella M. The Rett girls with preserved speech. Brain Dev 1992;14:98-101. [41] Se´ guin E. Traitement moral, hygie`ne et e´ ducation des idiots. Paris: Baille`re, 1846. Reprint: Comite´ d’histoire de la se´ curite sociale. Paris: Baille`re, 1997. [42] Se´ guin E. Idiocy and its treatment by the physiological method. New York: William Wood, 1866. Reprint from: New York: Gryfon Editions, 1994.
Introduction Knowledge expansion mandates frequent reorganization and sometimes rejection of traditional concepts that have become obsolete and distort the order of nature. Linear thinking is tempting, and it is difficult to reject appearances even when knowing they are wrong. It is still easier to see the sun going round the earth despite Copernicus and Galileo’s long-resisted demonstrations that such common sense is a fallacy. In the forest of
From the Brain Research Institute; UCLA; Los Angeles, CA.
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accumulating new leaves, how is it possible to find trees and paths leading to them? Like barnacles on an old clipper, old knowledge may become a burden. Will the metaphysics of water molecules be elaborated to explain their path down a mountain or will simple laws of least resistance and gravity that effectively dictate their behavior be identified? In this vein, Rett and Angelman’s syndromes first were classified as neurodegenerative or static encephalopathies and were often blamed on birth anoxia despite tenuous evidence of it, if any. Both disorders result from genetic mutations blocking further differentiation of the nascent brain organization, which depends on the turning on of genes still to be identified. The concept of lack or arrest of brain development provides a powerful framework to facilitate diagnosis and treatment. Adopting new concepts is a difficult task when dealing with acquired knowledge that we long for to be permanent. Going back to the roots and following the genesis of new ideas allows a sorting out and ordering the entangled mass of new data. A comprehensive historic review would require an encyclopedia where the grain gets lost in the chaff. This review focuses on the history of important concepts with immediate implications for simplifying the process of diagnosis and appropriate treatment. The word development has many meanings and is used rather blindly, with scant attention to its intimate significance. The word has been used within varying contexts in embryology, evolution, and psychology. Its most simple meaning is equivalent to growth, or “getting bigger.” The association between a small brain and mental retardation (“a Fool from his birth”) was first reported by Thomas Willis [1]. The notion of developmental arrest was introduced by Geoffroy St. Hilaire [2], a pioneer in embryology. The term was first defined in the context of mental retardation by Georget [3], who separated “idiocy” from insanity, which was a distinction that was later elaborated by Esquirol [4]. The concept of development in increasing complexity can be traced to Parmenides: “. . . the highest
Communications should be addressed to: Dr. Philippart; 300 UCLA Medical Plaza; Suite 1247; Los Angeles, CA 90095-6967. Received October 23, 2000; accepted April 3, 2001.
© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00288-0 ● 0887-8994/01/$—see front matter
degree of organization gives the highest degree of thought” [5]. In his developmental hypothesis, Spencer [6] defined evolution as a structure of increasing complexity and dissolution as its opposite. In Draper’s treatise [7] the term development implies growth, the increase in size of a structure and conjointly differentiation, which involves modification of fabric and the assumption of new function. The concept of dissolution was elaborated on by Jackson [8], who described the regression of the mature central nervous system (CNS) from a higher to lower level of organization. Since then neurology has focused on the damage to adult structures from neurodegenerative disease, infection, vascular compromises, tumors, and similar processes. The idea of damage had a powerful influence on pediatric neurology, and the view persisted that anoxia/ischemia was the almost exclusive etiology of cerebral palsy and, more recently, of autism. The study of simple animals at early stages of development was exploited in Cajal’s work [9], which identified pathways that become hard to trace amid the complexity of the adult CNS. Immature nerve cells grow connections through a dendritic tree, building the skeleton of the nascent CNS functions. Cajal’s masterful accomplishment, however, had little detectable impact on neurologists or developmentalists at the time. The implications of his work, based on the Golgi technique, have not been used fully by pathologists, who often complain of the unreliability of the method. Neurologists not trained in pediatrics do not appreciate that brain growth is more an increase in complexity than an increase in size. Huttenlocher [10] revived the studies of developmental processes and documented the burst of synaptic formation after birth in the human, followed by considerable elimination. Positron-emission tomography (PET) studies with fluoro-deoxy-glucose illustrated this process in vivo [11] and also demonstrated that the bulk of energy consumption takes place at the synapse [12], which is the basis for the enormous blood flow the brain needs. Brain development in neonates requires the presence of thyroid hormones. The concept of a therapeutic window allowing limited time to provide the necessary stimulus to dendrite growth and to prevent developmental arrest was slow to be accepted [13]. Remodeling cortical connections through usage underlies reflex conditioning. Fixed connections limit the freedom of movements and thought involved in the highest level of brain maturation. This balance was appreciated by Jackson [14], who noted that the highest levels were less organized and less automatic than the lower ones, and the most simple levels were more strongly organized from birth. Vital functions, such as respiration, blood pressure, heart rate, deglutition, and sympathetic controls illustrate the sophisticated organization of the brainstem in the human newborn. Automatic newborn walking requires a high level of basic limb connections, which are hidden under terms like reflex or automatic level. Elementary emotions, such as pain and
pleasure, are recognizable in early infancy; the “gastric smile” of the newborn is an example [15]. The complexity of early behavior that results from preprogrammed wiring, with augmentation and suppression of primitive reflexes, has often been attributed to mental activities that will only appear much later in human development. Because higher mental functions develop alongside motor functions, it is hard not to associate a complex motor behavior with mental functions that are difficult to test objectively. The increasingly intricate motor development of the growing child should not be confused with intellectual development. Conscious utilization of motor skills involves higher cortical functions, which are modulated by emotions. This type of events explains the irresistible conviction there is a “mind” lurking behind these phenomena. Of course, the mind grows with the brain [16], which is a fact that has met opposition since Aristotle fostered the concept of an immaterial spirit causing matter to live. The acquisition of purposeful movements and posture is discontinuous; it is characterized by periods of slow and rapid development. Infants have periods of aimless movements followed by intentional movements that are coordinated and progress in a regular fashion, which are often repeated for a long time in exactly the same way [17]. This natural method of learning is often misconstrued to be stereotyped activity or self-stimulation. Gesell [16] recognized that development is not a linear process, comparing it with a braiding pattern, shuttling back and forth. Psychomotor development, which he called behavior, is directly related to brain maturation. He designed simple tests to document objectively developing infant functions. Confusing steps of motor organization with “intelligence,” and using the developmental quotient to illustrate deviations from the norm rather than emphasizing the actual developmental/functional age has subsequently distorted the objective value of his work. A remarkable grasp of the developmental process was achieved by McGraw [18], who examined normal infants monthly and graphically documented discrete phases in the maturation of motor systems, such as posture, hand use, and ambulation. Vygotsky [19] stressed the interdependency between intellectual and emotional defects in mentally retarded children. Coghill [20] noted the early appearance of generalized movements in the embryo. A remarkable example of the intimate process of CNS development was achieved in studying how the visual system is prewired and remodeled by nascent function [21]. The nonlinear nature of brain development, with gains of skills and temporary regressions, reflects stages of reorganization [22]. Children with developmental disabilities are frequently arrested at a given stage from which they do not proceed to a higher level [3,23]. This is quite different from regression to a more elementary level in the Jacksonian sense. Degenerative diseases or insults to the grown brain have no relation to the normal developmental process with remodeling and emerging functional organization taking
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two decades to achieve. Higher functions require more neurons and connections, and are, therefore, more vulnerable to various insults. Regression is not a mirror image of normal brain growth. Damage in multiple areas of a rat brain causes a “mentally retarded rat” [24], illustrating how an intact organization is necessary for complex functions. The training of neurologists has remained influenced by the concepts of strong personalities, such as Osler and Gowers, who did not have the clinical background to recognize that children are not miniature adults. Adults forget that the mind is weaved woof and warp before the patches became unrecognizable in the final tapestry. Until the 1930s the biology of the phenomena underlying development was largely unknown and Cajal’s pioneering work was ignored. Failure to focus on the underlying anatomic structure building exposes can make idle speculations on unsupported assumptions. For Democritus, atoms dictate the structure of the world. Molecular arrangements and contacts determine self-organization, the basis for biology from bacteria to brain. Fairly stable arrangements make contacts of increasing complexity and hierarchized structures, like stair-steps leading to a higher level through multiple forks or loops. Some steps lead to a dead-end, others may be backwards. Representations of the structures remain conjectural. A visual integration may be considered, like Pribram’s holograms [25], or an auditory one, like musical notes arranged haphazardly in a cacophony or harmoniously in a symphony. Fairly stable is the key concept, which was pointed out by Freeman [26], because small variations, linked to the low rate of errors in transcribing DNA information, allow the appearance of new combinations. These will be selected when advantageous in a given endogenous and exogenous environment. The more simple arrangements, illustrated by bacteria that have been maintained unchanged for billions of years, are inherently more stable. The price for higher complexity, which allows more flexibility in adapting to the environment, is less tolerance for mistakes. This is the human predicament of possessing a complex nervous system requiring 20 years to build. Errors, dysfunctions, and failures are part of the molecular fabric of the biology, the entropy of the system. The time arrow is unidirectional in the sequential construction of the CNS scaffolding. The master plan is encoded in the genome. The homeobox [27] is the blueprint, which determines the architecture of the body plan in three dimensions, cephalocaudal, anteriorposterior, and lateral (left, right). The actual sequences are just starting to be deciphered. Precise timing in some way is also encoded; it is crucial in coordinating the construction of the inverted pyramid of development. Data on the molecular mechanisms of this process are rapidly accumulating. Primogenitor brain cells migrate, differentiate into various neuron colonies and glial cells, and establish connections with other CNS colonies. Many growth factors, neurotransmitters, cytokines, matrix molecules, and chaperones
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participate to the orchestration of the whole process. Much remodeling takes place to remove, reorganize, connect and disconnect, or reconnect the different neuron colonies. Use and function are an intimate part of the process, starting early during the fetal development [20]. Cell death is part of the fabric of biology at all stages and ages. Peculiar epileptic syndromes so common in the first year of life may be an expression of remodeling gone awry. Like a defective gearbox, it may prevent the moving up to a higher level of organization and sometimes disturb the functional level already achieved. Membranes are the strategic site of cell functions, controlling import and export through specific receptors and transporters. Synapses are specialized areas of the dendritic spines where a complex machinery [28] has been developed to allow growth and function of the neuronal assemblies. Connections are reinforced through constant use at a more and more elaborate level, or eliminated. A great deal of redundancy is found at many levels from the homeobox [27] to codes for receptors and neurotransmitters [28], striking examples of the process by which evolutionary tinkering may achieve more elaborate functions, by trial and error rather than rational design. A misstep may cause functional failure in the remodeling of developing neuronal systems or seldom may originate a new type of interaction with the molecules from the neuronal milieu. The concept of developmental arrest still needs to receive proper recognition, while facing the fact that it goes against the zeitgeist that expects imminent cures through gene therapy. Two diseases, Rett syndrome and Angelman’s syndrome, can be used as paradigms of genetically determined developmental arrest. They offer an opportunity to study stages of development that are normally too fleeting to be appreciated. Rett Syndrome Most Rett syndrome children have an unremarkable prenatal and perinatal history. They are probably hypotonic, judging from the number suspected of a lower motor neuron or Prader-Willi syndrome. Muscle biopsies are negative. They are quiet, feeding well and raising no concern. The first objective sign is the falling off of the head circumference to lower percentiles. After 3 months of age the lack of motor progress becomes apparent. Children clasp their hands in the middle but never transfer or grasp with full finger flexion. Milestones for sitting, standing, and cruising may remain normal or may never take place. Independent walking is a little late or never fully matures, the elbows remain flexed at 90 degrees or more, and the arms do not swing. The ability to blow saliva between pursed lips is a not well-known milestone of around 9 months of age; it is barely noted in normal children because it is immediately repressed. The ability to imitate gestures and mimic facial expression and sounds are key steps that never develop. The patient may move and make
sounds, thus giving the impression of apparent normality, except for the prelanguage skills of a 9-month-old infant throwing a tantrum to communicate all its needs and feelings in bulk fashion. They never learn differentiated patterns, which causes them to be regarded as capricious and searching for attention, rather than immature. There is a tendency to misunderstand developmental events that appear by small steps [18]. One is dealing with delay, which may be extreme, but is not associated with abnormal motor signs, such as spasticity. Social skills, one of their assets, may be ignored or sadly neglected, sometimes by professionals who mistake their impaired ocular pursuit for autistic features, or even hallucinations. These children are either regarded as quite normal or very deviant when focusing on their increasing delay. By 1 year of age, head circumference has fallen below the second pecentile and will generally remain around the fifth percentile after 2 years old, and the brain weight and structure is arrested at the 9-month-old level according to postmortem examinations of patients 2-35 years of age [29]. The developmental level is so low that a number of genetic or acquired conditions, including tuberous sclerosis, brain malformations, meningitis, or even prematurity, cannot be differentiated functionally. Two camps have handled the difficulty differently, one claims that all retarded children behave similarly, and the other claims that Rett syndrome children are distinctive because they have no identifiable etiologies. This is partially true but needlessly restricted now that a genetic mutation has been identified [30]. Separating “formes frustes” misses the fact that genes seldom breed true in a complex genetic organism. One striking event, which is actually exceptional, is a sudden dramatic change described as “stage 2” or acute regression when Rett syndrome was thought to be a degenerative disease. After an identified event, such as immunization or viral illness with high fever, children lose their hand skills. The need to rationalize is atavistic, and the search for a causal factor exerts a great fascination, which was cogently analyzed by David Hume’s classic discussion of causality [31]. Such events may be coincidences or may represent the shock of recognition when forcefully faced with more or less latent abnormalities, which can no longer be ignored. Many Rett syndrome children never present such sudden changes. Observations need to focus on underlying developmental process, such as synapse remodeling, “changing gears,” and reorganizing the loops controlling movements, for example, to proceed to a higher stage of function illustrated by McGraw [18]. Handwringing, which is a developmental step at 3-4 months old [32], is the most distinctive, but by no means pathognomonic sign, generally manifested at the end of the second year, sometimes in association with a regression in hand skills. The so-called loss of hand use has been widely accepted in the field, despite lack of evidence for “normal” hand skills at any age. The hand function, requiring a large cortical area, second only to
language, has received little attention from most professionals, as attested by indexes in textbooks. Handwringing, often associated with bruxism and hyperventilation, is a normal human expression of anxiety, fear, and frustration [32]. Its compulsive character in Rett syndrome, often mislabeled self-stimulation, reflects the immaturity of the underlying synaptic organization, unable to learn from experience, and repeating the same motor pattern, like a gramophone needle unable to move to the next groove. Stretching the elbow to an angle of at least 90 degrees will abolish it in a few seconds, and the use of elbows splints [33] to ensure sustained relaxation, is a simple effective method, whereas psychotropic medications, sedatives, and behavior conditioning are rather useless. Hand use permanently remains at a 3-month age level. Children may learn to grasp a spoon with a wide handle and feed themselves by using their biceps, never able to control the appropriate degree of pronation/supination. Some learn to swing their arms properly extended, or on command lift the arms using the deltoid or the legs using the psoas. They may rub their ears or vulva, or blow saliva between their pursed lips, a normal 9-month-old milestone. They may imitate smiling or laughing, not sounds or gestures. One of their best skills, communications through facial expression, is narrow. Epilepsy occurs in approximately two of three Rett syndrome patients. It can present with early onset and unusual severity, often leading to Lennox-Gastaut syndrome, but this is rare, except in the combination tuberous sclerosis and Rett syndrome [34], which presents an interesting equation to solve. Epilepsy is widely overdiagnosed and overmedicated in children with abnormal or excessive movements. Video-telemetry illustrates a lack of correlation between events called seizures by the parents and documented electrical seizures [35]. Gastrointestinal dysfunctions are the leading problem from infancy to old age. Patients enjoy eating, which is expected at their developmental age, which leads caretakers to ignore a grossly inadequate caloric intake that is difficult to demonstrate in a clinical setting. Swallowing difficulties, occult or not so occult, and gastroesophageal reflux (GER), in combination with impaired digestive transit, aerophagia, and excessive salivation, cause chronic malnutrition, repeated pneumonia, and sometimes premature death (a relatively rare event). Extensive gastrointestinal evaluation is generally unrevealing unless it documents GER and delayed gastric emptying, which are best treated with pyloromyotomy and Nissen fundoplication, although percutaneous gastrostomy (PEG) sometimes is effective. Ambulation is the best motor milestone, although some will not even achieve independent sitting. It may be extremely delayed, for instance 21 years in two personal reports. Some will tiptoe, which leads to heel cord lengthening on the basis of assumed cerebral palsy. Muscles do not develop normally, which should not be confused with atrophy. It may cause body imbalance and sometimes loss
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of ambulation when the necessary adjustments to increased height and weight cannot occur properly. Indeed, the appearance of the skinny legs kept akimbo with foot dorsiflexion and curling down of the toes may suggest the diagnosis in adult patients. Muscle biopsies in Rett syndrome children with severe hypotonia illustrate minor abnormalities, fiber disproportion, or small fibers without fetal character. Nerve biopsies also reveal minor abnormalities with no evidence of progressive neuropathy. Muscle stretch reflexes are generally brisk, like in anxious subjects. Magnetic stimulation depicts normal conduction in the pyramidal tract but less elaborate responses than in normal subjects of the same age [36]. Angelman’s Syndrome The early appellation happy puppet was a masterstroke of clinical acumen and concision. A personal patient correctly diagnosed on the basis of the original report [37] shortly after its publication did not make it in the official registry, which kept the favored “birth anoxia” until the chromosome 15q11 deletion was demonstrated 35 years later. Objective information on the early infantile development is not available because everybody was convinced it is normal. The sociable easy-to-content nature of the patient, appropriate for their developmental level, endears them so much that little attention is paid to the stagnation of their progress and clumsy motor skills. They are probably not as markedly hypotonic as Prader-Willi or Rett syndrome patients, many of whom undergo muscle biopsies. Walking is delayed but achieved by most. Parents become concerned by the failure of acquiring speech by 2-4 years of age. Some develop brief absences or may fall more often without evidence of loss of consciousness. Like Prader-Willi syndrome patients they may become overweight, a feature not mentioned in the literature. Many present a peculiar stereotyped tremor, distinct from classic myoclonus. It may be constant and suggests essential tremor, but is usually brief, associated with movements, not striking amid their general clumsiness but noted by parents when queried about it. This is commonly confused with epilepsy but not necessarily associated with it. Routine electroencephalograms may be normal or demonstrate trains of high voltage 4-6 Hz activity, which are highly characteristic but whose significance is frequently overlooked. A minority develops severe epileptic syndromes, including hypsarrhythmia and LennoxGastaut syndrome. A few have associated myoclonus [38]. Developmental testing characterizes low age level, around 12 months, with strong social skills, fair gross motor, low fine motor, and low daily living skills. For those who have been regularly tested for up to 40 years old, the age level remains constant, demonstrating developmental arrest and the reliability of Gesell techniques used by many psychologists. Some Angelman’s syndrome patients, nevertheless, may be diagnosed as autistic, their happy laughs being mistaken for a psychiatric disorder [39]. The patient’s
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tongue may protrude and, like Rett syndrome patients, they may suck on their fingers and drool profusely. Many have dysmorphic features with prognathism, fullness of the face, and flat occiput. This may not become obvious before adulthood. The patient’s gait is that of a toddler, often described as ataxic but without cerebellar features, they have a low incidence of fractures, and an amazing ability to avoid expected falls. Some develop a simple language, which is a feature shared with some Rett syndrome patients [40], may include a few parrot-like phrases, and may have an apparent pertinacy. A few with intractable seizures may never exhibit a happy nature or acquire ambulation. Thus, they may be indistinguishable from Rett syndrome until the proper genetic tests are performed. They never present severe scoliosis or failureto-thrive, which is the rule in nonambulatory Rett syndrome. They may present gastrointestinal problems in adulthood, but seldom require gastrostomy or fundoplication. Intractable seizures may persist into middle age. The myoclonus responds to clonazepam, which causes excessive muscle relaxation in these hypotonic, uncoordinated subjects. Valproate is frequently used but is best avoided in young children with a tendency to become overweight. Topiramate is becoming the most promising of the new antiepileptic drugs, but monotherapy may not always be successful. Carbamazepine has been reported to be contraindicated, but that assumption cannot be generalized. Older patients in their 50s may develop dystonia or Parkinsonism, another similarity to Rett syndrome, however, these patients present such problems in their 20s and suffer a severe form by their 40s. General Remarks on Treatment The impossibility of cure or treatment was the immediate consequence of Georget [3] and Esquirol’s [4] concept of mental retardation as a congenital developmental defect. When Se´ guin [41] took up Itard’s challenge in educating the wild male of the Aveyron he elicited bitter animosities from the French medical establishment. His emigration to the United States after the 1848 revolution gave him the opportunity to develop a comprehensive program of education for the mentally retarded in a sheltered environment. Se´ guin delineated a complete training of the motor, sensory and communication skills, including the construction of special equipment for the purpose if necessary [42]. Rather than normalizing the mentally retarded, Se´ guin realized that the world around these patients needed to be tailored to their needs and limitations. He nurtured their skills in the spirit of our current Individual Educational Plan without the mindless bureaucracy. Recognizing the developmental arrest and accepting it is difficult, especially for the patient’s parents, until they see the value of treatment appropriate to the developmental needs and peculiar risks, that is, dying from malnutrition and not from intractable epilepsy. Neither parents nor society will ever accept that nothing
can be done, defeating the traditional neurologist urge to stress the lack of cure or treatment. Children are naturally motivated to gain as much independence as they can, first crawling and then walking or pushing the wheel of their chair. They enjoy food and social interaction. Behaviorists have popularized concepts of attention deficit, lack of motivation, laziness, hyperactivity, self-stimulation, and indifference to pain, which misunderstands the emotional responses of children lost in a world with which they cannot properly connect but learn to fear as exhibited by their intense look on the face of approaching strangers. Multidisciplinary teams can be extremely effective [33] but often function like cogwheels that never connect. Simple goals and techniques go a long way. Growth curves including the head circumference are being increasingly neglected after the first year of age. Deviations from the original percentile are more valuable than serial neuroimaging. A plateau in height gain may point to scoliosis more effectively than serial spine x-rays. Failure to gain weight is the leading problem in Rett syndrome patients between 5 and 20 years of age. They have small muscles, the main site of carnitine storage, and lowplasma carnitine. Carnitine and medium-chain triglyceride (MCT) oil promotes weight gain in one third of the patients. The oil softens stools, preventing constipation, which is the nemesis of a child with limited mobility. Keeping Rett syndrome patients on their legs effectively prevents scoliosis. Spine fusion is popular, but its alleged value in preventing pulmonary and feeding difficulties still awaits validation. Patients in severe failure to thrive a decade after a spinal fusion may gain from one third to one half of their weight 1 or 2 years after a percutaneous gastrostomy or a fundoplication with pyloromyotomy. The proper time to proceed with surgery is difficult to determine in children who do not present with pneumonia or demonstrable reflux. Failure to reach 50-60 pounds at 14 years may well be a sufficient criterion. Epilepsy is seldom a major problem. For Lennox-Gastaut the ketogenic diet, always difficult to implement in a grossly underweight child, may be remarkably effective. Topiramate, among the new antiepileptic drugs, is the most promising for Rett syndrome and Angleman syndrome patients with intractable epilepsy, but weight loss may prevent monotherapy. Valproate, often in combination with clonazepam, is popular but both have undesirable side effects, including sedation, insomnia, muscle relaxation, bloating, and carnitine deficiency. Carbamazepine is the drug of choice for most, helping with emotional lability, anxiety, sleep, weight, and seizure control. In patients in whom carbamazepine is not effective, lamotrigine is promising. Phenobarbital still has a place. Trihexyphenidyl is useful for controlling drooling, and also reduces respiratory congestion. Large amounts may be necessary, up to 15-20 mg three times daily, and well tolerated by patients less than 20 years old. Children with Rett syndrome or Angelman’s syndrome, being normal although permanently immature, do well
with each other or with normal very young children who communicate with them and do not threaten them or bully them like older normal children generally do. They can enjoy a life free of competition or domination.
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PEDIATRIC NEUROLOGY
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