Neurology_Adams

Neurology_Adams. Regardless of the time and rapidity of onset, the autistic child exhibits a disregard for other persons; this is typically quite striking but can be subtle in milder cases. Little or no eye contact is made, and the child is no more interested in another person than in an article of furniture. Proffered toys may be manipulated cleverly, placed in lines, or rejected. Insistence on constancy of environment may reach a point where the patient becomes distraught if even a single one of his possessions has been moved from its original place and remains distressed until it is replaced. If speech develops at all, it is automatic (echolalic) and not used effectively to communicate. A repertoire of elaborate stereotyped movements—such as whirling of the body, manipulating an object, toe-walking, and particularly hand-flapping—are characteristics. It is important to point out, that in any sizable group of autistic children there is a wide range of deficits in sociability, drive, affect, and


Neurology_Adams

Neurology_Adams. and particularly hand-flapping—are characteristics. It is important to point out, that in any sizable group of autistic children there is a wide range of deficits in sociability, drive, affect, and communicative (verbal and gestural behavior) ability, ranging from an averbal, completely isolated state to considerable language skill and some capacity for attachment to certain people as well as for scholastic achievement. However, the IQ of the majority is below 70 and in 20 percent it is below 35; 1 percent, however, have normal or superior intelligence. In this higher-functioning group, taken to typify the Asperger syndrome, the child may be unusually adept or even supernormal in reading, calculating, drawing, or memorizing (“idiot savant”) while still having difficulty in adjusting socially and emotionally to others and in interpreting the actions of others. Many are clumsy and inept in athletic activities. The least degree of deficit allows success in a professional field but with


Neurology_Adams

Neurology_Adams. and emotionally to others and in interpreting the actions of others. Many are clumsy and inept in athletic activities. The least degree of deficit allows success in a professional field but with handicap in the social sphere.


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Neurology_Adams. We take the current emphasis on the term autistic spectrum disorders to reflect a concept that each of the core elements of autism (in social, language, cognitive, and behavioral domains) may occur in widely varying degrees of severity. This view expands the diagnosis to many children who are highly functional except for a tendency to gaze aversion and other “soft signs,” together called “pervasive developmental disorder” (Filipek). There is also crossover with a number of namable developmental delays as noted below.


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Neurology_Adams. Rapin, who drew on a large clinical experience, has carefully documented the linguistic, cognitive, and behavioral features of the syndrome. She uses the term semantic-pragmatic disorder to designate the characteristic problem with language and behavior and to distinguish it from other forms of developmental disorders and developmental delay. There is a striking ability to understand isolated facts but not to comprehend concepts or conceptual groupings; consequently, these children and adults seem to have difficulty generalizing from an idea. Temple Grandin, a patient with a high-functioning Asperger type of autism who has written of her experiences and has been described by Sacks, indicates that she thinks in pictures rather than in semantic language. She reports a curious comfort from being tightly swaddled and has a highly developed emotional sensibility to the experiences of cattle, which has allowed her success in reforming and designing abattoirs. According to Eisenberg, who


Neurology_Adams

Neurology_Adams. being tightly swaddled and has a highly developed emotional sensibility to the experiences of cattle, which has allowed her success in reforming and designing abattoirs. According to Eisenberg, who reviewed many of Kanner’s original cases and followed many other cases into adult life, one-third never spoke and remained social isolates, one-third acquired a rudimentary language devoid of communicative value, and the remainder were functional to various degrees, possessing an affected, stilted, colorless speech. It is in the latter group, representing the mildest degrees of autism, that one finds eccentrics, the mirthless, flat personalities, unable to adapt socially and habitually avoiding eye contact but sometimes possessing certain unusual aptitudes in memory, mathematics, factual knowledge, history, and science. Rutter, who has written extensively on the subject, says that the degree of language impairment and lowered intelligence predicts outcome; those who do not speak by 5 years


Neurology_Adams

Neurology_Adams. history, and science. Rutter, who has written extensively on the subject, says that the degree of language impairment and lowered intelligence predicts outcome; those who do not speak by 5 years of age will never learn to speak well.


Neurology_Adams

Neurology_Adams. As mentioned, elements of autism, but not the whole syndrome with its positive and negative attributes, may appear in other diseases that interfere with brain development, specifically fragile X and Rett syndromes, and fragmentary similarities are found in a few children with phenylketonuria, tuberous sclerosis, Angelman syndrome, and, rarely, Down syndrome—but these patients are easily distinguished from those with the far more common type of autism. Bolton and Griffiths have made the intriguing observation that autistic traits in patients with tuberous sclerosis correspond to the finding of tubers in the temporal lobe, and DeLong and Heinz point out that patients with seizures from bilateral (but not unilateral) hippocampal sclerosis may fail to develop (or may lose) language ability as well as failing to acquire social skills after a period of normal development, in a manner similar to autism. Etiology and Pathology of Autism


Neurology_Adams

Neurology_Adams. Etiology and Pathology of Autism The basis of childhood autism is as much a mystery today as it was when Kanner and Asperger described it. Most of these children are physically normal except for a slightly larger head size, on average, but with no other somatic anomalies. Despite instances in which the onset of mental and behavioral regression seems to be quite sudden, no environmental factors, including the often-mentioned measles-mumps-rubella (MMR) vaccination, mercury exposure, and food allergies, have been credibly connected to autism. The genetic microdeletions and microduplications described earlier have given few hints as to the biologic cause. The EEG is normal. Biological explanations have replaced psychological ones, prevalent at one time, largely due to the efforts of Frith, many years ago.


Neurology_Adams

Neurology_Adams. Early investigations into the neuroanatomic abnormalities associated with autism were inconclusive. The significance of cerebellar vermal changes, reported originally by Courchesne and colleagues, remains uncertain (Filipek). In 5 brains studied in serial sections by Bauman and Kemper, smallness of neurons and increased packing density were observed in the medial temporal areas (hippocampus, subiculum, entorhinal cortex), amygdala and septal nuclei, and mammillary bodies. In a subsequent review of the neuropathology, Kemper and Bauman concluded that three changes stood out: a curtailment of the normal development of neurons in the limbic system; a decrease in the number of Purkinje cells that appears to be congenital; and age-related changes in the size and number of the neurons in the diagonal band of Broca (located in the basal frontal and septal region), as well as in the cerebellar nuclei and inferior olive. The latter changes were inferred from studying the brains of autistic


Neurology_Adams

Neurology_Adams. diagonal band of Broca (located in the basal frontal and septal region), as well as in the cerebellar nuclei and inferior olive. The latter changes were inferred from studying the brains of autistic children who died at different ages, and they gave the appearance of a progressive or ongoing pathology that continues into adult life. These findings are in keeping with the concept of autism as a neurodevelopmental disorder, but they allow only speculation regarding the derivation of the clinical features of the disease. An increased concentration of platelet serotonin and low serum serotonin is detected in many but not all patients; also, serum oxytocin is reduced. The biologic significance of these findings is unclear.


Neurology_Adams

Neurology_Adams. More recently, cerebral overgrowth and increased brain volume, particularly but not exclusively in the frontal lobes, has been a finding in young children with autism. High resolution imaging techniques with morphometric and volumetric analysis have confirmed this. The abnormalities may be difficult or impossible to detect on routine CT or MRI. A recent neuroanatomic investigation by Stoner and colleagues has identified focal regions of abnormal cortical laminar architecture and neuronal disorganization in prefrontal and temporal lobes in children with autism. The abnormalities were most consistently found in cortical layers 4 and 5. These findings again support the conceptualization of autism as a neurodevelopmental disorder. Course, Treatment, and Prognosis


Neurology_Adams

Neurology_Adams. The disease is essentially nonprogressive although some patients, as they grow older, begin to manifest additional visuoperceptive or auditory defects. In the typical case, the outcome is bleak, although many less affected children show improvement in social relationships and schoolwork when given a serotonin reuptake inhibitor, sometimes in very small doses (DeLong; Filipek, personal communication). Administration of the peptide secretin had produced a number of anecdotal successes, but this could not be reproduced in controlled studies. Selective serotonin reuptake inhibitors (e.g., fluoxetine, citalopram) have also shown some benefit in managing repetitive behaviors and mood swings such that medications in this class are being widely prescribed to autistic children. In addition, serious behavioral changes such as self-injurious activities, aggression, and severe tantrums have been treated with drugs such as risperidone. These represent a therapeutic advance but, as pointed out by


Neurology_Adams

Neurology_Adams. behavioral changes such as self-injurious activities, aggression, and severe tantrums have been treated with drugs such as risperidone. These represent a therapeutic advance but, as pointed out by Hollander and colleagues in their review of the drug treatment of autism, the patients studied were selected for the severity and type of their symptoms for which reason these medications cannot be expected to be of help to all autistic individuals.


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Neurology_Adams. Management of Developmental Delay Because there is little or no possibility of treating most of the diseases underlying developmental delay and there is no way of restoring function to a nervous system that is developmentally subnormal, the objective is to assist in planning for the patient’s care, training, education, and social adjustment. The parents must be guided in forming realistic attitudes and expectations. Psychiatric and social counseling may help the family to maintain gentle but firm support of the patient so that he can acquire, to the fullest extent possible, good work habits and a congenial personality. Most individuals with an IQ above 60 and no other handicaps can be trained to live an independent life; special schooling may enable them to learn skills useful in a vocation. Social factors that contribute to underachievement must be sought and eliminated if possible.


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Neurology_Adams. If the IQ is below 20, institutionalization is almost inevitable, for few families can provide the long-term custodial care that is needed. Often institutional care is necessary for individuals with IQs of 20 to 50. Patients in this group, if stable in temperament and relatively well adjusted to society, can work under supervision, but they rarely become vocationally independent. For the more severely impaired, special training in perhaps hygiene and self-care is the most that can be expected.


Neurology_Adams

Neurology_Adams. Great care must be exercised in recommending institutionalization. Whereas the need will be all too apparent in the gravely impaired by the first or second year of life, the less-severely affected are difficult to evaluate at an early age. As stated earlier, psychologic tests alone are not altogether trustworthy. It is best to observe the patient over a period of time. As noted in Chap. 27, the method of evaluation suggested long ago by Fernald has a ring of soundness, albeit in quite dated terms. It should include observations of (1) the physical, medical, and neurologic findings; (2) family background; (3) developmental history; (4) school progress; (5) performance in schoolwork; (6) practical knowledge; (7) social behavior; (8) industrial efficiency (the ability to participate in work); (9) behavioral disinhibition, which was called in Fernald’s time “moral behavior”; and (10) intelligence as measured by psychologic tests.


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Neurology_Adams. Levine DN, Fisher MA, Caviness VS Jr: Porencephaly with microgyria: A pathologic study. Acta Neuropathol 29:99, 1974. Lichtenstein BW: Neurofibromatosis (Von Recklinghausen’s disease of the nervous system). Arch Neurol Psychiatry 62:822, 1949. Lorber J: Spina bifida cystica: Results of treatment of 270 cases with criteria for selection in the future. Arch Dis Child 47:854, 1972. Lorber J, Priestley BL: Children with large heads: A practical approach to diagnosis in 557 children with special reference to 109 children with megalencephaly. Dev Med Child Neurol 23:494, 1981. Losner RR, Glenn GM, Walther M, et al: von Hippel-Lindau disease. Lancet 361:2059, 2003. Louis-Bar D: Sur un syndrome progressif comprenant des télangiectasies capillaires cutanée et conjonctivales symetrique a disposition naevoide et des troubles cérébelleux. Confin Neurol 4:32, 1941. Lubs HA: A marker X chromosome. Am J Hum Genet 21:231, 1969.


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Neurology_Adams. Buchwald NA, Brazier MA (eds): Brain Mechanisms in Mental Retardation. New York, Academic Press, 1975, pp 141–171. Rapin I: Autism. N Engl J Med 337:97, 1997. Renpenning H, Gerard JW, Zaleski WA, et al: Familial sex-linked mental retardation. Can Med Assoc J 87:954, 1962. Riccardi VM: Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617, 1981. Riccardi VM, Mulvihill JJ (eds): Advances in Neurology. Vol 29: Neurofibromatosis (Von Recklinghausen Disease). New York, Raven Press, 1981. Roach ES, Williams OP, Laster DW: Magnetic resonance imaging in tuberous sclerosis. Arch Neurol 44:301, 1987. Roizen HJ, Patterson D: Down’s syndrome. Lancet 361:1281, 2003. Rosman NP, Pearce J: The brain in neurofibromatosis. Brain 90:829, 1967. Rousseau F, Heitz D, Biancalana V, et al: Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 325:1674, 1991.


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Neurology_Adams. Rousseau F, Heitz D, Biancalana V, et al: Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 325:1674, 1991. Rutter M: Infantile autism and other pervasive developmental disorders. In: Rutter M, Taylor EA, Hersov LA (eds): Child and Adolescent Psychiatry: Modern Approaches, 3rd ed. Oxford, England, Blackwell, 1994, pp 563–593. Sacks O: An Anthropologist on Mars. Seven Paradoxical Tales. New York, Alfred Knopf, 1995. Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress. Arch Neurol 33:696, 1976. Schreier H, Rapin I, Davis J: Familial megalencephaly or hydrocephalus? Neurology 24:232, 1974. Scottish Low Birthweight Study: II. Language attainment, cognitive status and behavioral problems. Arch Dis Child 67:682, 1992. Shankaran S, Laptook A, Ehrenkranz RA, et al: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574, 2005.


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Neurology_Adams. Shankaran S, Laptook A, Ehrenkranz RA, et al: Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574, 2005. Shapiro LR: The fragile X syndrome: A peculiar pattern of inheritance. N Engl J Med 325:1736, 1991. Sherr EH: The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): One gene leads to many phenotypes. Curr Opin Pediatr 15:567, 2003. Sherr EH, Michelson DJ, Shevell MI, et al: Neurodevelopmental disorders and genetic testing: Current approaches and future advances. Ann Neurol 74:164, 2013. Shibata M, Gulden FO, Sestan N: From trans to cis: Transcriptional regulatory networks in neocortical development. Trends Genet 31:77, 2015. Shillito J Jr, Matson DD: Craniosynostosis: A review of 519 surgical patients. Pediatrics 41:829, 1968. Shirley MD, Tang H, Gallione CJ, et al: Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368:1971, 2013.


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Neurology_Adams. Shirley MD, Tang H, Gallione CJ, et al: Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368:1971, 2013. Shuman RM, Selednik LJ: Periventricular leukomalacia. Arch Neurol 37:231, 1980. Sinha S, Davies J, Toner N, et al: Vitamin E supplementation reduces frequency of periventricular hemorrhage in very premature babies. Lancet 1:466, 1987. Solomon LM, Esterley NB: Epidermal and other congenital organoid nevi. Curr Probl Pediatr 6:1, 1975. Somerville MJ, Mervis CB, Young EJ, et al: Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353:1694, 2005. Srivastava S, Cohen JS, Vernon H, et al: Clinical whole exome sequencing in child neurology practice. Ann Neurol 76:473, 2014. Stoner R, et al: Patches of disorganization in the neocortex of children with autism. N Engl J Med 370:1209, 2014.


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Neurology_Adams. Stoner R, et al: Patches of disorganization in the neocortex of children with autism. N Engl J Med 370:1209, 2014. Taylor M, David AS: Agenesis of the corpus callosum: A United Kingdom series of 56 cases. J Neurol Neurosurg Psychiatry 64:131, 1998. van der Hoeve J: Eye symptoms of tuberous sclerosis of the brain. Trans Ophthalmol Soc UK 40:329, 1920. Vasudevan P, Suri M: A clinical approach to developmental delay and intellectual disability. Clin Med 17:558, 2017. Verhagen MM, Abdo WF, Willemsen MA, et al: Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology 73:430, 2009. Volpe JJ: Intraventricular hemorrhage in the premature infant: Current concepts, parts I and II. Ann Neurol 25:3, 109, 1989. Volpe JJ: Neurology of the Newborn, 3rd ed. Philadelphia, Saunders, 1995.


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Neurology_Adams. Volpe JJ: Neurology of the Newborn, 3rd ed. Philadelphia, Saunders, 1995. Weber F, Parkes R: Association of extensive haemangiomatous naevus of skin with cerebral (meningeal) haemangioma, especially cases of facial vascular naevus with contralateral hemiplegia. Proc R Soc Med 22:25, 1929. Weiss LA, Shen Y, Kom J, et al: Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358:667, 2008. Weller TH: The cytomegaloviruses: Ubiquitous agents with protean clinical manifestations. N Engl J Med 285:267, 1971. Williams JC, Barratt-Boyes BG, Lowe JB: Supravalvular aortic stenosis. Circulation 24:1311, 1961. Wilson GS, Desmond MM, Verniand W: Early development of infants of heroin-addicted mothers. Am J Dis Child 126:457, 1973. Winick M: Malnutrition and Brain Development. New York, Oxford University Press, 1976. Wohlwill FJ, Yakovlev PI: Histopathology of meningofacial angiomatosis (Sturge-Weber’s disease). J Neuropathol Exp Neurol 16:341, 1957.


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Neurology_Adams. Wohlwill FJ, Yakovlev PI: Histopathology of meningofacial angiomatosis (Sturge-Weber’s disease). J Neuropathol Exp Neurol 16:341, 1957. Woodward LJ, Anderson PJ, Austin NC, et al: Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 355:685, 2006. Yakovlev PI, Guthrie RH: Congenital ectodermoses (neurocutaneous syndromes) in epileptic patients. Arch Neurol Psychiatry 26:1145, 1931. Yakovlev PI, Wadsworth RC: Schizencephalies: A study of the congenital clefts in the cerebral mantle. J Neuropathol Exp Neurol 5:116, 169, 1946. Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al: Periventricular leukomalacia: Risk factors revisited. Dev Med Child Neurol 38:1061, 1996. Figure 37-1. Focal cortical dysplasia. A T2-FLAIR MRI in the coronal plane in a patient with seizures. Deep in the white matter, adjacent to the lateral ventricles, are multifocal heterotopic aggregates of gray matter, more apparent in the left hemisphere.


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Neurology_Adams. Figure 37-2. Dandy-Walker syndrome. MRI showing agenesis of the midline cerebellum and large midline cyst, representing the greatly dilated fourth ventricle, which occupies almost the entire posterior fossa. A. Axial view. B. Sagittal view. Figure 37-3. Sagittal T2-weighted MRI of an adult with tethered cord and a typical lipoma at its caudal extent. No dysraphism is present. The main clinical features were a flaccid bladder, asymmetrical weakness and atrophy of the forelegs, and spasticity in the legs. Figure 37-4. Chiari-type type I malformation and developmental syringomyelia. T2-weighted MRI of the low-lying cerebellar tonsils below the foramen magnum and behind the upper cervical cord and the syrinx cavity in the upper cord. Figure 37-5. Adenoma sebaceum of tuberous sclerosis. Figure 37-6. Shagreen patch on the skin of the lower back in a young patient with tuberous sclerosis.


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Neurology_Adams. Figure 37-5. Adenoma sebaceum of tuberous sclerosis. Figure 37-6. Shagreen patch on the skin of the lower back in a young patient with tuberous sclerosis. Figure 37-7. Tuberous sclerosis. A. MRI showing multiple hamartomas. B. Subependymal nodules are demonstrated on CT, where their calcific nature has led them to be termed “brain stones.” Figure 37-8. Typical large café-au-lait spot. The presence of 6 or more hyperpigmented lesions, each larger than 1.5 cm after puberty (>5 mm prepubertal), is diagnostic of neurofibromatosis type 1. Figure 37-9. Molluscum fibrosum nonneural skin tumors of von Recklinghausen disease. Figure 37-10. Hamartomas of the iris (Lisch nodules), typical of neurofibromatosis type 1. (Reproduced by permission from Damato BE, Spalton DJ: The uveal tract. In: Spalton DJ, Hitchings RA, Hunter PA (eds): Atlas of Clinical Ophthalmology, 3rd ed. Oxford, Mosby Elsevier Ltd, 2005.)


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Neurology_Adams. Figure 37-11. Neurofibromatosis. Upper left: T2-FLAIR MRI in the axial plane demonstrating multiple foci of hyperintensity, presumably hamartomas, in a patient with neurofibromatosis type 1. Upper right: Axial T1 MRI with gadolinium demonstrating bilateral (right larger than left) schwannomas in a patient with neurofibromatosis type 2. Lower panel: Axial T1 MRI with gadolinium of the thoracic spine showing a large left paraspinal schwannoma emanating from the neural foramen in a patient with schwannomatosis. Note the expansion and remodeling of the vertebral bones surrounding the lesion. (Images courtesy of Dr. Scott R. Plotkin.) Figure 37-12. Sturge-Weber. Left: Axial non-enhanced CT showing calcification of the right parietal vascular malformation and underlying cortical atrophy. Right: Axial T2-FLAIR MRI showing the pronounced atrophy in the same patient.


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Neurology_Adams. Figure 37-13. Ocular appearance of ataxia-telangiectasia. (Reproduced by permission from Lyon G, Kolodny EH, Pastores GM: Neurology of Hereditary Metabolic Diseases of Children, 3rd ed. New York, McGraw-Hill, 2006.) Figure 37-14. Ultrasonograph demonstration of subependymal matrix hemorrhage in a premature infant (arrow). Figure 37-15. MRI of an adult with congenital hemiplegia. There is severe cystic encephalomalacia mainly in the territory of the left middle cerebral artery, though the entire left hemisphere is abnormally small, as is the overlying calvarium. Figure 37-16. Axial CT from a developmentally delayed adult with healed congenital toxoplasmosis. There is hydrocephalus and multiple calcifications in the white matter. Contrast this image with Fig. 37-7, which shows the periventricular calcifications of tuberous sclerosis. Chapter 37 Developmental Diseases of the Nervous System Degenerative Diseases of the Nervous System


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Neurology_Adams. Fig. 37-7, which shows the periventricular calcifications of tuberous sclerosis. Chapter 37 Developmental Diseases of the Nervous System Degenerative Diseases of the Nervous System The adjective degenerative has no great appeal to the modern neurologist. It implies an inexplicable decline from a previous level of normalcy to a lower level of function—an ambiguous conceptualization of disease that satisfies neither a clinician nor a scientist. Moreover, it gives no hint as to the fundamental causation of a process and in all likelihood combines a number of mechanisms under one nondescript term. It would be tempting to attribute all progressive diseases of the nervous system that are of unknown cause to degeneration. The problem is that many degenerative diseases are caused in a proportion of cases by germ line genetic changes. All are currently called degenerative, but this nosology is a transitional method of holding a place while awaiting more refined understanding.


Neurology_Adams

Neurology_Adams. The principle behind what is currently called degenerative disease of the nervous system is a pattern of progressive neuronal loss in functionally related cells such as those of the basal ganglia, cerebellum, or cerebral cortex, and so on. These diseases can be identified clinically by a more or less smoothly progressive loss of neurologic function referable to the affected system, for example, parkinsonian features, ataxia, or dementia. Many of these diseases are characterized by the accumulation of abnormal deposition of proteins. What is lacking at the moment is a precise subcellular mechanism for cellular loss; knowledge that a protein aggregates within or between cells is not equivalent to understanding the cause of an illness. Degeneration is nonetheless used as a clinical and pathologic term that refers to a process of neuronal, myelin, or tissue breakdown, the degradative products of which evoke a reaction of phagocytosis and cellular astrogliosis but usually, with minimal or


Neurology_Adams

Neurology_Adams. term that refers to a process of neuronal, myelin, or tissue breakdown, the degradative products of which evoke a reaction of phagocytosis and cellular astrogliosis but usually, with minimal or no inflammation.


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Neurology_Adams. Gowers in 1902 suggested the term abiotrophy to encompass the degenerative diseases, by which he meant a lack of “vital endurance” of the affected neurons, resulting in their premature death. This concept embodies an unproven hypothesis—that aging and degenerative changes of cells are based on the same process. Understandably, contemporary neuropathologists are reluctant to attribute to simple aging the diverse processes of cellular diseases that are constantly being revealed by ultrastructural and molecular genetic techniques. It is increasingly evident that many of the diseases included in this category depend on genetic factors. Some appear in more than 1 member of the same family. Even more diseases, not differing in any fundamental way from the degenerative ones, occur sporadically, that is as isolated instances but still, genetic factors such as single nucleotide polymorphisms and copy number variations are often involved in pathogenesis, even if only as predispositions to the


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Neurology_Adams. that is as isolated instances but still, genetic factors such as single nucleotide polymorphisms and copy number variations are often involved in pathogenesis, even if only as predispositions to the disease.


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Neurology_Adams. A central concept that has been introduced in degenerative neurological disease is that certain types of protein deposition in the brain are toxic to adjacent neurons. Amyloid, tau, and synuclein are most often cited as implicated in this way. Moreover, “spread” of toxic species of normal proteins contiguously by physiochemical interactions (summarized by Hardy and Revesz), more typical of the induction of prion diseases (Chap. 32), are implicated and it has been suggested that there may be transynaptic spread of misfolded proteins. The toxic hypothesis is central in particular to Alzheimer disease, in which attempts to remove or reduce the production of the implicated amyloid proteins are driving clinical trials of new agents.


Neurology_Adams

Neurology_Adams. The basis of aging changes is also explainable at the neuronal level, but the nature of these alterations is not understood. A fundamental problem, as mentioned, is the distinction of these aging deteriorations from degenerative disease. When a degenerative neurological disease appears in adult life, one must assume that the clinical presentation is modified to some extent by life-cycle phenomena—the patient’s function being a sum of both processes. However, their separation is of fundamental importance in diagnosis and therapeutics. One has to reconcile the fact that most degenerative diseases manifest themselves in later life, leading to the tentative conclusion that some aspect of the aging process is entwined with the cellular degenerations of disease. This creates a problem for the clinician, who may be inclined to attribute changes in a person’s function to aging alone rather than searching for a disease that may allow for treatment or for specific prognostication and


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Neurology_Adams. for the clinician, who may be inclined to attribute changes in a person’s function to aging alone rather than searching for a disease that may allow for treatment or for specific prognostication and counseling. Moreover, a long-standing uncertainty pertains to certain degenerative conditions such as Alzheimer disease, which becomes so prevalent in later age as to offer the possibility that the disease is an invariable aspect of aging rather than an acquired perturbation in cellular function. For most degenerative diseases of the nervous system, however, this inevitability of occurrence with aging is clearly not the case. For example, the incidence of Alzheimer pathologic change is attenuated after the age of 75 according to Savva and colleagues. This is in part because of the competing risk of death from other causes but there remains a likelihood that the disease arises less frequently in the oldest old. This polemic regarding aging and degenerative disease is irresolvable and


Neurology_Adams

Neurology_Adams. risk of death from other causes but there remains a likelihood that the disease arises less frequently in the oldest old. This polemic regarding aging and degenerative disease is irresolvable and exposes difficulties with meaning of the term “disease.” If the human being lived another 50 years beyond the current expectation, would all nervous structures show the changes of degenerative disease? The answer is probably “no,” as there are distinctive cellular and subcellular features of degenerative diseases that are different from the uncomplicated, programmed loss of cells that is due to aging.


Neurology_Adams

Neurology_Adams. Much new and essential information has been gained regarding the biologic derangements that lead to neuronal death and dysfunction as a result of investigating the inherited forms of degenerative diseases. The application of the techniques of molecular genetics to these diseases has given stunning results. Even when the hereditary form of a degenerative condition is rare in comparison to the sporadic type, general principles have been exposed that are common to the mechanisms of both forms of the disorder. This approach holds promise for effective treatment of what heretofore have been considered progressive and incurable diseases.


Neurology_Adams

Neurology_Adams. It has been proposed that all degenerative diseases be classified according to their genetic and molecular abnormalities. However, when one notes the diversity of pathologic change that may accompany a single, seemingly unitary gene abnormality or, reciprocally, the diversity of genetic defects that may underlie a single phenotype, this type of classification does not prove immediately helpful to the clinician. In other words, the practice of creating new disease categories to encompass all the molecular and pathologic changes associated with a particular type of neuronal degeneration offers no great advantage in practice. For example, certain diseases are unified by the deposition of proteins and have been termed “tauopathies,” “synucleinopathies,” “amyloidopathies,” and so forth. We endorse a more useful clinical approach that is based on an awareness of constellations of clinical features that relate to degeneration of specific neural systems. Until such time as the causation of


Neurology_Adams

Neurology_Adams. a more useful clinical approach that is based on an awareness of constellations of clinical features that relate to degeneration of specific neural systems. Until such time as the causation of the degenerative neurologic diseases is known, there must be a name and a place for a group of diseases that are united only by the common attribute of gradually progressive disintegration of a part or parts of the nervous system.


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Neurology_Adams. General Clinical Characteristics of Degenerative Diseases


Neurology_Adams

Neurology_Adams. As mentioned, the diseases included in the degenerative category have 2 outstanding characteristics: (1) They affect specific parts or functional systems of the nervous system, and (2) They begin insidiously, after a long period of normal nervous system function, and pursue a gradually progressive course. Frequently, it is impossible to assign a date of onset. The patient or the patient’s family may give a history of the abrupt appearance of disability, particularly if some injury, infection, surgical procedure, stroke, or other memorable event coincided with the initial symptoms. A skillfully taken history will reveal that there had been subtle symptoms for some time but had attracted little attention. Whether a dramatic life event can actually evoke or aggravate a degenerative disease is a question that cannot be answered with certainty; evidence to this effect is largely anecdotal. Instead, these degenerative disease processes, by their very nature, appear to develop de novo,


Neurology_Adams

Neurology_Adams. is a question that cannot be answered with certainty; evidence to this effect is largely anecdotal. Instead, these degenerative disease processes, by their very nature, appear to develop de novo, without relation to known antecedent events, and their symptomatic expressions are late events in the pathologic process, occurring only when the degree of neuronal loss exceeds the ability of a system to function at a clinically acceptable level. Irreversibility and steady progression of clinical manifestations when measured over periods of months or years is another feature common to the neurodegenerative conditions. However, several of these diseases sometimes display periods of relative stability.


Neurology_Adams

Neurology_Adams. Although most degenerative disease do not manifest expression in other members of the family, the familial occurrence of degenerative disease is of great importance both clinically and for scientific reasons as mentioned earlier, but such information is often difficult to obtain. The family may be small or widely scattered, so that the patient is unaware of the health of other members. The patient or the patient’s relatives may be reluctant to acknowledge that a neurologic disease has affected another family member. Furthermore, it may not be realized that an illness is hereditary if other members of the family have a much more or much less severe, or a different form of the disorder than the patient. Or paternity may be in question. Sometimes, only the careful examination of other family members will disclose the presence of a hereditary disease. Also, it should be remembered that familial occurrence of a disease does not necessarily mean that it is inherited, but may indicate


Neurology_Adams

Neurology_Adams. family members will disclose the presence of a hereditary disease. Also, it should be remembered that familial occurrence of a disease does not necessarily mean that it is inherited, but may indicate instead that more than 1 member of a family had been exposed to the same infectious or toxic agent.


Neurology_Adams

Neurology_Adams. Many symptoms of degenerative disease, while not currently curable, can be alleviated by skillful management. The physician’s interest and advice are invaluable to the patient and his family by way of providing support, perspective, and information. This accords with the highest calling of the physician’s abilities to relieve suffering.


Neurology_Adams

Neurology_Adams. Most of the degenerative diseases, as emphasized in the earlier general comments, are characterized by the selective involvement of anatomically and physiologically related systems of neurons. This feature is exemplified by amyotrophic lateral sclerosis (ALS), in which the pathologic process is virtually limited to motor neurons of the cerebral cortex, brainstem, and spinal cord, and by the progressive ataxias, in which only the Purkinje cells of the cerebellum are affected. Many other examples could be cited (e.g., Friedreich ataxia, Parkinson disease) in which discrete neuronal systems disintegrate, leaving others unscathed. Thus, these degenerative diseases had in the past been called system atrophies. The selective vulnerability of certain systems of neurons is not an exclusive property of the degenerative diseases; several different processes of known cause have similarly circumscribed effects on the nervous system. Contrariwise, in many degenerative diseases, the pathologic


Neurology_Adams

Neurology_Adams. of the degenerative diseases; several different processes of known cause have similarly circumscribed effects on the nervous system. Contrariwise, in many degenerative diseases, the pathologic changes are somewhat less selective and eventually quite diffuse. Even then, there is an early tendency to involve special categories of neurons.


Neurology_Adams

Neurology_Adams. As one would expect of any pathologic process that is based on the slow wasting and loss of neurons, not only the cell bodies but also their dendrites, axons, and myelin sheaths disappear, unaccompanied by an intense tissue reaction or cellular response. The cerebrospinal fluid (CSF) shows little, if any, change, or at most a slight increase in protein content. Moreover, because these diseases invariably result in tissue loss, imaging examination shows either no change or only a volumetric reduction (atrophy) with a corresponding passive enlargement of the CSF compartments. These findings distinguish the neuronal atrophies from other large classes of progressive disease of the nervous system, namely, tumors, infections, and processes of inflammatory type.


Neurology_Adams

Neurology_Adams. At the cellular level, several processes characterize the death of individual cells. Among these mechanism is apoptosis, a term borrowed from embryology to specify the mechanisms that lead to neuronal degeneration. The original meaning of the term refers to a naturally occurring cell death during development that is driven by the expression of genes over a short period of time (i.e., “programmed” cell death), leaving no trace of a pathologic reaction. The process of neuronal degeneration is quite different in that it refers to a series of changes in mature neurons that occur over a protracted period of time, leading to cell death and often leaving a discrete glial scar, but not to regional tissue necrosis. In some models of degenerative disease, cell loss involves activation of specialized genes, although the time course and cellular morphology are not apoptotic in the original sense of the term. It is increasingly apparent that mechanisms other than programmed cell death will prove


Neurology_Adams

Neurology_Adams. genes, although the time course and cellular morphology are not apoptotic in the original sense of the term. It is increasingly apparent that mechanisms other than programmed cell death will prove central to understanding the degenerative diseases, and that the clinical features of these conditions are manifest even before cellular destruction occurs. For example, interference with synaptic signaling and dysfunction of supporting glia cells are equally important to morphologic neuronal death.


Neurology_Adams

Neurology_Adams. It will become clear in the following discussion that the current theme in the study of degenerative diseases is that of aggregation within specific neurons of normal cellular proteins such as amyloid, tau, synuclein, ubiquitin, and huntingtin. In some cases, the protein is overproduced as a result of the simple fact of a triplication or overactivity of its corresponding gene. In other instances, enzymatic cleavage of a normal precursor protein yields a product with physical properties that lead to its aggregation (as happens with amyloid in Alzheimer disease) or, there may be failure of the normal mechanisms of protein removal, resulting in its excess accumulation. As mentioned above, this has resulted in the denomination of groups of diseases by the type of protein aggregate: tauopathy, synucleinopathy, etc. Even this is an uncertain or intermediate classification as it is not known in most cases if the protein is the cause or the result of cellular damage, and in any case, the


Neurology_Adams

Neurology_Adams. synucleinopathy, etc. Even this is an uncertain or intermediate classification as it is not known in most cases if the protein is the cause or the result of cellular damage, and in any case, the fundamental mechanisms of cellular destruction are still being determined.


Neurology_Adams

Neurology_Adams. Another characteristic that has guided understanding of degenerative disease is the possible contiguous “spread” of protein aggregation from one to another region by synaptic connections. In some cases, this results in adjacent regions being affected sequentially and in others, circuits that are functionally integrated but not necessarily contiguous are affected. This geographic mechanism, proposed by Braak and colleagues, conforms to certain pathologic observations such as the sequential appearance of synuclein in the olfactory system, thence in the Meissner-Auerbach plexus of the gut, followed by the vagus, to involvement of the vagal nuclei in the medulla, ascending trans- synaptically to the pons and midbrain nuclei. Whether this accounts for the selectivity of disease in areas such as the substantia nigra that is most affected in Parkinson disease, is not entirely known. In any case, the biologic and the physicochemical properties of these aggregated proteins have assumed great


Neurology_Adams

Neurology_Adams. as the substantia nigra that is most affected in Parkinson disease, is not entirely known. In any case, the biologic and the physicochemical properties of these aggregated proteins have assumed great importance and the mechanisms by which they interfere with cellular function and potentially cause cell death are major areas of research in the degenerative diseases.


Neurology_Adams

Neurology_Adams. Because grouping of the degenerative diseases in terms of etiology is not entirely possible, except that a hereditary or genetic factor can be recognized in some. For this reason) we resort for practical purposes to a division based on the presenting clinical syndromes and their pathologic anatomy. Although this is the most elementary mode of classification of naturally occurring phenomena, it is a necessary prelude to diagnosis and scientific study and is more natural for the clinician than is a purely genetic or molecular classification. It is also an improvement on a haphazard listing of diseases by the names of the neurologists or neuropathologists who first described them. For reasons given in the introduction to this chapter, this approach remains effective in analyzing the problem presented by an individual patient. The main clinical categories are as follows: I. Syndrome of progressive dementia, other neurologic signs absent or inconspicuous A. Alzheimer disease


Neurology_Adams

Neurology_Adams. I. Syndrome of progressive dementia, other neurologic signs absent or inconspicuous A. Alzheimer disease B. Some cases of Lewy body disease C. Frontotemporal dementias—Pick disease, including behavioral variant, primary progressive aphasias (several types) D. Posterior cortical atrophy (visuospatial dementia) II. Syndrome of progressive dementia in combination with other neurologic abnormalities A. Huntington disease (chorea) B. Lewy-body disease (parkinsonian features) C. Corticobasal ganglionic degeneration (rigidity, dystonia) D. Cortical-striatal-spinal degeneration (spasticity) E. Frontotemporal dementia-amyotrophic lateral sclerosis complex F. Familial dementia with spastic paraparesis, amyotrophy, or myoclonus G. Polyglucosan body disease (neuropathy) III. Syndrome of disordered posture and movement A. Parkinson disease B. Multiple system atrophy, MSA-P (striatonigral degeneration, autonomic failure) C. Progressive supranuclear palsy


Neurology_Adams

Neurology_Adams. III. Syndrome of disordered posture and movement A. Parkinson disease B. Multiple system atrophy, MSA-P (striatonigral degeneration, autonomic failure) C. Progressive supranuclear palsy D. Dystonia musculorum deformans E. Huntington disease (chorea) F. Acanthocytosis with chorea G. Corticobasal ganglionic degeneration H. Lewy-body disease I. Restricted dystonias, including spasmodic torticollis and Meige syndrome IV. Syndrome of progressive ataxia A. Spinocerebellar ataxias 1. Friedreich ataxia 2. Non-Friedreich ataxia (retained reflexes, tremor, hypogonadism, myoclonus, and other disorders) B. Cerebellar cortical ataxias 1. Holmes type of familial pure cerebellar-olivary atrophy 2. Late-onset cerebellar atrophy


Neurology_Adams

Neurology_Adams. B. Cerebellar cortical ataxias 1. Holmes type of familial pure cerebellar-olivary atrophy 2. Late-onset cerebellar atrophy C. Complicated hereditary and sporadic cerebellar ataxias (later-onset ataxia with brainstem and other neurologic disorders) 1. Multiple system atrophies (MSA-C) 2. Dentatorubral degeneration (Ramsay Hunt type) 3. Dentatorubropallidoluysian atrophy 4. Machado-Joseph disease; SCA-3 (ataxia, basal ganglia features) 5. Other complicated late-onset, autosomal dominant ataxias with pigmentary retinopathy, ophthalmoplegia, slow eye movements, polyneuropathy, optic atrophy, deafness, extrapyramidal features, and dementia V. Syndrome of slowly developing muscular weakness and atrophy A. Motor disorders with amyotrophy 1. Amyotrophic lateral sclerosis 2. Progressive spinal muscular atrophy 3. Progressive bulbar palsy 4. Kennedy syndrome and other hereditary forms of progressive muscular atrophy and spastic paraplegia 5. Motor neuron disease with frontotemporal dementia


Neurology_Adams

Neurology_Adams. B. Spastic paraplegia without amyotrophy 1. Primary lateral sclerosis 2. Hereditary spastic paraplegia (Strümpell VI. Sensory and sensorimotor disorders (neuropathies; see Chap. 43) A. Hereditary sensorimotor neuropathies— B. Pure or predominantly sensory or motor neuropathic C. Riley-Day autonomic degeneration VII. Syndrome of progressive blindness with or without other neurologic disorders (see Chap. 12) A. Pigmentary degeneration of retina (retinitis pigmentosa) B. Stargardt disease C. Age-related macular degeneration (ARMD) VIII. Syndromes characterized by degenerative neurosensory deafness (see Chap. 14) A. Pure neurosensory deafness B. Hereditary hearing loss with retinal diseases C. Hereditary hearing loss with system atrophies of the nervous system


Neurology_Adams

Neurology_Adams. This is the most common and important degenerative disease of the brain, having an immense societal impact. Some aspects of the intellectual deterioration that characterize this disease were described in Chap. 20, under “The Neurology of Dementia,” and the still ambiguous relationship of this disease to the aging process is mentioned above and in Chap. 28. There it was pointed out that some degree of shrinkage in size and weight of the brain, that is “atrophy,” is an inevitable accompaniment of advancing age, but that these changes alone are of relatively slight clinical significance and uncertain structural basis (e.g., whether the loss of brain weight aging is the result of a simple depletion of neurons). By contrast, severe degrees of diffuse cerebral atrophy that evolve over a few years are associated with dementia, and the underlying pathologic changes in these cases most often prove to be those of Alzheimer disease. As also commented on in Chap. 28, the rate of cerebral atrophy,


Neurology_Adams

Neurology_Adams. are associated with dementia, and the underlying pathologic changes in these cases most often prove to be those of Alzheimer disease. As also commented on in Chap. 28, the rate of cerebral atrophy, specifically of the hippocampus and medial parts of the temporal lobes, is accelerated in the early stages of Alzheimer disease, and longitudinal studies by magnetic resonance imaging can identify individuals who will subsequently develop the disease (Rusinick). Nevertheless, there is not a continuous increase in the deposition of plaques and tangles, the pathologic markers of Alzheimer disease, with increasing age.


Neurology_Adams

Neurology_Adams. The now outdated practice of giving Alzheimer disease and senile dementia the status of separate diseases is attributable to the relatively young age (51 years) of the patient originally studied by Alois Alzheimer in 1907. Such a division is no longer tenable as, except for their age of onset, they are clinically and pathologically indistinguishable. It is probably useful to consider as related but separable, the several heredofamilial forms of Alzheimer disease discussed below.


Neurology_Adams

Neurology_Adams. Although Alzheimer disease has been described at every period of adult life, the majority of patients are in their sixties or older; a relatively small number have been in their late fifties or younger. It is one of the most frequent mental illnesses, making up a large proportion of persons in assisted living and skilled nursing facilities. The incidence of clinically diagnosed Alzheimer disease is similar throughout the world, and it increases with age, approximating 3 new cases yearly per 100,000 persons younger than age 60 years and a staggering 125 new cases per 100,000 of those older than age 60 years. The prevalence of the disease per 100,000 population is near 300 in the group aged 60 to 69 years; it is 3,200 in the 70to 79-year-old group and 10,800 in those older than age 80. In the year 2015, there were estimated to be more than 30 million persons with Alzheimer disease in the world. (It should be borne in mind that these are not pathologically proven cases and, while


Neurology_Adams

Neurology_Adams. In the year 2015, there were estimated to be more than 30 million persons with Alzheimer disease in the world. (It should be borne in mind that these are not pathologically proven cases and, while probably correct as an approximation, are likely combined with other diseases.) Prevalence rates, which depend also on overall mortality, are approximately 3 times higher in women, although the incidence of new cases is only slightly disproportionate in women. However, there is a suggestion that incidence rates for dementia in general are declining (see Satizabal et al) and it is likely that most of the cases are due to Alzheimer disease. The survival of patients with Alzheimer disease is reduced to half the expected rate, mainly because of respiratory and cardiovascular causes and inanition, but also for other reasons that are not entirely clear.


Neurology_Adams

Neurology_Adams. Several putative epidemiologic risk factors for Alzheimer disease proposed in the past, such as birth order, mother’s age at birth, and a family history of Down syndrome seem marginal at best and in some instances, may be a result of selection bias. Depression and possibly head injuries seem to confer a somewhat increased risk later in life. Whether low educational attainment is a risk factor for the development of Alzheimer disease or, conversely, whether cognitively demanding occupations or higher intelligence protects against dementia is still under discussion. Provocative data indicating that inherent intellectual endowment (cognitive reserve) is important were presented in Chap. 20 (Katzman; Cobb et al). Finally, associations between diabetes or hyperglycemia and dementia, in general, have emerged from epidemiologic studies, for example, one reported by Crane and coworkers, but the ostensible mechanism by which this confers risk (if it is even valid) has not been established. In


Neurology_Adams

Neurology_Adams. have emerged from epidemiologic studies, for example, one reported by Crane and coworkers, but the ostensible mechanism by which this confers risk (if it is even valid) has not been established. In their report, a higher than average glucose level over the preceding 5 years conferred a slightly increased risk of dementia but not necessarily of Alzheimer disease.


Neurology_Adams

Neurology_Adams. The familial occurrence of Alzheimer disease has been well established. In less than 1 percent of such cases there is a dominant inheritance pattern with a high degree of penetrance and appearance of disease at a younger age (Nee et al; Goudsmit et al; see further). Reports of substantial familial aggregations of dementia without a specific pattern of inheritance also suggest the operation of more than 1 genetic factor. Many studies have documented an increase in the risk of ostensibly sporadic Alzheimer disease among first-degree relatives of patients with this disorder. This risk is disproportionately greater in females, adding to the evidence that women in general are at slightly higher risk for Alzheimer disease (Silverman et al). Li and coworkers (1995) have provided evidence that patients with an earlier age of onset of Alzheimer disease (before age 70 years) are more likely to have relatives with the disease than are patients with later onset. Genetic studies are difficult to


Neurology_Adams

Neurology_Adams. with an earlier age of onset of Alzheimer disease (before age 70 years) are more likely to have relatives with the disease than are patients with later onset. Genetic studies are difficult to carry out because the disease does not appear at the same age in a given proband. Even in identical twins, the disease may develop at the age of 60 years in one of the pair and at 80 years in the other. Death from other causes may prevent its detection. The dominantly inherited type, which is prevalent in certain countries, is being used as a model to understand both the genetic aspects and therapeutic measures for the disease. The other genetic contributions to the occurrence of Alzheimer disease are discussed further on.


Neurology_Adams

Neurology_Adams. Clinical Features (See Also Chap. 20) The onset of mental changes is usually so insidious that neither the family nor the patient can date the time of its beginning and most patients come to attention months or years after the decline began. Occasionally, however, the process becomes manifest by an unusual degree of confusion in relation to a febrile illness, an operation, mild head injury, or the institution of a new medication. Other patients have as their initial complaints dizziness, mental fogginess, nondescript headaches, or other vaguely expressed and changeable somatic symptoms.


Neurology_Adams

Neurology_Adams. The gradual development of forgetfulness is the major symptom. Small day-to-day happenings are not remembered. Seldom-used names become particularly elusive. Little-used words from an earlier period of life also tend to be lost. Appointments are forgotten and possessions misplaced. Questions are repeated again and again, the patient having forgotten what was just discussed. It is said that remote memories are preserved and recent ones lost (one of Ribot’s laws of memory), but this is only relatively true and it is difficult to check the accuracy of distant personal memories. For example, Albert and associates, who tested Alzheimer patients’ recognition of dated political events and pictures of prominent people past and present, found that some degree of memory loss extends to all previous decades of the person’s life (neuropsychologic testing is discussed further on).


Neurology_Adams

Neurology_Adams. Once the memory disorder has become pronounced in the prototypic disorder, other failures in cerebral function become increasingly apparent. The patient’s speech is halting because of failure to access the needed word. The same difficulty interrupts writing. Vocabulary becomes restricted, and expressive language becomes stereotyped and inflexible. Comprehension of spoken words seems at first to be preserved, until it is observed that the patient does not carry out a complicated request; even then it is uncertain whether the request was not understood because of inattention or because it was forgotten. Almost imperceptible at first, these disturbances of language become increasingly apparent as the disease progresses. The range of vocabulary and the accuracy of spelling are reduced. Finally, after many years of illness, there is a failure to speak in full sentences; the finding of words requires a continuous search; and little that is said or written is fully comprehended. There is a


Neurology_Adams

Neurology_Adams. after many years of illness, there is a failure to speak in full sentences; the finding of words requires a continuous search; and little that is said or written is fully comprehended. There is a tendency to repeat a question and later, there may be a rather dramatic repetition of every spoken phrase (echolalia). The deterioration of verbal skills has by then progressed beyond a groping for names and common nouns to an obvious anomic aphasia. Other elements of receptive and executive aphasia are later added, but discrete aphasias of the Broca or Wernicke type are characteristically lacking. In general, there is a paucity of speech and a quantitative reduction in mentation.


Neurology_Adams

Neurology_Adams. Skill in arithmetic suffers a similar deterioration. Faults in balancing the checkbook, mistakes in figuring the price of items and in making the correct change; all these and others progress to a point where the patient can no longer carry out the simplest calculations (acalculia or dyscalculia). In some patients, visuospatial orientation becomes defective. The car cannot be parked; the arms do not find the correct sleeves of the jacket or shirt; the corners of the tablecloth cannot be oriented with the corners of the table; the patient turns in the wrong direction on the way home or becomes lost. The route from one place to another cannot be described, nor can given directions be understood. As this state worsens, the simplest of geometric forms and patterns cannot be copied.


Neurology_Adams

Neurology_Adams. Late in the course of the illness, the patient forgets how to use common objects and tools while retaining the necessary motor power and coordination for these activities. The razor is no longer correctly applied to the face; the latch of the door cannot be unfastened; and eating utensils are used awkwardly. Finally, only the most habitual and virtually automatic actions are preserved. Tests of commanded and demonstrated actions cannot be executed or imitated. Ideational and ideomotor apraxia are the terms applied to the advanced forms of this motor incapacity as described in Chaps. 3 and 21.


Neurology_Adams

Neurology_Adams. As these many amnesic, aphasic, agnostic, and apraxic deficits declare themselves, the patient at first seems unchanged in overall motility, behavior, temperament, and conduct. Social graces, whatever they were, are retained in the initial phase of the illness, but troublesome alterations may gradually appear in this sphere as well. Imprudent business deals may be made. Restlessness and agitation or their opposites—inertia and placidity—become evident. Dressing, shaving, and bathing are neglected. Anxieties and phobias, particularly fear of being left alone, may emerge. A disturbance of the normal day and night sleep patterns is prominent in some patients. A poorly organized paranoid delusional state, sometimes with hallucinations, may become manifest. The patient may suspect his elderly wife of having an illicit relationship or his children of stealing his possessions. A stable marriage may be disrupted by the patient’s infatuation with a younger person or by sexual indiscretions,


Neurology_Adams

Neurology_Adams. wife of having an illicit relationship or his children of stealing his possessions. A stable marriage may be disrupted by the patient’s infatuation with a younger person or by sexual indiscretions, which may astonish the community. The patient’s affect coarsens; he is more egocentric and indifferent to the feelings and reactions of others. A gluttonous appetite sometimes develops, but more often eating is neglected, resulting in gradual weight loss. Later, grasping and sucking reflexes and other signs of frontal lobe disorder are readily elicited (Neary et al), sphincteric continence fails, and the patient sinks into a state of relative akinesia and mutism, as described in Chap. 20.


Neurology_Adams

Neurology_Adams. Difficulty in locomotion, a kind of unsteadiness with shortened steps but with only slight motor weakness and rigidity, frequently supervenes. Elements of parkinsonian akinesia and rigidity and a fine tremor can be perceived in patients with advanced stages of the disease. Ultimately, the patient loses the ability to stand and walk, being forced to lie inert in bed and having to be fed and bathed, the legs curled into a fixed posture of paraplegia in flexion (in essence, a persistent vegetative state).


Neurology_Adams

Neurology_Adams. The symptomatic course of this illness is quite variable but usually extends over a period of 5 or more years, but judging from pathology studies, the pathologic course has a much longer asymptomatic duration. This concept of a preclinical stage is supported by the detailed studies of Linn and colleagues, who found that a lengthy period (7 years or more) of stepwise decline in memory and attention span preceded the clinical diagnosis. In the dominantly inherited forms of disease, careful studies of biomarkers in the spinal fluid and by imaging show that changes occur 15 years or longer before the clinical manifestations are apparent (Bateman et al). Throughout this period, corticospinal and corticosensory functions, visual acuity, ocular movements, and visual fields remain intact. If there is hemiplegia, homonymous hemianopia, and the like, either the diagnosis of Alzheimer disease is incorrect or the disease has been complicated by a stroke, tumor, or subdural hematoma. Exceptions to


Neurology_Adams

Neurology_Adams. is hemiplegia, homonymous hemianopia, and the like, either the diagnosis of Alzheimer disease is incorrect or the disease has been complicated by a stroke, tumor, or subdural hematoma. Exceptions to this statement are rare. The tendon reflexes are little altered and the plantar reflexes almost always remain flexor. There is no sensory or cerebellar ataxia. Convulsions are rare until late in the illness, when up to 5 percent of patients reportedly have infrequent seizures. Occasionally, widespread myoclonic jerks or mild choreoathetotic movements are observed late in the illness. Eventually, with the patient in a bedfast state, an intercurrent infection such as aspiration pneumonia or some other disease mercifully terminates life.


Neurology_Adams

Neurology_Adams. The sequence of neurologic disabilities may not follow this described order and one or another deficit may take precedence, presumably because the disease process, after becoming manifest in the memory cortex of the temporal lobes, affects a particular part of the associative cortex earlier or more severely in one patient than in another. This allows a relatively restricted deficit to become the source of early medical complaint, long before the full syndrome of dementia has declared itself.


Neurology_Adams

Neurology_Adams. There are at least 5 limited deficits that may represent the opening features of Alzheimer disease but each of which alone may be mild enough to qualify as mild cognitive impairment (MCI). According to Petersen and colleagues, who developed this concept, the MCI syndrome is defined by the presence of cognitive difficulties in one or all spheres that are not severe enough to interfere with daily life. The early presentation of Alzheimer disease may manifest mainly as one of the following syndromes with the first, memory dysfunction being the most common and, even as other aspects of the disease advance, it tends to remain the most prominent.


Neurology_Adams

Neurology_Adams. 1. Amnesia The early stages of Alzheimer disease are usually dominated by a disproportionate failure of episodic (autobiographical) memory, with integrity of other cognitive abilities. This may be the sole difficulty for many years. In such patients, immediate memory (essentially a measure of attention), tested by the capacity to repeat a series of numbers or words, is intact; it is the shortand long-term (retentive) memory that fails. Memory may become impaired but as a business executive, for example, the individual may continue to make acceptable decisions if the work uses long-established habit patterns and practices.


Neurology_Adams

Neurology_Adams. 2. Dysnomia The forgetting of words, especially proper names, may first bring the patient to a neurologist. Later the difficulty involves common nouns and progresses to the point where fluency of speech is seriously impaired. Every sentence is broken by a pause and search for the wanted word; if the desired word is not found, a circumlocution is substituted or the sentence is left unfinished. When the patient is given a choice of words, including the one that was missed, there may be a failure of recognition. Repetition of the spoken words of others, at first flawless, later brings out a lesser degree of the same difficulty. The defect in naming is evident with even simple tests, for example, asking the patient to generate a list of farm animals or car brands—a test that may elicit only 3 or 4 responses. A more extensive examination entails asking the patient to name as many items as possible in a subject category in 1 min—for example, vegetables, tools, or clothing. Alzheimer


Neurology_Adams

Neurology_Adams. only 3 or 4 responses. A more extensive examination entails asking the patient to name as many items as possible in a subject category in 1 min—for example, vegetables, tools, or clothing. Alzheimer patients fall well below 8 items in any 1 category or 25 items total if asked to give names in all 3.


Neurology_Adams

Neurology_Adams. 3. Visuospatial disorientation Parieto-occipital functions are sometimes deranged in the course of Alzheimer disease and in a few cases may fail while other functions are relatively preserved (see Mendez et al). When it occurs in a pure form it is termed posterior cortical atrophy, as discussed in a later section (see Renner et al). As remarked above and in Chap. 21, prosopagnosia (impaired facial recognition), losing one’s way in familiar surroundings or inability to interpret a road map, to distinguish right from left, or to park or garage a car, and difficulty in setting the table or dressing are all manifestations of a special failure to orient the schema of one’s body with that of surrounding space. Exceptionally, there is a neglect of stimuli in one visual field. In the late states, some of these patients develop the Balint syndrome or Gerstmann syndrome (Tang-Wai et al; McMonagle et al).


Neurology_Adams

Neurology_Adams. 4. Paranoia and personality changes Occasionally, at some point in the development of Alzheimer dementia, paranoia or bizarre behavior assumes prominence. This may appear before the more obvious memory or language defects announce themselves. The patient becomes convinced that relatives are stealing his possessions or that an elderly and even infirm spouse is guilty of infidelity. He may hide his belongings, even relatively worthless ones, and go about spying on family members. Hostilities arise, and wills may be altered irrationally. Many of these patients are constantly worried, tense, and agitated. Of course, paranoid delusions may be part of a depressive psychosis and of other dementias, but most of the elderly patients in whom paranoia is the presenting problem, seem not to be depressed, and their cognitive functions are for a time relatively well preserved. Social indiscretions, rejection of old friends, embarking on imprudent financial ventures, or an amorous pursuit that is


Neurology_Adams

Neurology_Adams. and their cognitive functions are for a time relatively well preserved. Social indiscretions, rejection of old friends, embarking on imprudent financial ventures, or an amorous pursuit that is out of character are other examples of these types of behavioral change.


Neurology_Adams

Neurology_Adams. 5. Executive dysfunction This may be the most disabling of the main aspects of the disease and when it appears early on, is not specific to Alzheimer dementia as it is a component of several other processes that affect the frontal lobes. These patients display early difficulties in coordinating and planning tasks and following complex conversations or instructions. They may become disinclined to participate in social activities and become withdrawn or quieter than usual. As the problem advances, simpler and formerly automatic actions such as driving become problematic for the patient; the degree of insight varies. Some are able to express that they feel “confused” but more often, it is the family that brings these changes to attention.


Neurology_Adams

Neurology_Adams. If one of the foregoing restricted deficits remains uncomplicated over a long period, one is justified in suspecting a cause other than Alzheimer disease, such as one of the lobar atrophies such as frontotemporal dementia (see further on), Binswanger disease, hydrocephalus, or embolic infarctions of the temporal or parietal lobes. Each of the restricted clinical disorders described above is only relatively pure. Careful testing of mental function—and this is of diagnostic importance—frequently discloses subtle abnormalities in several cognitive spheres. Initially, most patients have a disproportionate disorder of the temporoparietal cortices, reflected by an earlier impairment on the performance parts of the Wechsler Adult Intelligence Scale. Within a year or two, the more generalized aspects of mental deterioration become apparent, and the aphasic–agnosic–apraxic aspects of the syndrome become increasingly prominent. Although it is true that most patients with Alzheimer disease walk


Neurology_Adams

Neurology_Adams. of mental deterioration become apparent, and the aphasic–agnosic–apraxic aspects of the syndrome become increasingly prominent. Although it is true that most patients with Alzheimer disease walk normally until relatively late in their illness, infrequently a short-stepped gait and imbalance draw attention to the disease and worsen slowly for several years before cognitive manifestations become evident. The general decrepitude in appearance that accompanies the middle and late stages of the disease in many patients is commented on in Chap. 20.


Neurology_Adams

Neurology_Adams. For research purposes and to establish certain inclusive and exclusive criteria for the diagnosis of Alzheimer disease, a working group of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Diseases Association (ADRDA) in the past proposed the following criteria: (1) dementia defined by clinical examination, the Mini-Mental Scale, the Blessed Dementia Scale, or similar mental status examination—currently the Alzheimer Disease Assessment Scale (ADAS, which has 2 components, 1 for cognition, ADAS-cog and the other for activities of daily living, ADAS-ADL) is often used; (2) patient older than age 40 years; (3) deficits in 2 or more areas of cognition and progressive worsening of memory and other cognitive functions, such as language, perception, and motor skills (praxis); (4) absence of disturbed consciousness; and (5) exclusion of other brain diseases (McKhann et al, 1984; Tierney et al, 1988). These criteria


Neurology_Adams

Neurology_Adams. such as language, perception, and motor skills (praxis); (4) absence of disturbed consciousness; and (5) exclusion of other brain diseases (McKhann et al, 1984; Tierney et al, 1988). These criteria have essentially been reaffirmed by more recent consensus panels (see McKhann et al, 2011). Using these measures, the correct diagnosis is achieved in more than 85 percent of patients, but this is not surprising given that Alzheimer disease is overwhelmingly the most common cause of adult dementia. Most cases are identifiable without resorting to restrictive lists such as these, especially if the patient is observed serially over a period of months or years. There is strong interest in the addition of biomarkers such as positron emission tomography (PET) ligand for amyloid and tau/amyloid ratio in CSF to the diagnostic criteria for the disease but the diagnosis remains predominantly a clinical one, aided by imaging and other tests.


Neurology_Adams

Neurology_Adams. In the advanced stages of the disease, the brain presents a diffusely atrophied appearance and its weight is usually reduced by 20 percent or more. Cerebral convolutions are narrowed and sulci are widened. The third and lateral ventricles are symmetrically enlarged to varying degrees. Usually, the atrophic process involves the frontal, temporal, and parietal lobes, but cases vary considerably. The extreme atrophy of the hippocampus, the most prominent finding visible on MRI (mainly coronal images), is diagnostic in the proper clinical circumstances.