Brainstem Lesions in Autism:


Birth Asphyxia and Ischemia as Causative Factors



Nicole Simon, RN, PhD and George M. Morley, M.B., Ch. B., FACOG



Poster Presentation at the International Meeting for Autism Research


(IMFAR) November 1, 2002


Brainstem Lesions in Autism: Birth Asphyxia and Ischemia as Causative Factors


Nicole Simon and George M. Morley




   Immediate clamping of the umbilical cord at birth has become a standard procedure during the past two decades.  This merits investigation as the cause of increased incidence of autism.  Clamping of the umbilical cord before the lungs function induces a period of total asphyxia and produces severe hypovolemia by preventing placental transfusion - a 30% to 50% loss of blood volume - resulting in a hypoxic, ischemic neonate at risk for brain damage.

   As in circulatory arrest and other factors that disrupt aerobic metabolism, damage of brainstem nuclei and the cerebellum can result. Visible damage seen in some cases of autism also involves brainstem nuclei and the cerebellum.  The brainstem auditory pathway is especially vulnerable to brief total asphyxia.  Impairment of the auditory system can be linked to verbal auditory agnosia, which underlies the language disorder in some children with autism.

   Due to blood loss into the placenta, the immediately clamped neonate is very prone to develop infant anemia that has been widely correlated with mental deficiency and learning / behavior disorders that become evident in grade school.

   We propose that increased incidence of autism, infant anemia, childhood mental disorders and hypoxic ischemic brain damage, all originate at birth from one cause - immediate umbilical cord clamping.  This deserves to be investigated as extensively as genetics or exposure to toxic substances as an etiological factor for autism.  Normal cord closure, with placental oxygenation and transfusion, prevents asphyxia and ischemia.  Allowing physiological cord closure at every delivery could at least reduce the incidence of birth brain injuries.




umbilical cord clamping, placental transfusion, oxygen, aerobic, lungs, birth, asphyxia, brain damage, brainstem, cerebellum, verbal auditory agnosia, infant anemia, etiology, incidence, autism





1 – Language development and the auditory system

a) Inability to recognize syllable and word boundaries in rapid streams of speech has been identified as a problem in some children with autism [1, 2].  This handicap known as "verbal auditory agnosia" implies dysfunction within the auditory system.

b) The brainstem auditory system is myelinated and functional by 29 gestational weeks in the human fetus [3, 4, 5].  See FIGURE 1.

c) The language areas of the temporal and frontal lobes of the cerebral cortex are not myelinated or fully functional until a child is three or four years of age [4].  See FIGURE 2.

d) Language learning therefore begins before full maturation of cortical language areas.

e) Normal children recognize stressed syllables as a prominent feature of speech around them, which leads to a predictable first stage of language learning known as "telegraphic speech" [6, 7].


2 – Maturation and injury of brainstem auditory nuclei

a) Neurotrophic transmitters are produced within brainstem auditory nuclei; these are thought to guide maturation of the frontal and temporal lobes of the cerebral cortex [8, 9].  Impairment of brainstem systems will prevent normal development of higher cognitive centers.

b) FIGURE 3 is a diagram of the auditory system. The auditory pathway in the brainstem is much more than a simple transmission cable.  The nuclei along the way each perform important transformations on acoustic signals from the ears to their interpretation as language in the temporal lobes. [10, 11].

c) Injury of the inferior colliculus in the midbrain auditory pathway has been   reported in three cases to cause "word deafness" (inability to comprehend spoken language) in previously normal adults [12, 13, 14].

d) Impairment within the auditory system is worth considering as the locus of verbal auditory agnosia in children with autism.


3 – Vulnerability of brainstem auditory nuclei

a) The highest rates of blood flow and aerobic metabolism within the brain have been found in nuclei of the auditory system [15, 16, 17].  See FIGURE 4 and TABLES 1 and 2.

b) The auditory system is especially vulnerable to any lapse in aerobic metabolism [18-27].

c) The inferior colliculus has the highest rates of blood flow and aerobic metabolism of any structure of the brain [15-17, 28, 29].

d) The inferior colliculus is selectively damaged by a few minutes of total asphyxia at birth in newborn monkeys [30, 31].  See FIGURES 5 and 6.

e) Inferior colliculus damage has been found in the brains of human infants who died in the neonatal period [32-38].  See FIGURE 7.

f) Inferior colliculus damage occurs in adult monkeys subjected to several minutes of total asphyxia, as in the case of newborn monkeys [39].


4 – Effects of impaired aerobic metabolism

a) Myers [31] noted a "rank order" of brainstem nuclei damaged by an episode of total asphyxia.

b) Most prominent visible brain abnormalities reported in cases of autism have involved brainstem nuclei and the cerebellum [40-47].

c) Involvement of brainstem nuclei and the cerebellum is characteristic of damage caused by circulatory arrest and other factors that disrupt aerobic metabolism [21, 22, 39, 48, 49, 50].

d) Symmetric bilateral damage of brainstem nuclei, in which the cortex is largely spared, is known as Wernicke's encephalopathy [51, 52, 53].




5 – Immediate clamping of the umbilical cord and asphyxia at birth

a) Immediate clamping of the umbilical cord (before the infant has breathed) has become a common practice over the past 20 years [54].

b) Immediate clamping of the cord induces a period of asphyxia until the lungs begin to function, and the inferior colliculi are therefore a prime target for damage until pulmonary oxygenation is established.

c) Immediate clamping of the umbilical cord and preventing oxygenation of the lungs were part of the experimental procedures used by both Windle and Myers in their investigations of brain damage caused by asphyxia in newborn monkeys [30, 31].

d) Myers [31] described a marked and rapid loss of blood pressure during the period of asphyxia; likewise, immediate clamping of the umbilical cord leaves the newborn human infant very hypovolemic and hypotensive due to lack of placental transfusion.[55, 56].


6 – Recovery without cord clamping

a) Myers [31] induced prenatal partial asphyxia in some monkey fetuses, which, followed by birth asphyxia (immediate clamping of the cord) produced lesions typical of hypoxic ischemic encephalopathy (HIE) and spastic cerebral palsy (CP).

b) Quite remarkably in Myers' experiments, prenatal asphyxia to the point of severe depression handled by resuscitation without cord clamping resulted in full recovery of the neonate and no brain damage.

c) Following fetal distress, immediate cord clamping is routine in the resuscitation of human neonates.  Resuscitation with placental circulation and oxygenation intact (no cord clamping) should prevent HIE and CP; It should also prevent damage to the inferior colliculus and thus prevent autism. [55].




7 – Consequences of so-called "minor" brainstem impairment

a) Monkeys subjected to a few minutes of total asphyxia initially displayed "hypotonic" cerebral palsy.  These monkeys were considered to have "minor" brainstem damage and with time recovered normal muscle tone and strength.  But persistent memory and attention deficits remained.  See FIGURE 8.

b) The resultant behavioral dysfunction was likened to the syndrome of minimal brain dysfunction (MBD), which would now be referred to as attention deficit disorder or perhaps even pervasive developmental disorder (PDD) [57].  Autistic disorder was not mentioned.  (If autism is principally a language disorder, a precise animal model is not possible.)

c) Asphyxia at birth consistently damaged the auditory pathway while sparing the cerebral cortex.  Behavior changes in cats with lesions of the lateral lemniscal tracts had been described as similar to those of children with autism [58]; loss of environmental awareness in monkeys follows ablation of parts of the inferior and superior colliculi [59, 60].


8 – Language delay, Moebius syndrome, and Wernicke's encephalopathy

a) Gilles [48], in 1963, was first to suggest that damage of the inferior colliculi might lead to developmental language delay, such as that (Gilles suggested) observed in ocular-facial diplegia (Moebius) syndrome [61].

b) Population studies have revealed a high frequency of autistic behaviors in children with Moebius syndrome, and suggest that there may be a common site of dysfunction within the brainstem [62, 63].

c) The brainstem pattern of damage caused by asphyxia at birth is a variant of Wernicke's encephalopathy.  Facial and oculomotor nuclei are involved in this pattern of pathology [64].  Lack of facial expression and diminished oculomotor activity in children with autism suggests a similar kind of brainstem impairment.




9 – Protective mechanisms and the "rank order" of brainstem lesions

a) Impairment of aerobic metabolism results in vasodilation and increased blood flow to the inferior colliculi and other brainstem nuclei of high metabolic rate.

b) Increased blood flow under adverse conditions is one result of protective mechanisms that go into action to help preserve function in the metabolically most active components of the brain, leaving less active areas of the brain more vulnerable.

c) Preservation of function in the inferior colliculi will first lead to compromise and damage of slightly less active brain nuclei such as the mammillary bodies.  See TABLE 2.

d) The mammillary bodies are the most prominently affected nuclei in Wernicke's encephalopathy caused by alcohol intoxication [53].

e) Total asphyxia damages the inferior colliculi first [65, 66].  Lesser degrees of oxygen insufficiency will produce different patterns of involvement of the vulnerable "rank order" of brainstem nuclei.


10 – Protective mechanisms and spectrum of handicaps

a) Protective mechanisms are responsible for the wide variability of brain structures damaged by factors that disrupt aerobic metabolism.

 b) Prolonged hypoxia such as that caused by hypovolemia, infant anemia, or respiratory distress syndrome (RDS) leads to damage of the cerebral cortex as shown by Myers [31].

c) In both adult and fetal monkeys damage of the cerebral cortex was produced by prolonged partial anoxia (or hypoxia).

 d) A spectrum of disorders therefore results in circumstances of impaired aerobic metabolism, from auditory system damage caused by a brief period of total asphyxia to widespread involvement of the cerebral cortex under conditions of prolonged hypoxia and hypo-perfusion.

e) Cerebral palsy and severe autism are immediately apparent.  Asperger syndrome, attention deficit disorder, and learning disabilities often go unnoticed until the child is evaluated in grade school.




11 – The natural shift from placental to pulmonary respiration

a) At normal (physiological) birth, immediately following delivery, precise physiological coordination is required in the switch from placental to pulmonary respiration to ensure an uninterrupted supply of oxygen and blood to the brain. The natural transition occurs without any period of asphyxia, and with a large placental transfusion of oxygenated blood.

b) Initiation of pulmonary respiration requires:

     1 – Aeration of the lungs

     2 – Perfusion of the lungs (as fetal circulation changes to adult circulation)

c) The switch from fetal to adult circulation is effected by:

1.      A massive transfusion of blood from the placenta (a 30% to 50%             increase in blood volume) which fills the pulmonary vessels, and

2.      Reflexive relaxation of pulmonary arterioles following pulmonary aeration.

d) Placental oxygenation continues until pulmonary oxygenation is established, following which the umbilical vessels close reflexively.


12 – Hazards of early clamping of the umbilical cord

a) Most normal term babies appear to survive immediate clamping without overt difficulties, though many are slow to respond and most are pale.

b) Blood volume is reflexively switched to the lungs from other organs to establish the pulmonary circulation.  Even if adequate pulmonary circulation and oxygenation are established, there still is risk of organ (and especially brain) ischemia [67].

c) Ischemia/hypovolemia is most evident in preemies and in neonates that are born already hypovolemic from intrapartum cord compression that engorges the placenta.  In smaller preemies, the placenta and its blood content are disproportionately large.

d) The prevalence of neonatal hypovolemia and hypovolemic shock is mirrored by the frequency of use of blood volume expanders and blood transfusion, and the incidence of anemia in the neonatal intensive care unit (NICU).

e) Respiratory distress syndrome (RDS or shock lung) is the most common diagnosis in the NICU.  Hypoxic-ischemic encephalopathy (HIE), the neuropathology of cerebral palsy [31], is the most litigated.  Both correlate with immediate cord clamping and both should be virtually avoidable by physiological cord closure at birth with full placental transfusion – no cord clamp used.


13 – Long-term consequences of neonatal blood loss and ischemia

a) Perinatologists and neonatologists constantly promote the concept of "placental over-transfusion" harming the neonate, especially the preemie.  Yet a series of babies delivered using physiological cord closure (no cord clamp used) has never been studied and documented.

b) In experiments on asphyxia at birth in monkeys, none of the control animals (delivered naturally without cord clamp) had brain or other lesions.

c) Jaundice was found by a group of Windle's colleagues to discolor only brain areas already compromised by a brief period of asphyxia [68, 30].  See FIGURE 9.

d) Premature infants, who routinely have their cords clamped immediately, almost universally become anemic in the NICU, where the anemia is promptly corrected, sometimes by blood transfusion.  However, despite prompt treatment they have poor mental achievement outcomes through young adulthood [69].

e) Infant anemia has been correlated with childhood attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and learning disorders to the point of moderate mental deficiency that become evident only in grade school [70, 71].

f) At normal birth, no newborn has iron deficiency anemia; adequate iron is supplied from the mother regardless of her iron status.  Any newborn that receives a full placental transfusion at birth has enough iron to prevent anemia during the first year of life. [72] Therefore, full placental transfusion (natural cord closure) should prevent the behavioral disorders and learning disabilities that correlate with infant anemia.


14 – History of immediate cord clamping

ü      Immediate cord clamping saw its origin in the 1950’s when early cord clamping was advocated to reduce neonatal jaundice.

ü      In the late 1970’s, immediate clamping to facilitate resuscitation was demanded.

ü      In the 1990’s ACOG advocated immediate clamping for medico-legal documentation [54].

ü      Despite the procedure being universally condemned in the literature, it is practiced routinely today without a thought of the consequences.

ü      There is no clinical justification for immediate cord clamping:

      1 – Neonatal resuscitation is best achieved by ventilating the lungs with the placental circulation intact [55, 56].

      2 – Cord blood gases are available through a fine needle without disrupting placental function.


15 – Increased incidence of autism and related disorders

a) The increase in incidence of autism has occurred during the period since adoption of immediate cord clamping as a standard procedure.

b) The increase in autism that has occurred over the past 10 to 20 years has also been paralleled by increases in attention deficit hyperactivity disorder (ADD or ADHD), learning disabilities and under-achievement.  All coincide with increased use of immediate cord clamping.

c) From primate studies, it is clear a brief period of asphyxia at birth is extremely pathogenic for the brainstem nuclei.  Thus lack of placental transfusion and placental oxygenation from immediate cord clamping becomes a crucial risk factor in auditory pathway damage.

d) While the time of cord clamping is seldom recorded, a history of birth difficulty that would give rise to immediate clamping is not uncommon in autistic children [75-84].

e) Impairment of brain function by immediate cord clamping at birth deserves investigation as an etiological predisposition for autism that is just as important as research on genetics and/or exposure to toxic substances.




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80. Hultman CM, Sparen P, Cnattingius S (2002) Perinatal risk factors for infantile autism. Epidemiology. 2002 Jul;13(4):417-23.

81. Juul-Dam N, Townsend J, Courchesne E (2001) Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics. 2001 Apr;107(4):E63.

82. Levy S, Zoltak B, Saelens T (1988) A comparison of obstetrical records of autistic and nonautistic referrals for psychoeducational evaluations. J Autism Dev Disord. 1988 Dec;18(4):573-81.

83. Gillberg C, Enerskog I, Johansson SE (1990) Mental retardation in urban children: a population study of reduced optimality in the pre-, peri- and neonatal periods. Dev Med Child Neurol. 1990 Mar;32(3):230-7.

84. Bodier C, Lenoir P, Malvy J, Barthélemy C, Wiss M, Sauvage D. (2001) Autisme et pathologies associées. Étude clinique de 295 cas de troubles envahissants du developpment. Presse Médicale 30(24 Pt 1):1199-203.

Genetic/Metabolic Predispositions for Autism


85. Creak M (1963) Childhood psychosis: A review of 100 cases. British Journal of Psychiatry 109:84-89.

86. Darby JK (1976) Neuropathologic aspects of psychosis in children. Journal of Autism and Childhood Schizophrenia 6:339-352

Tuberous Sclerosis

87. Fisher W, Kerbeshian J, Burd L, Kolstoe P. (1986) Tuberous sclerosis and autism. Developmental Medicine and Child Neurology 28:814-815

88. Bolton PF, Griffiths PD (1997) Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 349(9049):392-395

89. Webb DW, Fryer AE, Osborne JP (1996) Morbidity associated with tuberous sclerosis: a population study. Developmental Medicine and Child Neurology 38:146-55

90. Griffiths PD, Martland TR (1997) Tuberous Sclerosis Complex: the role of neuroradiology. Neuropediatrics 28:244-52

91. Crino PB, Henske EP (1999) New developments in the neurobiology of the tuberous sclerosis complex. Neurology 53:1384-90

92. Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A. (2002) Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125:1247-1255


93. Gaffney GR, Kuperman S, Tsai LY, Minchin S. (1989) Forebrain structure in infantile autism. J Am Acad Child Adolesc Psychiatry. 28:534-537.

94. Gaffney GR, Kuperman S, Tsai LY, Minchin S, Hassanein KM (1987a) Midsagittal magnetic resonance imaging of autism. British Journal of Psychiatry 151:831-3

95. Gaffney GR, Tsai LY, Kuperman S, Minchin S (1987b) Cerebellar structure in autism. American Journal of Diseases of Children 141:1330-2

96. Gillberg C, Coleman M (1996). Autism and medical disorders: a review of the literature.  Developmental Medicine and Child Neurology 38:191-202.


97. Lowe TL, Tanaka K, Seashore MR, Young JG, Cohen DJ (1980). Detection of phenylketonuria in autistic and psychotic children. Journal of the American Medical Association 243:126-128.

98. Williams RS, Hauser S, Purpura DP, deLong GR, Swisher CN (1980) Autism and mental retardation: Neuropathologic studies performed in four retarded persons with autistic behavior.  Archives of Neurology 37:748-753.

99. Chen CH, Hsiao KJ (1989) A Chinese classic phenylketonuria manifested as autism. British Journal of Psychiatry 155:251-3

100. Miladi N, Larnaout A, Kaabachi N, Helayem M, Ben Hamida M (1992) Phenylketonuria: an underlying etiology of autistic syndrome. A case report. Journal of Child Neurology 7:22-23.

101. Leuzzi V, Trasimeni G, Gualdi GF, Antonozzi I (1995) Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients. Journal of Inherited Metabolic Disease 18:624-634.

Fragile X Syndrome

102. Brown WT, Jenkins EC, Friedman E, Brooks J, Wisniewski K, Raguthu S, French J. (1982) Autism is associated with the fragile-X syndrome. Journal of Autism and Developmental Disorders. 12:303-8.

103. Folstein SE, Rutter ML (1988) Autism: familial aggregation and genetic implications. Journal of  Autism and Developmental Disorders. 18:3-30.

Seizure Disorder

104. Chugani HT, Da Silva E, Chugani DC (1996) Infantile spasms: III. Prognostic implications of bitemporal hypometabolism on positron emission tomography. Annals Of Neurology 39:643-649.

105. daSilva EA, Chugani DC, Muzik O, Chugani HT (1997) Landau-Kleffner syndrome: metabolic abnormalities in temporal lobe are a common feature. Journal of Child Neurology 12:489-495.

Leber's Congenital Amaurosis

106. Rogers SJ, Newhart-Larson S (1989) Characteristics of infantile autism in five children with Leber's congenital amaurosis. Developmental Medicine and Child Neurology 31:598-608

107. Malamud N (1959) Heller's disease and childhood schizophrenia.  American Journal of Psychiatry 116:215-218.

Adenylosuccinate Lyase Defect

108. Jaeken J, Van den Berghe G. (1984) An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids. Lancet. Nov 10;2(8411):1058-61.

109. Jaeken J, Wadman SK, Duran M, van Sprang FJ, Beemer FA, Holl RA, Theunissen PM, de Cock P, van den Bergh F, Vincent MF, et al. (1988) Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis. European Journal of Pediatrics. 148:126-31.

110. Barshop BA, Alberts AS, Gruber HE. (1989) Kinetic studies of mutant human adenylosuccinase. Biochimica et Biophysica Acta. 999:19-23.

111. Van den Berghe G, Vincent MF, Jaeken J. (1997) Inborn errors of the purine nucleotide cycle: adenylosuccinase deficiency.  Journal of Inherited Metabolic Disease. 20:193-202.

Lactic Acidosis

112. Coleman M, Blass JP (1985) Autism and lactic acidosis.  Journal of Autism and Developmental Disorders 15 1-8.

113. Philippart M (1986) Clinical recognition of Rett syndrome. American Journal of Medical Genetics Supplement 1:111-8

114. Lombard J (1998) Autism: a mitochondrial disorder? Medical Hypotheses 50:497-500.

Krebs Cycle (aerobic metabolism) Defects

115. Shaw W, Kassen E, Chaves E (1995) Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features.  Clinical Chemistry 41:1094-1194.

Intestinal Inflammation

116. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet Feb 28;351(9103):637-41

Mitochondrial Disorders

117. Fillano JJ, Goldenthal MJ, Rhodes CH, Marin-Garcia J (2002) Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome. J Child Neurol. 2002 Jun;17(6):435-9.

118. Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA,Courchesne E, Haas RH (2000) Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. J Child Neurol. 2000 Jun;15(6):357-61.

Prenatal Exposure to Drugs

119. Nanson JL (1992) Autism in fetal alcohol syndrome: a report of six cases. Alcoholism, Clinical and Experimental Research 16:558-565.

120. Harris SR, MacKay LL, Osborn JA (1995) Autistic behaviors in offspring of mothers abusing alcohol and other drugs: a series of case reports. Alcoholism, Clinical and Experimental Research 19:660-5

121. Aronson M, Hagberg B, Gillberg C (1997) Attention deficits and autistic spectrum problems in children exposed to alcohol during gestation: a follow-up study. Developmental Medicine and Child Neurology 39:583-7

122. Church MW, Eldis F, Blakley BW, Bawle EV (1997) Hearing, language, speech, vestibular, and dentofacial disorders in fetal alcohol syndrome. Alcoholism, Clinical and Experimental Research 21:227-237.

123. Christianson AL, Chesler N, and Kromberg JGR (1994) Fetal valproate syndrome:  clinical and neuro-developmental features in two sibling pairs.  Developmental Medicine and Child Neurology 36:357-369.

124. Williams PG & Hersh JH (1997) A male with fetal valproate syndrome and autism. Developmental Medicine and Child Neurology 39:632-634.

125. Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. (2001) Fetal valproate syndrome and autism: additional evidence of an association. Developmental Medicine and Child Neurology 43:202-206.

126. Stromland K, Nordin V, Miller M, Akerstrom B, and Gillberg C (1994) Autism in thalidomide embryopathy:  a population study.  Developmental Medicine and Child Neurology 36:351-356.

Infectious Encephalitis

127. Desmond MM, Montgomery JR, Melnick JL, Cochran GG, Verniaud W (1969) Congenital rubella encephalitis. Effects on growth and early development. American Journal of Diseases of Children 118:30-31.

128. Chess S (1971) Autism in children with congenital rubella.  Journal of Autism and Childhood Schizophrenia 1:33-47.

129. Chess S, Fernandez P, Korn S. (1978) Behavioral consequences of congenital rubella. Journal of Pediatrics. 93:699-703.

130. Townsend JJ et al. (1975) Progressive rubella panencephalistis: Late onset after congenital rubella. New England Journal of Medicine 292:990.

131. Weil et al. (1975) Chronic progressive panencephalitis due to rubella virus simulating subacute sclerosing panencephalitis.  New England Journal of Medicine 292:994

132. deLong GR, Bean SC, Brown FR (1981) Acquired reversible autistic syndrome in acute encephalopathic illness in children. Archives of Neurology 38:191-194

133. Gillberg C (1986) Brief report: onset at age 14 of a typical autistic syndrome.  A case report of a girl with herpes simplex encephalitis.  Journal of Autism and Developmental Disorders 16: 369-375.

134. Gillberg IC (1991) Autistic syndrome with onset at age 31 years: herpes encephalitis as a possible model for childhood autism. Developmental Medicine and Child Neurology 33:920-4

135. Ghaziuddin M, Tsai LY, Eilers L, Ghaziuddin N. (1992) Brief report: autism and herpes simplex encephalitis. Journal of Autism and Developmental Disorders. 22:107-13.

136. Greer MK, Lyons-Crews M, Mauldin LB, Brown FR 3rd. (1989) A case study of the cognitive and behavioral deficits of temporal lobe damage in herpes simplex encephalitis.  Journal of Autism and Developmental Disorders 19:317-26.

137. Domachowske JB, Cunningham CK, Cummings DL, Crosley CJ, Hannan WP, Weiner LB (1996) Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children. Pediatric Infectious Disease Journal 15:871-5

138. Thivierge J. (1986) A case of acquired aphasia in a child. Journal of Autism and Developmental Disorders. 16:507-12.

139. Barak Y, Kimhi R, Stein D, Gutman J, Weizman A (1999) Autistic subjects with comorbid epilepsy: a possible association with viral infections. Child Psychiatry and Human Development 1999 Spring;29(3):245-51

Irrelevant and Metaphorical Language

140. Kanner L (1946) Irrelevant and metaphorical language of early infantile autism.  American Journal of Psychiatry 103:242-246.

Kanner's Original Description

141. Kanner L (1943) Autistic disturbances of affective contact.  Nervous Child 2:217-250.


NOTE 1:  Echolalia versus Early Telegraphic Speech


a) Speech productions of an autistic child at best consist of phrase fragments used badly out of context (echolalia); this is the "irrelevant and metaphorical language" described by Kanner (1946) [140].  No re-wording to fit new contexts is involved.  "Pronoun reversal" is part of the failure to re-word, as is frequent use of the prosodic intonation for a question.  Examples:

"You don't want to go swimming?"

"You want an apple?"

"Is that yours?"

b) Young children normally recognize stressed syllables as a prominent feature of speech around them.  This leads to a predictable first stage of language development known as "telegraphic speech" [6, 7].


c) Telegraphic speech includes use of elemental units of meaning rearranged to fit new contexts.  Examples:

"Don't want go swim."

"Apple, I want."

"That mine."

d) Use of telegraphic units facilitates re-wording and comprehension of grammatical structures.

e) Reliance on echolalic sound bytes impedes recognition of basic units of meaning or grammatical structures.

f) Inability to recognize syllable and word boundaries in rapid streams of speech (verbal auditory agnosia) has been identified as a problem in some children with autism.  Thus the first stage of telegraphic speech based on stressed syllables is missed.


NOTE 2:  Injury of the Inferior Colliculi in "Word Deafness"

The cases described by Meyer et al. (1996), Johkura et al. (1998), and Masuda et al. (2000) all had circumscribed lesions of both inferior colliculi [12, 13, 14].  All lost comprehension of spoken language.  All represent cases of acquired "verbal auditory agnosia."  Analysis of acoustic signals within brainstem nuclei like the inferior colliculus is important for speech understanding.



NOTE 3:  Trophic Factors Control Maturation of the Cerebral Cortex

a) Von Hungen et al. (1975) found serotonin sensitive post-synaptic receptors in the inferior and superior colliculi that declined with maturation in laboratory rats, and concluded that these receptors may be important in establishment of developing synapses.

b) Kungel and Friauf (1995) found neuro-peptides that appear in the auditory pathway then decline during early development of laboratory rats.  They proposed that these peptides are important in promoting synaptic connections and serve a developmental role.

c) Development of the frontal, temporal, and parietal lobes as well as subcortical structures like the amygdala and hippocampus takes place after maturation of brainstem systems, and the auditory system in particular.  Many more neurotrophic transmitters will surely be found that guide development of higher cortical centers of the cortex.



NOTE 4:  Vulnerability of the Auditory System

a) The auditory system is susceptible to early decline with aging.  Loss of aerobic enzyme activity and neurotransmitters is especially evident in the most metabolically active inferior colliculi (Gonzalez-Lima et al. 1997 [18], Caspary et al. 1995 [19], Sinha 1993 [23]).

b) Toxic substances such as mercury, lead, methyl bromide, and alpha-chlorohydrin are especially injurious to nuclei in the brainstem auditory pathway.  The high rate of blood flow to auditory structures exposes them to greater amounts of circulating toxins (Oyanagi et al. 1989 [25], Bertoni & Sprenkle 1989 [26], Cavanagh 1992 [20], Cavanagh & Nolan 193 [21]).

c) Defects of aerobic enzymes in mitochondrial disorders like Leigh's syndrome cause loss of function and damage in auditory nuclei (Cavanagh & Harding 1994 [20], Lombes et al. 1991 [24]).  Autistic disorder has been reported in cases of mitochondrial disorder (Fillano et al 2002 [117], Graf et al. 2000 [118])

d) Mirsky et al. (1979) demonstrated abnormal auditory evoked potentials in monkeys asphyxiated at birth with known damage in the inferior colliculi [27].  The measured abnormalities of auditory evoked potentials were similar to those found in children with autism.


NOTE 5:  Variants of Wernicke's encephalopathy

a) The symmetric bilateral lesions of brainstem nuclei caused by asphyxia at birth and toxic substances are variants of Wernicke's encephalopathy.


b) Brody & Wilkins (1968) provided a translation of the original article by Wernicke (1881) describing bilaterally symmetric brainstem lesions following sulfurinc acid ingestion in one case and alcohol intoxication in two others [51, 73].


c) Neubuerger (1954) described Wernicke-like lesions in a patient who succumbed one week following resuscitation from cardiac arrest [50].  Educated in Germany, Neubuerger was familiar with this pattern of damage confined to the brainstem.


d) Neubuerger (1937) described Wernicke's encephalopathy in three non-alcoholic elderly patients with atrophy of the lining of the stomach and suggested "auto‑intoxication" by products of putrefaction as the cause [74].


e) Many believe that autism associated with intestinal disorders may also involve auto-intoxicants that affect the brain


f) Thiamine (vitamin B1) deficiency causes Wernicke's encephalopathy.  See Vortmeyer et al., 1992 [65].  FIGURE 10 shows damage of the inferior colliculus in a patient with severe thiamine deficiency.


g) Thiamine is an essential cofactor for aerobic enzymes, found in greatest concentration in the inferior colliculi.  See Calingasan et al., 1994 [29].


h) Alcoholism causes intestinal damage and failure to absorb thiamine, which adds to the toxic effects of alcohol on the brain by further impairing aerobic metabolism.



NOTE 6:  Medical Conditions with Associated Autistic Disorder


a) TABLE 3 lists several medical conditions in which autistic behaviors are observed.  These include genetic/metabolic disorders, prenatal exposure to alcohol and other drugs, and infections [85-139].


b) The variety of obstetric complications associated with autism is almost as numerous as the other medical conditions.  Juul-Dam et al (2001) remarked, "The specific complications that carried the highest risk of autism and PDD-NOS represented various forms of pathologic processes with no presently apparent unifying feature" [81].


c) One unifying feature of autism caused by obstetric complications or other medical conditions is the vulnerability of brainstem nuclei of high metabolic rate, especially nuclei like the inferior colliculi in the auditory pathway.

NOTE 7:   From Windle (1969)



"The role of asphyxia neonatorum in brain damage has been debated for more than a century…


…retrospective clinical studies can never logically answer the question of whether asphyxia at birth causes brain damage resulting in cerebral palsy and mental retardation or whether other factors causing cerebral palsy and mental retardation also induce asphyxia.


The answer can be found only by experiment."




"Spontaneous neurological deficits are practically unknown among rhesus monkeys born in their natural habitat…


The female squats and drops the infant on the ground.  During delivery most of the blood in the placenta passes to the infant."




"Human infants are born in much the same way in many parts of the world…


In the squatting position, and the infant being below her, recovers most of the blood from the vessels of the placenta and the umbilical cord.


The squatting position has other advantages…  It avoids compression of the blood vessels supplying the placenta."




"In any delivery it is important to keep the umbilical cord intact until the placenta has been delivered.


To clamp the cord immediately is equivalent to subjecting the infant to a massive hemorrhage, because almost a fourth of the fetal blood in in the placental circuit at birth."

From Windle (1969)



"…there was loss of nerve cells in the thalamus and the inferior colliculus of the midbrain … and in some other groups of cells in the brain stem.


Symmetrical lesions were produced on both sides of the brain…




"It is no longer acceptable to assume that the human fetus or newborn infant is so resistant to oxygen deficiency that it will escape harm from a short exposure to asphyxia neonatorum.


If the infant's brain can be compared to the monkey's, asphyxia of such duration that resuscitation was required will certainly have damaged it.


What effect such minimal brain damage will have as the child matures is not known."




"The briefly asphyxiated infant monkeys with minimal brain damage lost their signs of neurological deficit…  The extent of this 'recovery' was surprising.


The adjustment to handicaps began to be evident during the first month.


The residual deficits of the surviving animals are now inadequate manual dexterity…"




"It is commonly recognized that improvement can be expected after a distressful birth…


We know that the brain of a 'recovered' monkey is structurally damaged, whereas we only assume on clinical grounds that the brain of a 'recovered' human infant is normal."


NOTE 8:  Myers' Rank-Order of "Minor" Brainstem Damage


a) Newborn monkeys subjected to a few minutes of total asphyxia, produced by clamping of the umbilical cord and preventing aeration of the lungs were found to have damage restricted to the brainstem, without involvement of the immature cerebral cortex.


b) Brainstem lesions were considered to represent a "minor" pattern of damage, perhaps responsible for the so-called syndrome of "minimal brain dysfunction" (MBD).


c) Myers' commented," The brain centers earliest damaged are the inferior colliculi (illustrated here in FIGURE 6).  Thereafter, in a monotonously repetitive rank order, follow other brainstem structures including:

The superior olives (auditory)

Sensory nuclei of the trigeminal nerve (facial)

Gracile and cuneate nuclei (lower & upper body sensory)

Medial and spinal vestibular nuclei

Posterior and lateral ventral thalamic nuclei."


            d) The "minor" brainstem pattern of damage was associated with early developmental hypotonia of the muscles (FIGURE 9) and long-term impairments of memory and attention.  Parents and teachers do not regard such problems as minor.



NOTE 9:  ACOG Committee Opinion Number 138


ACOG Committee Opinion Number 138 - April 1994, published in the International Journal of Gynaecology and Obstetrics 45:303-304 [54], reaffirmed 2000, and listed as current in OBSTETRICS & GYNECOLOGY, February 2002, under the heading "TECHNIQUE", states:


 "Immediately after delivery of the neonate, a segment of umbilical cord should be doubly clamped, divided, and placed on the delivery table pending assignment of the 5-minute Apgar score."



NOTE 10:  The Core Syndrome of Kanner Autism


a) Kanner (1943) [141] described children who did not display physical stigmata.


b) Children with autism associated with medical disorders such as tuberous sclerosis, fragile X syndrome, prenatal exposure to alcohol, other drugs, or infections display signs of disrupted physical development.


c) Children with the core syndrome of Kanner autism are physically perfect and often exceptionally handsome.  These are not children malformed in utero by chromosomal deletions.  They are children who suffered brain damage at the time of birth or in the first few postnatal months or years.


d) The recent increase in incidence of autism cannot be attributed to genetic causes, but to some injurious factor in the environment.


e) There is an urgent need to uncover the environmental causes of autism.  These may include vaccines and problems at birth, or a combination of both.


f)  Obstetrical standards of care must be critically examined as part of the effort to reverse the current increase in numbers of children with autism and other developmental problems.


NOTE 11:  Forgetting May Be A Matter of Birth Injury


MIAMI, Oct 27 (Reuters Health)

Many children who experienced oxygen deprivation at birth are being told by their teachers that they are not paying attention and by their parents that they forgot to do what they told them to do.

They may also grow up and be unable told hold a job, Dr. Faranch Vargha-Khadem, of the University College London Medical School, told session attendees at the annual meeting of the Society of Neuroscience meeting in Miami.  Dr. Vargha-Khadem said that the basis of the problem may be a particular kind of developmental amnesia that is a result of damage to the hippocampus due to oxygen deprivation at birth. Damage to the hippocampus affects short-term memory, she said.  To date, Dr. Vargha-Khadem's group has evaluated 19 of these children, and demonstrated that their hippocampi are only 40% to 60% of normal size bilaterally. "In contrast, we found no obvious abnormalities in surrounding areas that are known to be important for long-term memory."  She said that to help these children learn, schools will have to have computers that contain knowledge accessible in several different ways.

In a related report on the effects of early brain injury on development, Dr. Jocelyn Bachevalier of the University of Texas Science Center in Houston found that lesions of the temporal lobe in young rats caused them to develop social behaviors similar to those seen in autistic children.  She said that the temporal lobe is very important for the formation of memory and less important for other types of learning .  Young animals with lesions to this part of the brain had memory problems early on, and also exhibited a lack of social interaction with others. "These findings are significant because these are like syndromes we see in children with autism..." who have severe social interaction and memory problems.

In another report, Dr. Bryan Kolb, of the University of Lethbridge in Alberta, Canada, found that the timing of brain damage in infancy was critical.  He injured the cortex of young rats, with resulting lesions in the frontal lobes, and observed that "...the age at injury correlated with outcome." A rat with a lesion in the cortex during the first days of life had a "...miserable outcome, with normal behavior severely disrupted."  Dr. Kolb also found the animals unusually sensitive to their environments, which suggested to the investigator that the animals responded to behavioral therapies such as environmental stimulation.

Dr. Morton Mishkin of the National Institute of Mental Health commented that much remains to be learned about brain damage that occurs early versus late in life, and that some of the previous theories about how the young brain can recover faster may be dispelled by studies such as these.