Neurology_Adams

Neurology_Adams. For overactive children of normal intelligence who have failed to control their impulses, who at all times have boundless energy, require little sleep, exhibit a wriggling restlessness (the “choreiform syndrome” of Prechtl and Stemmer), and manifest incessant exploratory activity that repeatedly gets them into mischief, even to their own dismay, medical therapy is justified. Paradoxically, stimulants have a quieting effect on these children, whereas sedatives may do the opposite.


Neurology_Adams

Neurology_Adams. Methylphenidate is the drug most widely used and its use has been validated in several studies. Children weighing less than 30 kg are given 5 mg each morning on school days for 2 weeks, after which the dose can be raised to 5 mg morning and noon. Children weighing more than 30 kg can be given a single 20-mg sustained-release tablet each morning. If methylphenidate proves ineffective after several weeks or cannot be tolerated, dextroamphetamine 2.5 to 5 mg three times daily or a mixed amphetamine-dextroamphetamine is suitable substitute. Atomoxetine, a norepinephrine inhibitor, is also effective and is not classified as a stimulant but has caused a few cases of liver failure. If these agents control the activity and improve school performance (they can be continued for a number of years), there is then no need to alter the child’s school program. It is not clear if there should be a long-term concern about hypertension, but the blood pressure is not generally measured at frequent


Neurology_Adams

Neurology_Adams. there is then no need to alter the child’s school program. It is not clear if there should be a long-term concern about hypertension, but the blood pressure is not generally measured at frequent intervals. If stimulants are ineffective, tricyclic antidepressants, particularly desipramine, may be tried. Multiple medications should be generally avoided. Classroom behavioral conditioning techniques and psychotherapy may be needed for brief periods but are not as effective as medication. Remedial education is reserved for recalcitrant cases. Biederman and Faraone have summarized approaches to treatment.


Neurology_Adams

Neurology_Adams. Certainly this disease is a lifelong problem for a proportion of children, although it is just as clear that many “outgrow” the hyperactivity and attention deficit. Hill and Schoener estimate that there is a 50 percent decline in prevalence with each 5 years that pass. Other authorities state that the problem persists in 80 percent. In addition to the child with ADHD who grows to adulthood with persistent problems, there recently has emerged an emphasis on a group of adults who present for the first time with features of difficulty focusing or concentrating that they or their physicians attribute to ADHD. The hyperactivity component is generally absent and may not have occurred in childhood, making the validity of the diagnosis uncertain in adults who were not identified as having ADHD in childhood. A study by Kessler and colleagues suggests that 4.4 percent of adults in the United States have the disorder. European investigators use more restrictive criteria for diagnosis and find


Neurology_Adams

Neurology_Adams. in childhood. A study by Kessler and colleagues suggests that 4.4 percent of adults in the United States have the disorder. European investigators use more restrictive criteria for diagnosis and find far lower frequencies in both children and adults, with consequentially far fewer prescriptions being written for stimulant drugs.


Neurology_Adams

Neurology_Adams. An approach to screening in adults has been given by McCann and Roy-Byrne. Most often these adults come to realize they have had a lifelong problem that is similar to the motor restlessness and wandering attention that led to the diagnosis of ADHD in their own children. The efficacy and safety of stimulant drugs in the adult group are not known with certainty, but this class of medications has been tried with some benefit according to many patients. Some data have emerged that the cardiovascular risks are greater in adults than in children; reports of anxiety and palpations, as well as elevations in blood pressure, are common among adults taking the medications.


Neurology_Adams

Neurology_Adams. Many such individuals are of above-average intelligence and have attained high degrees of professional success, perhaps as a result of strategies developed implicitly over the years, such as note taking, organizers, mental reminders to focus, etc. These same adjustments can be quite useful to others who are struggling with the disorder so that medication is not the only alternative to surmount the cognitive problem. In relation to persistent traits of ADHD from childhood, several psychiatrists have pointed out that there may be an increase in drug and alcohol dependence among adolescents with the disorder (Zametkin and Ernst) and a slight overrepresentation of tic disorders such as Gilles de la Tourette syndrome. Our general clinical experience suggests that these additional problems do not arise in the great majority of such children. Recent studies have been reassuring in this regard, but the concern regarding tics has remained.


Neurology_Adams

Neurology_Adams. Voluntary sphincteric control develops according to a predetermined time scale. Usually normal children stop soiling themselves before they can remain dry, and day control precedes night control. Some children are toilet trained by their second birthday, but many do not acquire full sphincteric control until the fourth year. Constant dribbling usually indicates spina bifida, another form of dysraphism, or a tethered cord, but in the boy, one must look also for obstruction of the bladder neck, and in the girl, for an ectopic ureter entering the vagina.


Neurology_Adams

Neurology_Adams. When a child 5 years of age or older wets the bed nearly every night and is dry by day, the child is said to have nocturnal enuresis. This condition afflicts approximately 10 percent of children between 4 and 14 years of age, boys more than girls, and continues in many cases to be a problem even into adolescence and adulthood. Although developmentally delayed children are notably late in acquiring sphincter control (some never do), the majority of enuretic individuals are normal in other respects.


Neurology_Adams

Neurology_Adams. The cause of this condition is disputed. Often there is a family history of the same complaint. Some psychiatrists have insisted that overzealous parents “pressure” the child until he develops a “complex” about his bedwetting; this is highly doubtful. The underlying condition is believed by most neurologists to be a delay in the maturation of higher control of spinal reflex centers during sleep. These and other abnormalities of bladder function in the enuretic child, as well as treatment, are also discussed in Chap. 18 in relation to sleep.


Neurology_Adams

Neurology_Adams. Extremes of egocentricity, lack of understanding of the feelings, needs, and actions of others, and an inability to judge one’s own strengths and weaknesses stand as the central issues in a certain type of personality disorder. Such difficulties usually become manifest by adolescence. The complete detachment of the child with psychosis, the amorality of the constitutional sociopath, the major disturbances in thinking of the schizophrenic, and the mood swings of the bipolar also express themselves in many, if not most, instances by adolescence and sometimes by late childhood. Here one confronts a key problem in psychiatry—the extent to which sociopathy has its roots in genetically determined personality traits or in derangements in the affective and social life of the individual consequent to a harmful environment. The answers to these questions cannot be given with finality but most clinicians believe that genetic factors are more important than environmental ones. The discovery that


Neurology_Adams

Neurology_Adams. to a harmful environment. The answers to these questions cannot be given with finality but most clinicians believe that genetic factors are more important than environmental ones. The discovery that unusually tall males with severe acne vulgaris and aggressive sociopathic behavior may have a karyotype of XYY chromosomes is an extreme but instructive example of a genetic relationship. The patients with Turner syndrome in whom competent social adaptation is linked closely to an X chromosome of paternal origin is another example. Furthermore, there is no critical evidence to show that deliberate alteration of the familial and social environmental measures now so popular have ever prevented sociopathy.


Neurology_Adams

Neurology_Adams. It is during the period of late childhood and adolescence, when the personality is evolving and least stable, that transient symptoms resembling the psychopathologic states of adult life are most frequent and difficult to interpret. Some of these disorders represent the early signs of schizophrenia or bipolar disease. Others are forerunners of sociopathy. But many of these traits have a way of disappearing as adult years are reached so that one can only surmise that they represented either a maturational delay in the attainment of mature social behavior or were expressions of adolescent turmoil, or what has been called “adolescent adjustment reaction.” Many issues that have been touched upon in the preceding discussion are considered more fully in the section on psychiatric disorders (particularly Chap. 50). INTELLECTUAL AND DEVELOPMENTAL DISABILITY (SEE ALSO CHAP. 37)


Neurology_Adams

Neurology_Adams. INTELLECTUAL AND DEVELOPMENTAL DISABILITY (SEE ALSO CHAP. 37) A symptom complex of incomplete development of global cognitive capacities and certain associated behavioral changes combines many of the developmental abnormalities already discussed. What had been called mental retardation and now, intellectual and developmental delay, stands as the single largest neuropsychiatric disorder in every industrialized society. In deference to changed attitudes toward the formerly used term “mental retardation,” we employ alternatives in this text. The overall frequency of the problem cannot be stated precisely but rough estimates are that in children between 9 and 14 years of age, approximately 2 percent or slightly more will be unable to profit from conventional education or to adapt socially and, when grown, to live independently.


Neurology_Adams

Neurology_Adams. Using any one of a number of indices of social and cognitive delay, two somewhat overlapping groups are recognized: (1) the mildly impaired (IQ 45 to 70), and (2) the severely impaired, corresponding to an IQ below 45. The second group, called the pathologically delayed, makes up approximately 10 percent of the impaired population. The more mildly affected first group, which includes a group of the familial developmentally delayed, is much larger.


Neurology_Adams

Neurology_Adams. Within the severely delayed there are gradations. Because of the objectionable implications of the previously used terms idiot, imbecile, and moron, the developmentally delayed can be grouped instead into four categories: (1) those with profound deficiency, incapable of self-care (IQ below 25); (2) those with severe deficiency, incapable of living an independent existence and essentially untrainable (IQ 25 to 39); (3) those with moderate deficiency, trainable to some extent (IQ 40 to 54); and (4) those with mild deficiency, who are impaired but trainable and to some extent educable. The above newer terms, while in common use, satisfy neither neurologists nor psychologists because, in their generality, they do not capture deficits in performance in other spheres. Moreover, they express only one aspect of impaired mental function—the cognitive—and ignore the inadequate development of personality, social adaptation, and behavior. A more comprehensive view is provided by assessing the


Neurology_Adams

Neurology_Adams. only one aspect of impaired mental function—the cognitive—and ignore the inadequate development of personality, social adaptation, and behavior. A more comprehensive view is provided by assessing the individual’s adaptive abilities along the lines of conceptual, social, and practical skills that allow planning for maximizing independence and productivity.


Neurology_Adams

Neurology_Adams. When the brains of severely affected people are examined by conventional methods, gross lesions are found in approximately 90 percent of cases. Just as noteworthy is the fact that among the remaining 10 percent of the severely delayed, the brains are grossly and microscopically normal. Despite the recent discovery of many mutations that may give rise to a delay in cognitive development only a modest proportion of cases of those with milder deficiency can presently be traced to one of the congenital abnormalities of development that are described in Chap. 37 and the vast majority of the less-severely delayed also lack a recognizable tissue pathology and have not exhibited any of the conventional signs of cerebral disease.


Neurology_Adams

Neurology_Adams. In our view, a more acceptable view of the mildly affected group is that they represent the proportion of the population that is on the low end of the Gaussian curve of intelligence, that is, they constitute the group that falls between 2 and 3 standard deviations (SD) below the mean (Fig. 27-4) and are the opposite in this respect to genius. Lewis was one of the first to call attention to this large group of mildly delayed individuals and he referred to them by the ambiguous term subcultural. The term familial retardation was in the past applied to this group, because in some of the families, members of the same and previous generations have reduced cognitive ability.


Neurology_Adams

Neurology_Adams. An important advance in the understanding of developmental delay emerged from careful genetic studies that have identified specific loci at which deletions or duplications result in intellectual disability. Some of these express particular syndromes such as cognitive delay with autism or epilepsy; however, the same genetic changes can be found among individuals who have only autism or schizophrenia. While a unifying explanation for these disparate disorders has yet to be defined, they probably have subcellular and synaptic changes in common as summarized by Mefford, Batshaw, Hoffman in their review that is recommended to the reader. Both the milder and more-severe forms of developmental delay are associated with physical abnormalities and diseases of the brain, as well as nondysmorphic and genetic forms of delayed development are discussed in Chap. 37. Alvarez-Buylla A, Garcia-Verdugo JM: Neurogenesis in adult subventricular zone. J Neurosci 22:629, 2002.


Neurology_Adams

Neurology_Adams. Alvarez-Buylla A, Garcia-Verdugo JM: Neurogenesis in adult subventricular zone. J Neurosci 22:629, 2002. Anderson LD: The predictive value of infancy tests in relation to intelligence at five years. Child Dev 10:203, 1939. André-Thomas JM, Chesni Y, Dargassies Saint-Annes S: The Neurological Examination of the Infant. London, Medical Advisory Committee, National Spastics Society, 1960. Andrews G, Harris M: Clinics in Developmental Medicine: No 17. The Syndrome of Stuttering. London, Heinemann, 1964. Asperger H: Die “Autistischen Psychopathie” im Kindesalter. Arch Psychiatr Nervenkr 117:76, 1944. Ayotte J, Peretz I, Hyde K: Congenital amusia. A group of adults afflicted with a music-specific disorder. Brain 1125:238, 2002. Baker L, Cantwell DP, Mattison RE: Behavior problems in children with pure speech disorders and in children with combined speech and language disorders. J Abnorm Child Psychol 8:245, 1980.


Neurology_Adams

Neurology_Adams. Baker L, Cantwell DP, Mattison RE: Behavior problems in children with pure speech disorders and in children with combined speech and language disorders. J Abnorm Child Psychol 8:245, 1980. Barlow C: Mental Retardation and Related Disorders. Philadelphia, Davis, 1978. Bayley H: Comparisons of mental and motor test scores for age 1–15 months by sex, birth order, race, geographic location and education of parents. Child Dev 36:379, 1965. Bender L: A Visual-Motor Gestalt Test and Its Use. New York, American Orthopsychiatric Association, 1938. Benton AL: Right-left discrimination. Pediatr Clin North Am 15:747, 1968. Benton AL: Revised Visual Retention Test. New York, Psychological Corporation, 1974. Biederman J, Faraone SV: Attention-deficit hyperactivity disorder. Lancet 366:237, 2005. Biederman J, Munir K, Knee D, et al: A family study of patients with attention deficit disorder and normal controls. J Psychiatr Res 20:263, 1986.


Neurology_Adams

Neurology_Adams. Biederman J, Munir K, Knee D, et al: A family study of patients with attention deficit disorder and normal controls. J Psychiatr Res 20:263, 1986. Birch HG, Belmont L: Auditory-visual integration in normal and retarded readers. Am J Orthopsychiatry 34:852, 1964. Bond AM, Ming GL, Song H: Adult mammalian neural stem cells and neurogenesis: Five decades later. Cell Stem Cell. 17:385, 2015. Byne W: The biological evidence challenged: A scientific American article. In: The Scientific American Book of the Brain. New York, Lyons Press, 1999, pp 181–194. Canevini MP, Chifari R, Piazzini A: Improvement of a patient with stuttering on levetiracetam. Neurology 59:1288, 2002. Capute AJ, Accardo PJ: Developmental Disabilities in Infancy and Childhood. Baltimore, MD, Brookes, 1996. Casanova MF, Buxhoeveden DP, Cohen M, et al: Minicolumnar pathology in dyslexia. Ann Neurol 52:108, 2002. Chugani HT: Functional brain imaging in pediatrics. Pediatr Clin North Am 39:777, 1992.


Neurology_Adams

Neurology_Adams. Casanova MF, Buxhoeveden DP, Cohen M, et al: Minicolumnar pathology in dyslexia. Ann Neurol 52:108, 2002. Chugani HT: Functional brain imaging in pediatrics. Pediatr Clin North Am 39:777, 1992. Conel J: The Postnatal Development of the Human Cerebral Cortex. Vols 1–8. Cambridge, MA, Harvard University Press, pp 1939–1967. Cowan WM: The development of the brain. Sci Am 241:112, 1979. Craig-McQuaide A, Akram H, Zrinzo L, Tripoliti E: A review of brain circuitries involved in stuttering. Front Hum Neurosci 8:884, 2014. Critchley M, Critchley EA: Dyslexia Defined. Springfield, IL, Charles C Thomas, 1978. Damon W: The moral development of children. Sci Am 281:72, 1999. De Ajuriaguerra J: Manuel de psychiatrie de l’enfant, 2nd ed. Paris, Masson, 1974. Denckla MB, Rudel RG, Chapman C, et al: Motor proficiency in dyslexic children with and without attentional disorders. Arch Neurol 42:228, 1985. De Renzi E, Luchelli F: Developmental dysmnesia in a poor reader. Brain 113:1337, 1990.


Neurology_Adams

Neurology_Adams. De Renzi E, Luchelli F: Developmental dysmnesia in a poor reader. Brain 113:1337, 1990. Fantz RL: The origin of form perception. Sci Am 204:66, 1961. Feess-Higgins A, Larroche J-C: Development of the Human Fetal Brain. Paris, Masson, 1987. Fleet WS, Heilman KM: Acquired stuttering from a right hemisphere lesion in a right hander. Neurology 35:1343, 1985. Fox P, Ingham R, Ingham JC, et al: Brain correlates of stuttering and syllable production. A PET performance-correlation analysis. Brain 123:1985, 2000. Galaburda AM, Sherman CF, Rosen GD, et al: Developmental dyslexia: Four consecutive patients with cortical anomalies. Ann Neurol 18:222, 1985. Gesell A (ed): The First Five Years of Life: A Guide to the Study of the Pre-School Child. New York, Harper & Row, 1940. Gibson EJ, Olum V: Experimental methods of studying perception in children. In: Mussen P (ed): Handbook of Research Methods in Child Development. New York, Wiley, 1960, pp 311–373.


Neurology_Adams

Neurology_Adams. Gibson EJ, Olum V: Experimental methods of studying perception in children. In: Mussen P (ed): Handbook of Research Methods in Child Development. New York, Wiley, 1960, pp 311–373. Gubbay SS, Ellis E, Walter JN, Court SDM: Clumsy children: A study of apraxic and agnosic defects in 21 children. Brain 88:295, 1965. Hécaen N, De Ajuriaguerra J: Left-Handedness. New York, Grune & Stratton, 1964. Hill JC, Schoener EP: Age-dependent decline of attention deficit hyperactivity disorder. Am J Psychiatry 153:1143, 1996. Hinshelwood J: A case of dyslexia—a peculiar form of word blindness. Lancet 2:1454, 1896. Humphreys P, Kaufmann WE, Galaburda AM: Developmental dyslexia in women: Neuropathological findings in three patients. Ann Neurol 28:727, 1990. Hynd GW, Semrud-Clikeman M, Lorys AR, et al: Brain morphology in developmental dyslexia and attention deficit disorder/hyper-activity. Arch Neurol 47:919, 1990.


Neurology_Adams

Neurology_Adams. Hynd GW, Semrud-Clikeman M, Lorys AR, et al: Brain morphology in developmental dyslexia and attention deficit disorder/hyper-activity. Arch Neurol 47:919, 1990. Illingworth RS: The Development of the Infant and Young Child, Normal and Abnormal, 3rd ed. Edinburgh, Churchill Livingstone, 1966. Ingram TTS: Developmental disorders of speech. In: Vinken PJ, Bruyn W (eds): Handbook of Clinical Neurology. Vol 4: Disorders of Speech, Perception and Symbolic Behavior. Amsterdam, North-Holland, 1969, pp 407–442. Irwin OC: Can infants have IQ’s? Psychol Rev 49:69, 1942. Kagan J, Moss HA: Birth to Maturity: A Study of Psychological Development. New York, Wiley, 1962. Kanner I: Early infantile autism. J Pediatr 25:211, 1944. Kempermann G: Adult neurogenesis: An evolutionary perspective. Cold Spring Harb Perspect Biol 8:a018986, 2016. Kennedy CR, McCann DC, Campbell MJ, et al: Language ability after early detection of permanent childhood hearing impairment. N Engl J Med 354:2131, 2006.


Neurology_Adams

Neurology_Adams. Kennedy CR, McCann DC, Campbell MJ, et al: Language ability after early detection of permanent childhood hearing impairment. N Engl J Med 354:2131, 2006. Kessler RC, Adler L, Barkley R, et al: The prevalence and correlates of adult ADHD in the Unites States: Results from the National Comorbidity Survey Replication. Am J Psychiatry 163:716, 2006. Kinsbourne M: Developmental Gerstmann’s syndrome: A disorder of sequencing. Pediatr Clin North Am 15:771, 1968. Kinsbourne M: Disorders of mental development. In: Menkes JH (ed): Textbook of Child Neurology, 5th ed. Baltimore, MD, Williams & Wilkins, 1995, pp 924–964. Kinsey A, Pomeroy W, Martin C, Gebhard P: Sexual Behavior in the Human Female. Philadelphia, Saunders, 1948. Kirby A, Sugden DA: Children with developmental coordination disorders. J R Soc Med 100:182, 2007. Konopka G, Roberts TF: Insights into the neural and genetic basis of vocal communication. Cell 164:1259, 2016.


Neurology_Adams

Neurology_Adams. Konopka G, Roberts TF: Insights into the neural and genetic basis of vocal communication. Cell 164:1259, 2016. Kuhn HG, Eisch AJ, Spalding K, Peterson DA. Detection and phenotypic characterization of adult neurogenesis. Cold Spring Harb Perspect Biol. 8;a025981, 2016. Landau WM, Kleffner FR: Syndrome of acquired aphasia with convulsive disorder in children. Neurology 7:523, 1957. Lenneberg EH: Biological Foundations of Language. New York, Wiley, 1967. Leonard CM, Voeller KKS, Lombardino LJ, et al: Anomalous cerebral structure in dyslexia revealed with magnetic resonance imaging. Arch Neurol 50:461, 1993. LeVay S: A difference in hypothalamic structure between heterosexual and homosexual men. Science 253:1034, 1991. LeVay S, Hamer DH: Evidence for a biological influence in male homosexuality. Sci Am 270:44, 1994. Lewis EO: Types of mental differences and their social significance. J Ment Sci 79:298, 1933.


Neurology_Adams

Neurology_Adams. LeVay S, Hamer DH: Evidence for a biological influence in male homosexuality. Sci Am 270:44, 1994. Lewis EO: Types of mental differences and their social significance. J Ment Sci 79:298, 1933. Livingstone MS, Rosen GD, Drislane FW, Galaburda AM: Physiological and anatomical evidence for a magnocellular defect in developmental dyslexia. Proc Natl Acad Sci U S A 88: 7943, 1991. McCann BS, Roy-Byrne P: Screening and diagnostic utility of self-report attention deficit hyperactivity disorder scales in adults. Compr Psychiatry 45:175, 2004. Mefford HC, Batshaw ML, Hoffman EP: Genomics, intellectual disability, and autism. N Engl J Med 366:733, 2012. Minifie FD, Lloyd LL: Communicative and Cognitive Abilities—Early Behavioral Assessment. Baltimore, MD, University Park Press, 1978. Moulton C: Perfect pitch reconsidered. Clin Med 14;517, 2014. Orton ST: Reading, Writing and Speech Problems in Children. New York, Norton, 1937.


Neurology_Adams

Neurology_Adams. Moulton C: Perfect pitch reconsidered. Clin Med 14;517, 2014. Orton ST: Reading, Writing and Speech Problems in Children. New York, Norton, 1937. Ozeretzkii NI: Technique of investigating motor function. In: Gurevich M, Ozeretzkii NI (eds): Psychomotor Function. Moscow, 1930. Quoted by Luria AR: Higher Cortical Functions in Man. New York, Basic Books, 1966. Packman A, Onslow M: Searching for the cause of stuttering. Lancet 360:655, 2002. Paulesu E, Demonent J-F, Fazia F, et al: Dyslexia; cultural diversity and biological unity. Science 291:2165, 2001. Piaget J: The Psychology of Intelligence. London, Routledge & Kegan Paul, 1950. Prechtl HFR, Beintema D: The Neurological Examination of the Full Term Newborn Infant. Little Club Clinics in Developmental Medicine, no 12. London, Heinemann, 1964. Prechtl HFR, Stemmer CJ: The choreiform syndrome in children. Dev Med Child Neurol 4:119, 1962.


Neurology_Adams

Neurology_Adams. Prechtl HFR, Stemmer CJ: The choreiform syndrome in children. Dev Med Child Neurol 4:119, 1962. Rabinowicz T: The differential maturation of the cerebral cortex. In: Falkner F, Tanner JM (eds): Human Growth. New York, Plenum Press, 1986. Rakic P: Neurogenesis in adult primate neocortex: An evaluation of the evidence. Nat Rev Neurosci 3:55, 2002. Rapin I, Allen DA: Developmental language disorders: Nosologic considerations. In: Kirk U (ed): Neuropsychology of Language, Reading and Spelling. New York, Academic Press, 1983, pp 155–184. Rosenberger PB: Morphological cerebral asymmetries and dyslexia. In: Pavlidis GT (ed): Perspectives on Dyslexia. Vol 1. New York, Wiley, 1990, pp 93–107. Rosenberger PB: Learning disorders. In: Berg B (ed): Principles of Child Neurology. New York, McGraw-Hill, 1996, pp 335–369. Rumsey JM, Donohue BC, Brady DR, et al: A magnetic resonance imaging study of planum temporale asymmetry in men with developmental dyslexia. Arch Neurol 54:1481, 1997.


Neurology_Adams

Neurology_Adams. Rumsey JM, Donohue BC, Brady DR, et al: A magnetic resonance imaging study of planum temporale asymmetry in men with developmental dyslexia. Arch Neurol 54:1481, 1997. Rutter M, Martin JAM (eds): Clinics in Developmental Medicine. No 43. The Child with Delayed Speech. London, Heinemann, 1972, pp 48–51. Saint-Anne Dargassies S: Neurological Development in the Full-Term and Premature Neonate. New York, Excerpta Medica, 1977. Sandak R, Fiez JA: Stuttering: A view from neuroimaging. Lancet 356:445, 2000. Scarr S, Webber RA, Weinberg RA, Wittig MA: Personality resemblance among adolescents and their parents in biologically related and adoptive families. Prog Clin Biol Res 69:99, 1981. Schain RJ: Neurology of Childhood Learning Disorders, 2nd ed. Baltimore, MD, Williams & Wilkins, 1977. Shaywitz SE: Dyslexia. N Engl J Med 338:307, 1998. Shaywitz SE, Shaywitz BA, Fletcher JM, et al: Prevalence of reading disabilities in boys and girls. JAMA 264:998, 1990.


Neurology_Adams

Neurology_Adams. Shaywitz SE: Dyslexia. N Engl J Med 338:307, 1998. Shaywitz SE, Shaywitz BA, Fletcher JM, et al: Prevalence of reading disabilities in boys and girls. JAMA 264:998, 1990. Simos PG, Fletcher JM, Bergman G, et al: Dyslexia-specific brain deterioration profile becomes normal following remedial training. Neurology 58:1203, 2002. Spearman C: Psychology Down the Ages. London, Macmillan, 1937. Staples R: Responses of infants to color. J Exp Psychol 15:119, 1932. Swaab DF, Hofman MA: An enlarged suprachiasmatic nucleus in homosexual men. Brain Res 537:141, 1990. Theusch E, Basu A, Gitschier J: Genome-wide study of families with absolute pitch reveals linkage to 8q24.21 and locus heterogeneity. Am J Human Genetics 85:112, 2009. Thurstone LL: The Vectors of the Mind. Chicago, University of Chicago Press, 1953. Tirosh E: Fine motor deficit: An etiologically distinct entity. Pediatr Neurol 10:213, 1994. Travis LE: Speech Therapy. New York, Appleton-Century, 1931.


Neurology_Adams

Neurology_Adams. Chicago Press, 1953. Tirosh E: Fine motor deficit: An etiologically distinct entity. Pediatr Neurol 10:213, 1994. Travis LE: Speech Therapy. New York, Appleton-Century, 1931. Turner G, Turner B, Collins E: X-linked mental retardation without physical abnormality: Renpenning’s syndrome. Dev Med Child Neurol 13:71, 1971. Vernes SC, Newbury DF, Abrahams BS, et al: A functional genetic link between distinct developmental language disorders. N Engl J Med 359:2337, 2008. Weiss G, Hechtman L, Milroy T, Perlman T: Psychiatric status of hyperactives as adults: A controlled prospective 15-year follow-up of 63 hyperactive children. J Am Acad Child Adolesc Psychiatry 24:211, 1985. Worster-Drought C: Congenital suprabulbar paresis. J Laryngol Otol 70:453, 1956. Yakovlev PI, Lecours AR: The myelogenetic cycles of regional maturation of the brain. In: Minkowski A (ed): Regional Development of the Brain in Early Life. Oxford, UK, Blackwell, 1967, pp 3–70.


Neurology_Adams

Neurology_Adams. Yakovlev PI, Lecours AR: The myelogenetic cycles of regional maturation of the brain. In: Minkowski A (ed): Regional Development of the Brain in Early Life. Oxford, UK, Blackwell, 1967, pp 3–70. Zametkin AJ, Ernst M: Problems in the management of attention-deficit hyperactivity disorder. N Engl J Med 340:40, 1999. Figure 27-1. Lateral views of the fetal brain, from 10 to 40 weeks of gestational age. (Reproduced by permission from Feess-Higgins and Larroche.)


Neurology_Adams

Neurology_Adams. Figure 27-2. Cox-Golgi preparations of the leg area of the motor cortex (area 4). Upper row, left to right: 1 month premature (8 months gestation); newborn at term; 1 month; 3 months; and 6 months. Lower row, left to right: 15 months; 2 years; 4 years; 6 years. Apical dendrites of Betz cells have been shortened, all to the same degree, for the purposes of display. (Courtesy of T. Rabinowicz, University of Lausanne.) 4SENSORY ROOTS2567FETAL MONTHSFIRST YEAR, MONTHS3STATO ACOUSTIC TECTUM & TEGMENTUM5INNER DIV INF CEREB PED6OUTER DIV INF CEREB PED89101234567891011122 yrs3 yrs4 yrs7 yrs10 yrsOLDER2ndDECADE3rdDECADE11BR SUP COL & OPTIC NERVE & TRACT1MOTOR ROOTS4MEDIAL LEMNISCUS8MID CEREBELLAR PED.9?RETICULAR FORMATION10BR. INF. COL.7SUP CEREBELLAR PED.12THALAMIC FASCICULUS AND MAMMILOTHALAMIC TRACT14FASCICULUS LENTICULARIS AND PUTAMEN15OPTIC RAD.13ANSA LENTICULARIS AND PALLIDUM16SOMESTHETIC RAD.17ACOUSTIC RAD.18NON-SPECIFIC THALAMIC RAD.2419?STRIATUM23CINGULUM20PYRAMIDAL


Neurology_Adams

Neurology_Adams. MAMMILOTHALAMIC TRACT14FASCICULUS LENTICULARIS AND PUTAMEN15OPTIC RAD.13ANSA LENTICULARIS AND PALLIDUM16SOMESTHETIC RAD.17ACOUSTIC RAD.18NON-SPECIFIC THALAMIC RAD.2419?STRIATUM23CINGULUM20PYRAMIDAL TRACTS21FRONTO-PONTINE TRACT22?FORNIX25INTRA-CORTIC,NEUROPIL. ASSOC. AREAS?GREAT CEREBRAL COMMISSURES


Neurology_Adams

Neurology_Adams. Figure 27-3. The myelogenetic chronology. (Reproduced from Yakovlev and Lecours.) Figure 27-4. Gaussian or bell-shaped curve of intelligence and its skewing by the group of intellectually delayed individuals with diseases of the brain. The shaded areas indicate the two groups of persons who have delays in this sphere. The population on the extreme left is largely comprised of those with overt cerebral pathology and is intended to illustrate a slight overlap with those whose intelligence falls in the lower end of the normal distribution. The latter group is considered not to have a pathologic basis of low intelligence, in the past called “subcultural” as discussed in the text and in Chap. 37. Chapter 27 Normal Development and Deviations in Development of the Nervous System The Neurology of Aging


Neurology_Adams

Neurology_Adams. Chapter 27 Normal Development and Deviations in Development of the Nervous System The Neurology of Aging As indicated in the preceding chapter, standards of growth, development, and maturation provide a frame of reference against which every pathologic process in early life must be viewed. It has been less appreciated, however, that at the other end of the life cycle, neurologic deficits must be judged in a similar way, against a background of normal aging changes. The earliest of these changes begins long before the acknowledged period of senescence and continues throughout the remainder of life. Most authors use the terms aging and senescence interchangeably, but some draw a fine semantic distinction between the purely passive and chronologic process of aging and the composite of bodily changes that characterize this process (senescence).


Neurology_Adams

Neurology_Adams. Biologists have measured many of these changes. Table 28-1 gives estimates of the structural and functional decline that accompanies aging between ages 30 and 80 years. It appears that all structures and functions share in the aging process. Some persons withstand the onslaught of aging far better than others, and this constitutional resistance to the effects of aging seems to be familial. It can also be said that such changes are unrelated to Alzheimer disease and other degenerative diseases but that in general, the changes of aging reduce the capacity to recover from virtually any illness or trauma. An entity of “frailty” has been conceived to encompass the sum of breakdown in multiple organ systems that result from the later stages of aging. With respect to the nervous system, it entails loss of muscle mass, strength and endurance, decreased appetite, unintentional weight loss, and reduced mobility and balance, to which may be added the deteriorations in vision and hearing that


Neurology_Adams

Neurology_Adams. loss of muscle mass, strength and endurance, decreased appetite, unintentional weight loss, and reduced mobility and balance, to which may be added the deteriorations in vision and hearing that occur to varying degrees in the aged. A working definition of frailty has been given by Fried and is summarized in Table 28-2. In the past, this was referred to as “failure to thrive,” a term adopted from pediatrics. A simplified approach has been given the British Geriatrics Society. They have identified slowed walking speed, meaning the inability to cover 4 m in less than 5 s, the inability to stand from a chair and walk 3 m and return to sit down again in under 10 s, a score of 3 or more on a questionnaire called PRISMA 7, which focuses on age over 85, health problems that require the individual to stay at home, and the need for a cane, walker, or wheelchair. The British Geriatrics Society paper and the review by Clegg and colleagues are recommended on this subject.


Neurology_Adams

Neurology_Adams. Effects of Aging on the Nervous System Of all the age-related changes, those in the nervous system are of paramount importance. Actors portray old people as being feeble, idle, obstinate, given to reminiscing and having tremulous hands, quavering voices, stooped posture and slow, shortened steps. In so doing, they have selected some of the most obvious effects of aging on the nervous system. The lay observer, as well as the medical one, often speaks glibly of the changes of advanced age as a kind of second childhood. “Old men are boys again,” said Aristophanes.


Neurology_Adams

Neurology_Adams. Critchley, in 1931 and 1956, drew attention to a number of neurologic abnormalities that he had observed in octogenarians and for which no cause could be discerned other than the effects of aging itself. Several reviews of this subject have appeared subsequently (see especially those of Jenkyn, of Benassi, and of Kokmen [1977] and their associates). The most consistent of the neurologic signs of aging are the following: • Neuro-ophthalmic: progressive smallness of pupils, decreased reactions to light, and near farsightedness (hyperopia) as a result of impairment of accommodation (presbyopia), insufficiency of convergence, restricted range of upward conjugate gaze, frequent loss of the Bell phenomenon, diminished dark adaptation, and increased sensitivity to glare. • Progressive hearing loss (presbycusis), especially for high tones, and commensurate decline in speech discrimination. Mainly these changes are a result of a diminution in the number of hair cells in the organ of Corti.


Neurology_Adams

Neurology_Adams. • Diminution in the sense of smell and, to a lesser extent, of taste (see Chap. 11). • Motor signs: reduced speed and amount of motor activity, slowed reaction time, impairment of fine coordination and agility, reduced muscular power (legs more than arms and proximal muscles more than distal ones) and thinness of muscles (sarcopenia), particularly the dorsal interossei, thenar, and anterior tibial muscles. A progressive decrease in the number of anterior horn cells is partially responsible for these changes, as described further on.


Neurology_Adams

Neurology_Adams. • Changes in tendon and frontal reflexes: A depression of tendon reflexes at the ankles in comparison with those at the knees is observed frequently in persons older than 70 years of age, as is a loss of Achilles reflexes in those older than 80 years of age. The snout or palmomental reflexes, which can be detected in mild form in a small proportion of healthy adults, are frequent findings in the elderly (in as many as half of normal subjects older than 60 years of age, according to Olney). Other so-called cortical release signs, such as suck and grasp reflexes, when prominent, are indicative of frontal lobe disease but sometimes are expected simply as a result of aging.


Neurology_Adams

Neurology_Adams. • Impairment or loss of vibratory sense in the toes and ankles. Proprioception, however, is impaired very little or not at all. Thresholds for the perception of cutaneous stimuli increase with age but require the use of refined methods of testing for their detection. These changes correlate with a loss of sensory fibers on sural nerve biopsy, reduced amplitude of sensory nerve action potentials, probably as a result of loss of dorsal root ganglion cells. • The most obvious neurologic aging changes—those of stance, posture, and gait—are fully described in Chap. 6 and further on in this chapter. Jenkyn and colleagues, based on their examinations of 2,029 individuals aged 50 to 93 years, have determined the incidence of certain of these common neurologic signs of aging. Notable again is the high frequency of snout and glabellar responses, but also limited downgaze and upgaze in approximately one-third of persons older than age 80 years. Table 28-3 summarizes these data.


Neurology_Adams

Neurology_Adams. With regard to the interesting population of the “oldest old,” those older than 85 or 90 years of age, Kaye and colleagues reported that deficits in balance, olfaction, and visual pursuit are distinctly worse than in younger elderly persons. Also of interest is the observation by van Exel and colleagues that women in this age group perform better than men on cognitive tests.


Neurology_Adams

Neurology_Adams. One of the weaknesses of studies of the aged has been the bias in selection of patients. Many of the reported observations have been made in cohorts of individuals residing in nursing homes. Studies of functionally intact old people of comparable age and living independently, such as those of Kokmen (1977) and of Benassi and their colleagues, reveal fewer deficits, consisting mainly of forgetfulness of names, smallness of pupils, restriction of convergence and upward conjugate gaze, diminished Achilles reflexes and vibratory sense in the feet, stooped posture, and impairments of balance, agility, and gait (as mentioned earlier and in the following text). Effects of Aging on Memory and Other Cognitive Functions


Neurology_Adams

Neurology_Adams. Effects of Aging on Memory and Other Cognitive Functions Probably the most detailed information as to the effects of age on the nervous system comes from the measurement of cognitive functions. In the course of standardization of the original Wechsler-Bellevue Intelligence Scale (1955), cross-sectional studies of large samples of the population indicated that there was a steady decline in cognitive function starting at 30 years of age and progressing into old age. Apparently all forms of cognitive function partake of this decline—although in general certain elements of the verbal scale (vocabulary, fund of information, and comprehension) withstand the effects of aging better than those of the performance scale (block design, reversal of digits, picture arrangement, object assembly, and the digit symbol task).


Neurology_Adams

Neurology_Adams. However, the concept of a linear regression of cognitive function with aging has had to be modified in the light of subsequent longitudinal studies. If the same individual is examined over a period of many years, there is virtually no decline in performance, as measured by tests of verbal function, until about 60 years of age. Beyond this age, verbal intelligence does decline, but very slowly—by an average of less than 5 percent through the seventh decade and by less than 10 percent through the eighth decade (Schaie and Hertzog). Also, in a series of 460 community-dwelling individuals (55 to 95 years of age) studied by Smith and coworkers (1992), there was no significant decline with age in verbal memory and in registration–attention; similar results were found by Petersen and colleagues in 161 normal, community-dwelling individuals 62 to 100 years of age. The most definite effects of age were in learning and memory and in problem solving—cognitive impairments probably attributable to


Neurology_Adams

Neurology_Adams. 161 normal, community-dwelling individuals 62 to 100 years of age. The most definite effects of age were in learning and memory and in problem solving—cognitive impairments probably attributable to a progressive reduction in the speed of processing information. The latter may be reflected in the slowing of event-related evoked potentials and by a number of special psychologic tests (see


Neurology_Adams

Neurology_Adams. Verhaeghen et al). As regards these cognitive functions, the ability to memorize, acquire, and retain new information, recall of names, and avoidance of distraction once set on a course of action, diminishes with advancing age, particularly in those older than 70 years of age. Moreover, memory function may be disturbed in this way despite the relative retention of other intellectual abilities. Characteristically, there is difficulty with recall of a name or the specific date of an experience (“episodic” memory) despite a preservation of memory for the experience itself or for the many features of a person whose name is momentarily elusive (“tip-of-the-tongue syndrome”). Also characteristic is an inconsistent retrieval of the lost name or information at a later date. It has been found, however, that if older persons are allowed to learn new material very well, until no errors are made, they forget this information at a rate similar to that of younger individuals.


Neurology_Adams

Neurology_Adams. Kral, who first wrote informatively on this type of memory disturbance 50 years ago, referred to it as benign senescent forgetfulness. He pointed out that such a memory disturbance, in distinction to that of Alzheimer disease, worsens very little or not at all over a period of many years and does not interfere significantly with the person’s work performance or activities of daily living. Crook and coworkers have refined the diagnostic criteria for senescent forgetfulness and proposed the term age-associated memory impairment (AAMI). The diagnostic criteria for AAMI include age of 50 years or older, a subjective sense of decline in memory, impaired performance on standard tests of memory function (at least one SD below the mean), and absence of any other signs of dementia. The current terminology is minimal cognitive impairment, but there has been increasing recognition that Kral’s original notion of a benign condition may have been incorrect and that cognitive decline in later years


Neurology_Adams

Neurology_Adams. is minimal cognitive impairment, but there has been increasing recognition that Kral’s original notion of a benign condition may have been incorrect and that cognitive decline in later years may be a premonitory symptom of Alzheimer disease.


Neurology_Adams

Neurology_Adams. In judging the degree of cognitive decline, several abbreviated tests of mental status have been developed and are of practical value (Kokmen et al, 1991; Folstein et al) in that they can be administered in the office or at the bedside in 5 to 10 min. Repetition of spoken items, such as a series of digits, orientation as to place and time, capacity to learn and to retain several items, tests of arithmetic and calculation (concentration), and specific tests for memory (particularly tests of delayed recall or forgetfulness) distinguish the performance of normal aging persons from that of patients with Alzheimer disease (Larrabee et al). With regard to performance on the Mini-Mental Status Examination (MMSE, range 0 to 30 with higher scores signifying better performance), a study by Crum and associates of a large urban population indicates a median score of 19 to 20 for individuals older than age 80 years who have a fourth grade education and 27 for those with a college education (out of


Neurology_Adams

Neurology_Adams. associates of a large urban population indicates a median score of 19 to 20 for individuals older than age 80 years who have a fourth grade education and 27 for those with a college education (out of maximum score of 30). A similar Montreal Cognitive Assessment has become popular in recent years (MOCA, range 0 to 30 with higher scores being better). Many other scales have been devised that detect cognitive decline with age, most conceived for the purpose of clinical trials, but they do not find much use in daily practice.


Neurology_Adams

Neurology_Adams. The foregoing effects of age on mental abilities are extremely variable. Some 70-year-olds perform better on psychologic testing than some “normal” 20-year-olds. And a few individuals retain exceptional mental power and perform creative work until late life. Verdi, for example, composed Otello at the age of 73 and Falstaff at 79.


Neurology_Adams

Neurology_Adams. Humboldt wrote the 5 volumes of his Kosmos between the ages of 76 and 89 years; Goethe produced the second part of Faust when he was more than 70 years old; Galileo, Laplace, and Sherrington continued to make scientific contributions in their eighth decades; and Picasso continued to paint in his nineties. It must be pointed out, however, that these accomplishments were essentially continuations of lines of endeavor that had been initiated in early adult life. Indeed, from general observation it can be concluded that little that is truly new and original to the individual is started after the 50th year. High intelligence, well-organized work habits, and sound judgment compensate for many of the progressive shortcomings of old age. Personality Changes in the Aged


Neurology_Adams

Neurology_Adams. Personality Changes in the Aged These are less-easily measured than cognitive functions, but certain trends are nevertheless observable and may seriously disturb the lives of aged persons and those around them. Many old people become more opinionated, repetitive, self-centered, and rigid and conservative in their thinking; the opposite qualities—undue pliancy, vacillation, and the uncritical acceptance of ideas—are observed in others. Often these changes can be recognized as exaggerations of lifelong personality traits. Elderly persons tend to become increasingly cautious; many of them seem to lack self-confidence and require a strong probability of success before undertaking certain tasks. These changes may impair their performance on psychologic testing. Kallman’s studies of senescent monozygotic twins suggest that genetic factors are more important than environmental ones in molding these traits.


Neurology_Adams

Neurology_Adams. Effects of Aging on Stance and Gait and Related Motor Impairments (See Also Chap. 6)


Neurology_Adams

Neurology_Adams. These are among the most conspicuous manifestations of the aging process. Motor agility actually begins to decline in early adult life, even by the 30th year; it seems related to a gradual decrease in neuromuscular control as well as to changes in joints and other structures. The reality of this motor decrement is best appreciated by professional athletes who retire at age 35 or thereabout because their legs give out and cannot be restored to their maximal condition by training. They cannot run as well as younger athletes, even though the strength and coordination of their arms, when tested independently of other functions, are relatively preserved. More subtle and imperceptibly evolving changes in stance and gait are ubiquitous features of aging (see Chap. 6). Gradually the steps shorten, walking becomes slower, and there is a tendency to stoop. The older person becomes less confident and more cautious in walking and habitually touches the handrail in descending stairs, to prevent a


Neurology_Adams

Neurology_Adams. walking becomes slower, and there is a tendency to stoop. The older person becomes less confident and more cautious in walking and habitually touches the handrail in descending stairs, to prevent a misstep.


Neurology_Adams

Neurology_Adams. To be distinguished from the ubiquitous and subtle changes in gait of the “normal” older population is a more rapidly evolving and inordinate deterioration of gait that afflicts a small proportion of the aging population while they remain relatively competent in other ways. In all likelihood, this latter disorder represents an age-linked degenerative disease of the brain, as most instances of it are sooner or later accompanied by mental changes. The basis of this gait disorder is probably a combined frontal lobe–basal ganglionic degeneration, the anatomy of which has never been fully clarified, as discussed in “Frontal Lobe Disorder of Gait” in Chap. 6. However, in many of such patients we have observed, there is no disproportionate atrophy or reduction of blood flow in the frontal lobes, making the cause of the gait disorder obscure. It has also been postulated that age-related changes in the substantia nigra are the cause of the parkinsonian appearance of the gait of the aged, but


Neurology_Adams

Neurology_Adams. making the cause of the gait disorder obscure. It has also been postulated that age-related changes in the substantia nigra are the cause of the parkinsonian appearance of the gait of the aged, but it does not respond to l-dopa or to any other therapeutic measure. An important differential diagnostic consideration is normal-pressure hydrocephalus, correctable sometimes by a ventriculoperitoneal shunt, which accounts for the gait disorder of a group of these elderly patients, as discussed in Chaps. 6 and 29. Parkinson disease is yet another potentially treatable cause of walking difficulty. Progressive supranuclear palsy is a degenerative process in which gait and stability are affected early and profoundly.


Neurology_Adams

Neurology_Adams. Urinary incontinence, defined as a state in which involuntary loss of urine is a social or hygienic problem and is objectively demonstrated, is a common occurrence in the elderly (Wells and Diokno). Doubtless this complex of sphincteric impairments is based on the aforementioned neuronal losses in the spinal cord, cerebellum, and cerebrum as well as on mechanical factors. Falls in the Elderly Among elderly persons without apparent neurologic disease, falls constitute a major health problem. Approximately 30 percent suffer one or more falls each year; this figure rises to 40 percent among those older than age 80 years and to more than 50 percent among elderly persons living in nursing homes. According to Tinetti and Speechley, 10 to 15 percent of falls in the elderly result in fractures and other serious injuries; they are reportedly an underlying cause of about 9,500 deaths annually in the United States.


Neurology_Adams

Neurology_Adams. Several factors, some mentioned earlier in regard to deterioration of gait, are responsible for the inordinately high rate of falling among older persons. Impairment of visual function and particularly of vestibular function with normal aging are important contributors. In a group of 34 elderly patients who were free of neurologic disease, postural hypotension, and leg deformities, Weiner and colleagues found a moderate or severe degree of postural reflex impairment in two-thirds. The failure to make rapid postural adjustments, which is a product of aging alone, accounts for the occurrence of falls in the course of usual activities such as walking, changing position, or descending stairs. Orthostatic hypotension, often because of antihypertensive agents and the use of sedative drugs, is another important cause of falling in the elderly.


Neurology_Adams

Neurology_Adams. Of course, falling is an even more prominent feature of certain age-related neurologic diseases: stroke, Parkinson disease, normal-pressure hydrocephalus, and progressive supranuclear palsy, among others. Other Restricted Motor Abnormalities in the Aged These are too numerous to be more than catalogued. They reflect the many ways in which the motor system can deteriorate. Compulsive, repetitive movements are the most frequent: mouthing movements, stereotyped grimacing, protrusion of the tongue, side-to-side or to-and-fro tremor of the head, odd vocalizations such as sniffing, snorting, and bleating. In some respects these disorders resemble tics (quasivoluntary movements to relieve tension), but careful observation shows that they are not really voluntary. Haloperidol, tetrabenazine, and other drugs of this class have an unpredictable therapeutic effect, seeming at times to benefit the patient perhaps in part by the superimposition of a drug-induced rigidity.


Neurology_Adams

Neurology_Adams. Old age is thought always to carry a liability to tremulousness, and indeed, one sees this association with some frequency. The head, chin, or hands tremble and the voice quavers, yet there is not the usual slowness and poverty of movement, facial impassivity, or flexed posture that would stamp the condition as parkinsonian. Some instances of tremor are clearly familial, having appeared or worsened only late in life. However, the relation of tremulousness to aging is sometimes open to doubt. Charcot, in a review of over 2,000 elderly inhabitants of the Salpêtrière Hospital, could find only about 30 with tremor. Some cases probably represent the exaggeration or emergence of essential tremor, but many cases cannot be explained on this basis. Spastic or spasmodic dysphonia, a disorder of middle and late life characterized by spasm of all the throat muscles on attempted speech, is discussed in Chap. 4.


Neurology_Adams

Neurology_Adams. Not to be minimized are the limitations of movement and gait that result from degenerative orthopedic conditions that accompany aging, foremost limitations in the range of motion of the hips, knees, and spine. These contribute greatly to the aforementioned global appearance of truncal and limb control of the aged. Some peculiar aspects that have come to our attention because they simulate neurological problems include a “tall-man” syndrome, in which a gentleman may not be able to arise from a chair because the knees cannot be flexed adequately to plant the feet behind the trunk and push off to stand. Morphologic and Physiologic Changes in the Aging Nervous System


Neurology_Adams

Neurology_Adams. Morphologic and Physiologic Changes in the Aging Nervous System From the third decade of life to the beginning of the 10th decade, the average decline in weight of the male brain is from 1,394 to 1,161 g, a loss of 233 g. The pace of this change, very gradual at first, accelerates during the sixth or seventh decades. The loss of brain weight, which correlates roughly with enlargement of the lateral ventricles and widening of the sulci, is presumably the result of neuronal degeneration and replacement gliosis. The counting of cerebrocortical neurons is fraught with technical difficulties, even with the use of computer-assisted automated techniques (see the critical review of neuron-counting studies by Coleman and Flood). Nevertheless, most studies point to a depletion of the neuronal population in the neocortex, especially evident in the seventh, eighth, and ninth decades.


Neurology_Adams

Neurology_Adams. Cell loss in the limbic system (hippocampus, parahippocampal, and cingulate gyri) is of special interest in regard to memory. Ball, who measured the neuronal loss in the hippocampus, recorded a linear decrease of 27 percent between 45 and 95 years of age. Dam reported a similar degree of cell loss and replacement gliosis. These changes seem to proceed without relationship to Alzheimer neurofibrillary changes and senile plaques (Kemper). However, more recent morphologic work, summarized by Morrison and Hof, suggests that cerebral cell loss with aging is less pronounced than previously thought. Furthermore, as pointed out by Morrison, the hippocampus may have only minimal cell loss. Moreover, this is partially a result of neurogenesis in this region. Brain shrinkage is accounted for in part by the reduction in size of large neurons, not their disappearance. There is a more substantial reduction in neuronal number in the substantia nigra, locus ceruleus, and basal forebrain nuclei. It


Neurology_Adams

Neurology_Adams. by the reduction in size of large neurons, not their disappearance. There is a more substantial reduction in neuronal number in the substantia nigra, locus ceruleus, and basal forebrain nuclei. It may be possible to differentiate normal aging from disease in the medial temporal lobe by distinguishing between cell loss in specific regions (see Small et al), but novel techniques are required.


Neurology_Adams

Neurology_Adams. Mueller and colleagues employed quantitative volumetric MRI techniques to examine a cohort of 46 nondemented elderly individuals. They found small, constant rates of loss of brain volume with aging. Moreover, the rates of volume loss in the last decades of life were no greater than in the immediately preceding decades, suggesting that large changes in brain volume in the elderly are attributable to the dementing diseases common to this age period. Rusinek and colleagues found that serial MRIs of elderly persons predict which individuals will develop disproportionate atrophy and dementia. In particular, hippocampal atrophy increases at the rate of less than 2 percent per year in healthy elderly people, in comparison to 4 to 8 percent a year in early Alzheimer disease. This longitudinal method of study is more sensitive than cross-sectional population studies.


Neurology_Adams

Neurology_Adams. Among lumbosacral anterior horn cells, sensory ganglion cells, and putaminal and Purkinje cells, neuronal loss amounts to at most 25 percent between youth and old age. Not all neuronal groups are equally susceptible. For example, the locus ceruleus and substantia nigra, as already commented, lose approximately 35 percent of their neurons, whereas the vestibular nuclei and inferior olives maintain a fairly constant number of cells throughout life. A very subtle loss, decade by decade, of the major systems of nerve cells and myelinated fibers of the spinal cord was demonstrated by Morrison. This accelerates after the age of 60 (Tomlinson and Irving).


Neurology_Adams

Neurology_Adams. As described earlier in normal aging, there is a gradual decline in memory and in some cognitive functions. In light of the studies just summarized, it is no longer considered that these changes can be ascribed simply to neuronal loss. Rather, they are probably caused, at least in part, by alterations in synaptic connectivity within critical cortical structures.


Neurology_Adams

Neurology_Adams. Scheibel and coworkers have described a loss of neuronal dendrites in the aging brain, particularly the horizontal dendrites of the third and fifth layers of the neocortex. However, the Golgi method, which was used in these studies, is difficult to interpret because of artifacts. The morphometric studies of Buell and Coleman showed that the surviving neurons actually exhibit expanded dendritic trees, suggesting that even aging neurons have the capacity to react to cell loss by developing new synapses. With advancing age, there is an increasing tendency for neuritic (amyloid and neurofibrillary) plaques to appear in the brains of nondemented individuals. At first the plaques appear in the hippocampus and parahippocampus, but later they become more widespread. These are loose aggregates of amorphous argentophilic material containing amyloid. They occur in increasing numbers with advancing age; by the end of the ninth decade of life, few brains are without them. However, as shown by


Neurology_Adams

Neurology_Adams. Tomlinson and colleagues (1968 and 1970), relatively fewer plaques are present in the brains of mentally intact old people, in contrast to the large numbers in those with Alzheimer disease (Roth et al). Even more impressive is the correlation of neurofibrillary tangles and Alzheimer disease. Very few such tangles are found in the brains of mentally sound individuals, and those that are found are essentially confined to the hippocampus and adjacent entorhinal cortex. By contrast, neurofibrillary tangles are far more abundant and diffusely distributed in patients with Alzheimer disease.


Neurology_Adams

Neurology_Adams. The view is often expressed that neuritic plaques and Alzheimer type of neurofibrillary changes simply represent an acceleration of the natural aging process in the brain. Most investigators are more inclined to the idea that they represent an acquired age-linked disease, analogous in this respect to certain cerebrovascular diseases or osteoarthritis. In support of this latter view are several observations. First, Homo sapiens is the only animal species in which Alzheimer neurofibrillary changes and neuritic plaques are regularly found in the aging brain. A few plaque-like structures (but no neurofibrillary changes) have been seen occasionally in old dogs and monkeys but not in mice or rats. It seems unbiologic that human aging should differ from that of all other animal species. Second, some of the most severe forms of Alzheimer disease occur in middle adult life, long before old age. Third, these histopathologic changes in variable proportion occur in a number of other diseases


Neurology_Adams

Neurology_Adams. some of the most severe forms of Alzheimer disease occur in middle adult life, long before old age. Third, these histopathologic changes in variable proportion occur in a number of other diseases unrelated to aging, such as dementia pugilistica (“punch-drunk” state), Down syndrome, postencephalitic Parkinson disease, and progressive supranuclear palsy. Fourth, neurofibrillary tangles can be reproduced in the experimental animal by such toxins as aluminum, vincristine, vinblastine, and colchicine. Finally, a small proportion of Alzheimer cases are definitely familial, as described in Chap. 38.


Neurology_Adams

Neurology_Adams. Virtually every molecular structure within the cell is subject to age-related biochemical modifications, such as the formation of carbonyl proteins, glycation of sugars, and oxidative changes in lipids. Some of these subcellular phenomena contribute to the aging process (see Mrak et al for details), as do the accumulation of mitochondrial DNA mutations and shortened lengths of the telomeres. Among the visible biochemical alterations is an increasing accumulation of lipofuscin granules in the cytoplasm of neurons, sometimes extreme in degree. Also, there is an age-related neuronal accumulation of iron and other pigment bodies. Granulovacuolar changes are a regular finding in aging hippocampi, regardless of the mental state of the individual. The accumulation of glycogen-containing concretions (corpora amylacea) around nerve roots and diffusely in the subpial space is yet another aging effect, which has no known clinical correlate.


Neurology_Adams

Neurology_Adams. Cerebral atherosclerosis is, of course, a frequent finding in the elderly, but it does not parallel aging with any degree of precision, being severe in some 30to 40-year-old individuals and practically absent in some octogenarians. In the normotensive individual, it tends to occur in scattered, discrete plaques mostly in the aorta and cervical arteries (carotid bifurcation and higher segments), proximal middle cerebral arteries, and at the vertebrobasilar junction and basilar portions of the cerebral arterial system. In the hypertensive and diabetic, it is more diffuse and extends into finer branches of the cerebral and cerebellar arteries. One or more cerebral infarcts are found in approximately 25 percent of all individuals older than 70 years of age who were carefully examined postmortem. In addition to atherosclerotic disease, the basilar arteries become somewhat larger and more tortuous and opaque in the elderly.


Neurology_Adams

Neurology_Adams. Cerebral blood flow has been extensively investigated in the elderly population. Most studies show that flow declines with age and that the cerebral metabolic rate declines in parallel. There is also an age-related increase in cerebrovascular resistance. Declines in flow are somewhat greater in the cortex than in white matter and greater in prefrontal regions than in other parts of the hemispheres. Obrist demonstrated a 28 percent reduction in cerebral flow by age 80. It is noteworthy, however, that every cohort of elderly persons tested in this way contained a significant proportion in which cerebral blood flow was equivalent to that in young control subjects. In fact, in a group of 72-year-old men rigorously selected on the basis of freedom from disease, Sokoloff demonstrated that cerebral blood flow and oxygen consumption did not differ from those of normal men 22 years of age. Nevertheless, cerebral glucose metabolism was reduced in all the elderly subjects.


Neurology_Adams

Neurology_Adams. With advancing age there is a general tendency for the electroencephalogram (EEG) to show a slowing of the alpha rhythm, an increase in beta activity, a decline in the percentage of slow-wave sleep, and an increasing intrusion of theta rhythms, particularly over the temporal lobes, although there are large individual differences.


Neurology_Adams

Neurology_Adams. With respect to the neurotransmitters, it is generally agreed that the concentrations of acetylcholine, norepinephrine, and dopamine decline in the course of normal aging. Also, the concentration of gamma-aminobutyric acid (GABA) has been shown to decline with age, particularly in the frontal cortex (Spokes et al). Analyses of postmortem human and animal brains have failed to demonstrate a decline with age in the concentration of serotonin or its metabolites (McEntee and Crook). Accurate assessment of other neurotransmitters has been more difficult because of their marked lability in postmortem material. Data from experiments in rats suggest that the glutamate content of the brain and the number of N-methyl-d-aspartate (NMDA) receptors diminish with age, but the functional significance of this finding is unclear. Unlike the case in Alzheimer disease, normal aging is associated with only slight and inconsistent abnormalities of cholinergic innervation of the hippocampus and cortex.


Neurology_Adams

Neurology_Adams. of this finding is unclear. Unlike the case in Alzheimer disease, normal aging is associated with only slight and inconsistent abnormalities of cholinergic innervation of the hippocampus and cortex. This is true also of the acetylcholine content and the activity of choline acetyltransferase (the synthesizing enzyme of acetylcholine) in these regions and the number of cholinergic neurons in the nucleus basalis of Meynert (substantia innominata) and other nuclei of the basal forebrain (Decker). Again, the significance of these changes is difficult to judge. They probably reflect the depletion of cells that occurs with aging. The topics of cholinergic and glutamatergic function in the aging brain have been critically reviewed by McEntee and Crook.


Neurology_Adams

Neurology_Adams. With advancing age, skeletal muscles lose cells (fibers) and undergo a gradual reduction in their weight more or less parallel to that of the brain. Atrophy of muscles and diminution in peak power and endurance are clinical expressions of these changes. Many processes contribute to this age-dependent loss of lean muscle mass, described as sarcopenia. These include decreased physical activity; diminished appetite associated with loss of smell and elevated levels of cholecystokinin, a satiety hormone; other endocrine changes such as diminished levels of growth hormone and androgens; and (as in the brain) the accumulation of subcellular defects such as nuclear and mitochondrial DNA mutations alluded to earlier. Moreover, with aging, the slow loss of motor neurons contributes to a component of denervation atrophy. Our own observations, with Dr. R.D. Adams, of neuropathologic material indicate that the wasting involves several processes, some principally myopathic and others relating to


Neurology_Adams

Neurology_Adams. of denervation atrophy. Our own observations, with Dr. R.D. Adams, of neuropathologic material indicate that the wasting involves several processes, some principally myopathic and others relating to disuse or denervation from loss of motor neurons. In this material, denervation atrophy of the gastrocnemius muscles was found in 80 percent of individuals older than 70 years of age. The lost muscle fibers are gradually replaced by endomysial connective tissue and fat cells. The surviving fibers are generally thinner than normal (possibly because of disuse atrophy), but some enlarge, resulting in a wider-than-normal range of fiber size. Groups of fibers all at the same stage of atrophy undoubtedly relate to loss of motor innervation. The reduction in conduction velocity and decrease in amplitude of motor nerve potentials and, to a greater extent, of sensory nerves in the aged may be taken as other indices of loss of motor and sensory axons. All these changes are more marked in the legs


Neurology_Adams

Neurology_Adams. of motor nerve potentials and, to a greater extent, of sensory nerves in the aged may be taken as other indices of loss of motor and sensory axons. All these changes are more marked in the legs than elsewhere. However, when Roos and colleagues examined the contractile speed and firing rates of the quadriceps muscle in young men and compared them to those of men close to 80 years old, they found little difference despite a 50 percent reduction in the maximum voluntary contraction force developed by the muscle in the older men.


Neurology_Adams

Neurology_Adams. It has been repeatedly observed that age is an important prognostic factor in a large number of human diseases. This effect is very evident, for example, in the markedly slower and less-complete recovery from Guillain-Barré polyneuropathy in older age groups compared with younger ones. One presumes that the structural changes of aging in peripheral nerves limit the degree of myelin regeneration and lower the threshold for failure of electrical transmission.


Neurology_Adams

Neurology_Adams. Gerontology is defined as the study of aging and geriatrics as the study of the disorders of aging, both of aging itself and of the age-related diseases. Geriatric neurology has emerged as a subspecialty focused on age-related disorders of the nervous system (see the review of the field by Stanton). In comparison to pediatric neurology, these disciplines have not aroused much interest, yet many neurologic patients seen in practice are elderly, especially if one includes those with vascular diseases of the brain. Furthermore, many of their diseases are preventable or therapeutically controllable such as hypertension, atrial fibrillation, and hypercholesterolemia as causes of stroke. Some of the age-related nutritional and endocrine disorders (e.g., vitamin B deficiencies, diabetes mellitus) and many of the common restricted involutional changes (e.g., presbyopia) can be corrected. And always, there is the need to counsel the elderly patient on matters pertaining to health and daily


Neurology_Adams

Neurology_Adams. and many of the common restricted involutional changes (e.g., presbyopia) can be corrected. And always, there is the need to counsel the elderly patient on matters pertaining to health and daily activities. This was appreciated even in the time of Cicero, who, in his De Senectute, urged the practice of moderation in exercise and giving due attention to the mind, which must be kept active or, like a lamp that is not supplied with oil, it will grow dim.


Neurology_Adams

Neurology_Adams. As medical science and public health measures have brought diseases of aging and other diseases under control, the number of elderly persons has increased and will continue to do so. The U.S. Census Bureau reported a 18.5 percent increase in persons 60 years and older (45.8 to 57.1 million) and a 9.0 percent increase in persons 70 years and older (25.5 to 27.8 million) between the years 2000 and 2010. As the number of elderly increases, the need to look after them will occupy an increasing amount of the energies of physicians and the resources of society at large. Ball MJ: Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with aging and dementia. Acta Neuropathol 27:111, 1977. Benassi G, D’Alessandro R, Gallassi R, et al: Neurological examination in subjects over 65 years: An epidemiological survey. Neuroepidemiology 9:27, 1990.


Neurology_Adams

Neurology_Adams. Benassi G, D’Alessandro R, Gallassi R, et al: Neurological examination in subjects over 65 years: An epidemiological survey. Neuroepidemiology 9:27, 1990. British Geriatrics Society. Fit for frailty. Consensus best practices guidelines for the care of older people living with frailty in community and outpatient settings. London. British Geriatrics Society, 2014. https://www.bgs.org.uk/resources/resource-series/fit-for-frailty. Accessed November 19, 2018. Buell SJ, Coleman PD: Dendritic growth in the aged human brain and failure of growth in senile dementia. Science 206:854, 1979. Clegg A: The frailty syndrome. Clin Med (Lond) 11:72, 2011. Coleman PD, Flood DG: Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol Aging 8:521, 1987. Critchley M: The neurology of old age. Lancet 1:1221, 1931. Critchley M: Neurologic changes in the aged. J Chronic Dis 3:459, 1956.


Neurology_Adams

Neurology_Adams. Critchley M: The neurology of old age. Lancet 1:1221, 1931. Critchley M: Neurologic changes in the aged. J Chronic Dis 3:459, 1956. Crook T, Bartus RT, Ferris SH, et al: Age-associated memory impairment: Proposed diagnostic criteria and measures of clinical change—report of a National Institute of Mental Health Work Group. Dev Neuropsychol 2:261, 1986. Crum RM, Anthony JC, Bassett SS, Folstein MF: Population-based norms for the mini-mental status examination by age and educational level. JAMA 18:2386, 1993. Dam AM: The density of neurons in the human hippocampus. Neuropathol Appl Neurobiol 5:249, 1979. Decker MW: The effects of aging on hippocampal and cortical projections of the forebrain cholinergic system. Brain Res 434:423, 1987. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189, 1975.


Neurology_Adams

Neurology_Adams. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189, 1975. Fried LP: Frailty. In: Cassel C, Liepzig R, Cohen H, et al (eds): Geriatric Medicine. New York, Springer-Verlag, 2003, pp 1067–1074. Jenkyn LR, Reeves AG, Warren T, et al: Neurologic signs in senescence. Arch Neurol 42:1154, 1985. Kallman FJ: Genetic factors in aging: Comparative and longitudinal observations on a senescent twin population. In: Hoch PH, Zubin J (eds): Psychopathology of Aging. New York, Grune & Stratton, 1961. Kaye JA, Oken BS, Howieson DB, et al: Neurologic evaluation of the optimally healthy oldest old. Arch Neurol 51:1205, 1994. Kemper TL: Neuroanatomical and neuropathological changes during aging and dementia. In: Albert ML, Knoefel JE (eds): Clinical Neurology of Aging, 2nd ed. New York, Oxford University Press, 1994, pp 3–67.


Neurology_Adams

Neurology_Adams. University Press, 1994, pp 3–67. Kokmen E, Bossemeyer RW Jr, Barney J, Williams WJ: Neurologic manifestations of aging. J Gerontol 32:411, 1977. Kokmen E, Smith GE, Petersen RC, et al: The short test of mental status: Correlations with standardized psychometric testing. Arch Neurol 48:725, 1991. Kral VA: Senescent forgetfulness: Benign and malignant. Can Med Assoc J 86:257, 1962. Larrabee GH, Levin HS, High WM: Senescent forgetfulness: A quantitative study. Dev Neuropsychol 2:373, 1986. McEntee WJ, Crook TH: Serotonin, memory, and the aging brain. Psychopharmacology (Berl) 103:143, 1991. Morrison JH, Hof RP: Life and death of neurons in the aging brain. Science 278:412, 1997. Morrison LR: The Effect of Advancing Age upon the Human Spinal Cord. Cambridge, MA, Harvard University Press, 1959. Mrak RE, Griffin ST, Graham DI: Aging-associated changes in human brain. J Neuropathol Exp Neurol 56:1269, 1997.


Neurology_Adams

Neurology_Adams. Mrak RE, Griffin ST, Graham DI: Aging-associated changes in human brain. J Neuropathol Exp Neurol 56:1269, 1997. Mueller EA, Moore MM, Kerr DC, et al: Brain volume preserved in healthy elderly through the eleventh decade. Neurology 51:1555, 1998. Obrist WD: Cerebral circulatory changes in normal aging and dementia. In: Hoffmeister F, Muller C (eds): Brain Function in Old Age. Berlin, Springer-Verlag, 1979, pp 278–287. Olney RK: The neurology of aging. In: Aminoff MJ (ed): Neurology and General Medicine, 3rd ed. New York, Churchill Livingstone, 2001, pp 939–952. Petersen RC, Smith GE, Kokmen E, et al. Memory function in normal aging. Neurology 42:396, 1992. Roos MR, Rice CL, Connelly DM, Vandervoort AA: Quadriceps muscle strength, contractile properties, and motor unit firing rates in young and old men. Muscle Nerve 22:1094, 1999.


Neurology_Adams

Neurology_Adams. Roos MR, Rice CL, Connelly DM, Vandervoort AA: Quadriceps muscle strength, contractile properties, and motor unit firing rates in young and old men. Muscle Nerve 22:1094, 1999. Roth M, Tomlinson BE, Blessed G: Correlation between scores for dementia and counts of senile plaques in cerebral grey matter of elderly subjects. Nature 209:109, 1966. Rusinek H, De Santi S, Frid D, et al: Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MRI imaging study of normal aging. Radiology 229:691, 2003. Schaie KW, Hertzog C: Fourteen-year cohort-sequential analyses of adult intellectual development. Dev Psychol 19:531, 1983. Scheibel M, Lindsay RD, Tomiyasu U, Scheibel AB: Progressive dendritic changes in aging human cortex. Exp Neurol 47:392, 1975. Small SA, Tsai WY, DeLaPaz R, et al: Imaging hippocampal function across the human life span: Is memory decline normal or not? Ann Neurol 51:290, 2002.


Neurology_Adams

Neurology_Adams. Small SA, Tsai WY, DeLaPaz R, et al: Imaging hippocampal function across the human life span: Is memory decline normal or not? Ann Neurol 51:290, 2002. Smith GE, Malec JF, Ivnik RJ: Validity of the construct of nonverbal memory: A factor-analytic study in a normal elderly sample. J Clin Exp Neuropsychol 14:211, 1992. Sokoloff L: Effects of normal aging on cerebral circulation and energy metabolism. In: Hoffmeister F, Muller C (eds): Brain Function in Old Age. Berlin, Springer-Verlag, 1979, pp 367–380. Spokes EGS, Garrett NJ, Rossor MN, et al: Distribution of GABA in postmortem brain tissue from control, psychotic, and Huntington’s chorea subjects. J Neurol Sci 48:303, 1980. Stanton BR: The neurology of old age. Clin Med (Lond) 11:54, 2011. Tinetti ME, Speechley M: Prevention of falls among the elderly. N Engl J Med 320:1055, 1989. Tinetti ME, Speechley M, Ginter SF: Risk factors for falls among elderly persons living in the community. N Engl J Med 319:1701, 1988.


Neurology_Adams

Neurology_Adams. N Engl J Med 320:1055, 1989. Tinetti ME, Speechley M, Ginter SF: Risk factors for falls among elderly persons living in the community. N Engl J Med 319:1701, 1988. Tomlinson BE, Blessed G, Roth M: Observations on the brains of non-demented old people. J Neurol Sci 7:331, 1968. Tomlinson BE, Blessed G, Roth M: Observations on the brains of demented old people. J Neurol Sci 11:205, 1970. Tomlinson BE, Irving D: The numbers of limb motor neurons in the human lumbosacral spinal cord throughout life. J Neurol Sci 34:213, 1977. Van Exel E, Gussekloo J, De Craen AJ, et al: Cognitive function in the oldest old: Women perform better than men. J Neurol Neurosurg Psychiatry 71:29, 2001. Verhaeghen P, Marcoen A, Goossens L: Facts and fiction about memory aging: A quantitative integration of research findings. J Gerontol 48:157, 1993. Weiner WJ, Nora LM, Glantz RH: Elderly inpatients: Postural reflex impairment. Neurology 34:945, 1984.


Neurology_Adams

Neurology_Adams. Weiner WJ, Nora LM, Glantz RH: Elderly inpatients: Postural reflex impairment. Neurology 34:945, 1984. Wells TJ, Diokno AC: Urinary incontinence in the elderly. Semin Neurol 9:60, 1989. Chapter 28 The Neurology of Aging Disturbances of Cerebrospinal Fluid, Including Hydrocephalus, Pseudotumor Cerebri, and


Neurology_Adams

Neurology_Adams. In the chapters to follow, reference is made to the ways in which changes in the cerebrospinal fluid (CSF) reflect the basic pathologic processes in a variety of inflammatory and infectious, neoplastic, demyelinative, and degenerative diseases. The CSF alterations in these circumstances raise so many important problems that we consider it worthwhile to discuss in one chapter the mechanisms of the formation, circulation, and absorption of the CSF, particularly as they pertain to alterations of intracranial pressure (ICP). It follows that the diseases that result from perturbations in these mechanisms, namely hydrocephalus, pseudotumor cerebri, and syndromes produced by reduced pressure in the CSF compartment, are also presented. Further information on the management of raised ICP, particularly as it pertains to traumatic brain injury, can be found in Chap. 34. Examination of the CSF as a diagnostic aid in neurology was discussed in Chap. 2, and the primary infectious and noninfectious


Neurology_Adams

Neurology_Adams. as it pertains to traumatic brain injury, can be found in Chap. 34. Examination of the CSF as a diagnostic aid in neurology was discussed in Chap. 2, and the primary infectious and noninfectious inflammatory reactions of the pia-arachnoid (leptomeninges) and ependyma of the ventricles are considered in Chap. 31.


Neurology_Adams

Neurology_Adams. A few historical points call to mind that our understanding of the physiology, chemistry, and cytology of the CSF is the result of a technical innovation that was introduced a century ago. Although the lumbar puncture was introduced by Quincke in 1891, it was not until 1912 that Mestrezat made correlations between disease processes and the cellular and chemical changes in the CSF. In 1937, Merritt and Fremont-Smith published a monograph on CSF changes in a broad variety of disease. Our knowledge of CSF cytology has accumulated since the late 1950s, when membrane filtration techniques (particularly the cellulose ester or Millipore filter) were introduced. The studies of Dandy (1919) and of Weed (1935) provided the basis of our knowledge of CSF formation, circulation, and absorption. The important studies of Pappenheimer and colleagues and of Ames and colleagues followed, and then the monographs of Fishman and of Davson and coworkers, which are important modern contributions. (See Chap.


Neurology_Adams

Neurology_Adams. studies of Pappenheimer and colleagues and of Ames and colleagues followed, and then the monographs of Fishman and of Davson and coworkers, which are important modern contributions. (See Chap. 2 for references.) More recent inceptions in analyzing the lymphocytic cells and protein fractions in the CSF for diagnostic purposes in cancer, immune disorders such as multiple sclerosis and a variety of infections, have expanded on modern technology that was developed in hematology.


Neurology_Adams

Neurology_Adams. The primary function of the CSF appears to be a mechanical one; it serves as a kind of water jacket for the spinal cord and brain, protecting them from potentially injurious blows to the spinal column and skull and acute changes in venous pressure. Also, it provides the brain with buoyancy. As pointed out by Fishman, the 1,500-g brain, which has a water content of approximately 80 percent, weighs only 50 g when suspended in CSF, so the brain virtually floats in its CSF. Many of the physiologic mechanisms described below are committed to maintaining the relatively constant volume–pressure relationships of the CSF. In addition, because the brain and spinal cord have no lymphatic channels, the CSF, through a “sink action,” serves to remove waste products of cerebral metabolism, the main ones being CO2, lactate, and hydrogen ions. The composition of the CSF is maintained within narrow limits, despite major alterations in the blood; thus the other main function of CSF, by its contiguity


Neurology_Adams

Neurology_Adams. being CO2, lactate, and hydrogen ions. The composition of the CSF is maintained within narrow limits, despite major alterations in the blood; thus the other main function of CSF, by its contiguity with the extracellular compartment of the brain, is to preserve a stable chemical environment for neurons, astrocytes, and nerve fibers. There is no reason, however, to believe that the CSF is actively involved in the metabolism of the cells of the brain and spinal cord.


Neurology_Adams

Neurology_Adams. In the adult, the average intracranial volume is 1,700 mL; the volume of the brain is from 1,200 to 1,400 mL, CSF volume ranges from 70 to 160 mL (mean: 104 mL), and that of blood is approximately 150 mL. In addition, the spinal subarachnoid space contains 10 to 25 mL of CSF. Thus, at most, the CSF occupies less than 10 percent of the intracranial and intraspinal spaces. The proportion of CSF in the ventricles, and cerebral cisternae and sulci in the subarachnoid spaces varies with age. These variations have been plotted in CT scans by Meese and coworkers; the distance between the caudate nuclei at the anterior horns gradually widens by approximately 1.0 to 1.5 cm during an adults lifetime, and the width of the third ventricle increases from 3 to 6 mm by age 60 years. Formation of CSF


Neurology_Adams

Neurology_Adams. Formation of CSF The introduction of the ventriculocisternal perfusion technique by Pappenheimer and colleagues over 50 years ago made possible measurements of the rates of formation and absorption of the CSF. They established that the average rate of CSF formation is 21 to 22 mL/h (0.35 mL/min), or approximately 500 mL/d; thus the volume of CSF as a whole is renewed 4 or 5 times daily.


Neurology_Adams

Neurology_Adams. The choroid plexuses, located in the floor of the lateral, third, and fourth ventricles, are the main sites of CSF formation (some CSF is formed by the meninges even after the choroid plexuses are removed). The thin-walled vessels of the plexuses allow passive diffusion of substances from the blood plasma into the extracellular space surrounding choroid cells. The choroidal epithelial cells, like other secretory epithelia, contain organelles, indicating their capacity for an energy-dependent secretory function, that is, active transport. The blood vessels in the subependymal regions and the pia also contribute to the CSF, and some substances enter the CSF as readily from the meninges as from the choroid plexuses. Thus, electrolytes and glucose equilibrate with the CSF at all points in the ventricular and subarachnoid spaces. The transport of sodium, the main cation of the CSF, is accomplished by the action of a sodium-potassium-ion exchange pump at the apical surface of the choroid


Neurology_Adams

Neurology_Adams. ventricular and subarachnoid spaces. The transport of sodium, the main cation of the CSF, is accomplished by the action of a sodium-potassium-ion exchange pump at the apical surface of the choroid plexus cells, the energy for which is supplied by adenosine triphosphate (ATP); drugs that inhibit the ATP system therefore reduce CSF formation (Cutler and Spertell). Electrolytes enter the ventricles somewhat more readily than they enter the subarachnoid space (water does the opposite). It is also known that the penetration of certain drugs and metabolites into the CSF (and brain) is in direct relation to their lipid solubility. Ionized compounds, such as hexoses and amino acids, being relatively insoluble in lipids, enter the CSF slowly unless facilitated by a membrane transport system. This type of facilitated (carrier) diffusion is stereospecific; that is, the carrier (a specific protein or proteolipid) binds only with a solute having a specific configuration, and conducts it across the


Neurology_Adams

Neurology_Adams. of facilitated (carrier) diffusion is stereospecific; that is, the carrier (a specific protein or proteolipid) binds only with a solute having a specific configuration, and conducts it across the membrane, where it is released into the CSF, and intercellular fluid.


Neurology_Adams

Neurology_Adams. Passive diffusion gradients appear to determine the entry of serum electrolytes and some small proteins into the CSF, and also the exchanges of CO2. Water and sodium diffuse as readily from blood to CSF and intercellular spaces as in the reverse direction. This explains the rapid effects on CSF sodium and water of intravenously injected hypotonic and hypertonic fluids.


Neurology_Adams

Neurology_Adams. Studies using radioisotopic tracer techniques confirm that the main constituents of the CSF (see Table 2-2) are in dynamic equilibrium with the blood. Similarly, CSF in the ventricles and subarachnoid spaces is in equilibrium with the intercellular fluid of the brain, spinal cord, and olfactory and optic nerves. Certain structures and physiologic mechanisms that maintain this equilibrium are subsumed under the term blood–brain barrier, which is used to designate all of the interfaces between blood, brain, spinal cord and CSF. The site of the barrier varies for the different plasma constituents. One is the endothelium of the choroidal and brain capillaries; another is the plasma membrane and adventitia (Rouget cells) of these vessels; a third is the pericapillary foot processes of astrocytes. Large molecules, such as albumin, are prevented from entry by the capillary endothelium, and this is the barrier also for such molecules as are bound to album in, for example, aniline dyes (trypan


Neurology_Adams

Neurology_Adams. Large molecules, such as albumin, are prevented from entry by the capillary endothelium, and this is the barrier also for such molecules as are bound to album in, for example, aniline dyes (trypan blue), bilirubin, and many drugs. Other smaller molecules are blocked from entering the brain by active mechanisms at the capillary plasma membrane or astrocytes.


Neurology_Adams

Neurology_Adams. The substances formed in the nervous system during its metabolic activity diffuse rapidly into the CSF. Thus, the CSF has, as mentioned, a “sink action,” to use Davson’s term, by which the products of brain metabolism are removed into the bloodstream as CSF is absorbed.


Neurology_Adams

Neurology_Adams. Harvey Cushing aptly termed the CSF the “third circulation,” comparable to that of blood and lymph. From its principal site of formation in the choroid plexus of the lateral ventricles, CSF flows downward sequentially through the third ventricle, aqueduct, fourth ventricle, and foramina of Magendie (medially) and Luschka (laterally) at the base of the medulla, to the perimedullary and perispinal subarachnoid spaces, thence around the brainstem and rostrally to the basal and ambient cisterns, through the tentorial aperture, and finally to the lateral and superior surfaces of the cerebral hemispheres, where most of it is absorbed (Fig. 29-1). The pressure in the CSF compartment is highest in the ventricles and diminishes successively along the subarachnoid pathways. Arterial pulsations of the choroid plexuses help drive the fluid centrifugally from the ventricular system.


Neurology_Adams

Neurology_Adams. The spinal fluid is in contact everywhere with the extracellular fluid of the brain and spinal cord, but the extent of bulk flow of the CSF through the brain parenchyma is small under normal conditions. The periventricular tissue offer considerable resistance to the entrance of CSF and, although the pressure difference between the ventricles and the subarachnoid spaces over the convexity of the hemispheres (transmantle pressure) is above zero, the open ventricular–foraminal–subarachnoid pathway directs the bulk of CSF flow in this direction. Only if this conduit is obstructed does the transmantle pressure rise, compressing the periventricular tissues and leading to ventricular enlargement, that is, hydrocephalus, and to transependymal flow of CSF.


Neurology_Adams

Neurology_Adams. Absorption of CSF is mainly through the arachnoid villi. These are microscopic excrescences of arachnoid membrane that penetrate the dura and protrude into the superior sagittal sinus and other venous structures. Multiple villi are aggregated in these locations to form the pacchionian granulations or bodies, some of them large enough to indent the inner table of the calvarium. These may increase in size with aging, and large ones (3.0 to 9.5 mm in diameter) may rarely herniate through bony defects and erode the skull, providing a portal of entry to organisms from the ear that lead to meningitis (Samuels et al).


Neurology_Adams

Neurology_Adams. The arachnoid villi, most numerous on both sides of the superior sagittal sinus, are also present at the base of the brain and around the spinal cord roots and have been thought to act as functional valves that permit unidirectional bulk flow of CSF into the vascular lumen. However, electron microscope studies show that the arachnoid villi have a continuous membranous covering. This layer is extremely thin, and CSF passes through the villi at a linearly increasing rate as CSF pressures rise above 68 mm H2O. This passive route is not the only manner in which CSF water and other contents are transported. Tripathi and Tripathi, in serial electron micrographs, found that the mesothelial cells of the arachnoid villus continually form giant cytoplasmic vacuoles that are capable of transcellular bulk transport. Certain substances, such as penicillin and organic acids and bases, are also absorbed by cells of the choroid plexus; the bidirectional action of these cells resembles that of the


Neurology_Adams

Neurology_Adams. bulk transport. Certain substances, such as penicillin and organic acids and bases, are also absorbed by cells of the choroid plexus; the bidirectional action of these cells resembles that of the tubule cells of the kidneys. Some substances have also been shown to pass between the ependymal cells of the ventricles and to enter subependymal capillaries and venules.


Neurology_Adams

Neurology_Adams. By infusing and withdrawing CSF under controlled circumstances, the resistance to CSF absorption and its rate of replacement can be calculated. The resistance to the passage of CSF into the venous system has been termed R0 and can be expressed in terms similar to the Ohm law (E = IR): the voltage (E) reflects the difference in pressure between the CSF and the venous system (PCSF – PV), which drives CSF into the dural sinuses, and the equivalent of electrical current, termed If, represents the flow rate of CSF. In the steady state, this flow rate is equal to the rate of CSF production (0.3 mL/min). R0, the resistance to absorption, which under normal circumstances is approximately 2.5, rises when there is a blockage in the CSF circulation. The equation for CSF pressure can therefore be expressed as PCSF – PV = If × R0; when rearranged, PCSF = PV + If × R0. Because the product of If × R0 is only 0.8 mm Hg, it can be appreciated that the main contribution to CSF pressure—as measured by


Neurology_Adams

Neurology_Adams. as PCSF – PV = If × R0; when rearranged, PCSF = PV + If × R0. Because the product of If × R0 is only 0.8 mm Hg, it can be appreciated that the main contribution to CSF pressure—as measured by spinal puncture—is the venous pressure, PV. Restated, the intracranial pressure and CSF pressure, which are in equilibrium, are the result predominantly of vascular pressures and not CSF outflow resistance. However, in pathologic conditions such as bacterial meningitis and subarachnoid hemorrhage, R0 may rise to levels that impede CSF circulation, raise pressure.


Neurology_Adams

Neurology_Adams. In the recumbent position, ICP and, consequently, CSF pressure are normally about 8 mm Hg or 110 mm H2O (1 mm Hg equals 13.7 mm H2O), with an upper limit of normal that is higher in children than in adults according to Huh and colleagues. As the head and trunk are progressively elevated, the weight of the column of CSF is added incrementally to the pressure in the lumbar subarachnoid space, and the intracranial CSF pressure drops correspondingly, so that it is close to zero in the standing position. As described above, the CSF pressure is in equilibrium with the capillary and prevenous vascular pressures, which are influenced mainly by circulatory changes that alter arteriolar tone. Elevations in systemic arterial pressure cause little or no increase of pressure at the capillary level because of cerebrovascular autoregulation, and hence, little increase in CSF pressure. Extremely low blood pressure (BP), in the range of a mean of 40 mm Hg, however, cannot be compensated for and