Viewpoint on the Brain Disorder in Autism

  (based on a review of research papers in the medical literature)

Viewpoint on the brain disorder(2003) (View in 2000)

The auditory system The inferior colliculus Hemoglobin & the brain

Concepts of autism Autism spectrum Social responsibility

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Date posted:  January 20, 2023 06:44 PM
© Copyright 2003
Eileen Nicole Simon
Introduction | I. Brain damage at birth | II. Auditory system | III. Language
IV.  Childhood handicaps | V. Brainstem Damage | VI.  References | Summaries 		  Scroll/Print Version

Topics (section links):

Introduction

I. BRAIN DAMAGE AT BIRTH
1 - Asphyxia at Birth
2 - Hypoxic Birth
3 - Asphyxia Versus Hypoxia
4 - Human Conditions
5 - Stages of Asphyxia
6 - The Umbilical Cord Lifeline
7 - Developmental Delay
8 - Poor Manual Dexterity
9 - Progressive Degeneration
10 - Autism and Complications at Birth
11 - Mercury, and Other Toxic Factors

II. THE AUDITORY SYSTEM
12 - Metabolic Rank Order
13 - The Auditory System
14 - Auditory Dysfunction

III. LANGUAGE
15 - Language by Ear
16 - Verbal Auditory Agnosia
17 - Echolalic Speech
18 - Echolalic Speech is Pragmatic

IV. CHILDHOOD HANDICAPS
19 - Auditory and Motor Handicaps
20 - Increased Incidence of Autism
21 - Fetal to Postnatal Adaptation
22 - Forgotten History
23 - Worth Remembering
24 - Hemoglobin
25 - Infant Anemia
26 - Autism in Twins
27 - Male-Female Differences

V. BRAINSTEM DAMAGE
28 - Variable Vulnerability
29 - Patterns of Damage
30 - Wernicke's Encephalopathy
31 - Suffocation at the Molecular Level
32 - Thiamine Deficiency
33 - Brain-Gut Relationship

VI. REFERENCES (for all sections)
34 - Bibliography
35 - Autism and Complications at Birth
36 - Umbilical Cord Clamping

Summaries (for all sections)
    Summaries (for section V)
[Site Links]


Overview (Brainstem Damage):

Damage to the cerebral cortex is the most common consequence of oxygen deficiency. Protective mechanisms increase blood flow in response to factors that decrease metabolism in brainstem nuclei of high metabolic rate. The inferior colliculus is often spared at the expense even of other brainstem nuclei that are slightly less active; thus the mammillary bodies are most prominently affected in the Wernicke's encephalopathy pattern of damage that occurs with chronic alcohol intoxication.

Brainstem pathology found in survivors of resuscitation from cardiac arrest, drowning, or suffocation has long been viewed as puzzling. Janzer and Friede (1980) aptly suggested this pattern of damage be referred to as "cardiac arrest encephalopathy." The brainstem pattern of damage also occurs with obstruction of aerobic metabolism by poisonous substances or deficiency of essential enzyme cofactors such as vitamin B1.

The gastrointestinal system is often affected in alcoholism and other conditions in which the brainstem pattern of damage occurs. Brainstem autonomic centers that control functions like peristalsis may become damaged and the damage compounded by non-absorption of essential nutrients like thiamine or absorption of toxic metabolites of deranged digestive processes.

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V. BRAINSTEM DAMAGE

28 - Variable Vulnerability
Preservation of function in the auditory system is apparently important for survival and homeostasis. Mechanisms that increase blood flow under adverse conditions protect the auditory system in most circumstances, as shown by research using the autoradiographic methods for blood flow and deoxyglucose uptake For example the nerve gas Soman administered to laboratory animals in sub-toxic doses stimulated increased blood flow, with the greatest increase in the inferior colliculus [233-235].

Adjustment of aerobic metabolism as well as increased blood flow takes place with use of alcohol and other drugs. Research on the effects of amphetamine drugs revealed increased blood flow and metabolism in the inferior colliculus and visual cortex with metabolic depression elsewhere in the brain [236].

Grünwald et al. (1993) found that administration of one dose of alcohol to laboratory rats depressed glucose utilization throughout the brain, and this was most pronounced in the auditory system [24]. Increasing doses of alcohol given over a three week period increased deoxyglucose uptake in the inferior colliculus in dramatic contrast to lowered uptake in other areas of the brain. But an additional dose given two hours before measurement of deoxyglucose led to depressed uptake in the inferior colliculus.

If increased metabolism leads to auditory sensitivity that is diminished by an additional dose of alcohol, this might provide one explanation for addiction. In any event it provides an example of how metabolism as well as blood flow adapts to substances like alcohol.

Neuropathology caused by alcohol intoxication has long been known (as Wernicke's encephalopathy, in Wernicke-Korskoff syndrome), and the mammillary bodies are most predictably involved [237-241]. The mammillary bodies are among the brain areas of high glucose utilization as can be seen in table 2. Protective mechanisms that spare the inferior colliculi may then make slightly less active nuclei like the mammillary bodies most vulnerable to compromise.

Damage to the cerebral cortex is the most common consequence of oxygen deficiency. Clamping the carotid arteries of neonatal gerbils led to decreased blood flow to the forebrain but increased circulation in the inferior colliculi from collateral blood vessels [21]. Partial obstruction of placental blood flow to fetal monkeys produced damage in the cerebral cortex and cerebral palsy [2].
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29 - Patterns of Damage

(1) Cortical and brainstem patterns
Damage caused by partial oxygen insufficiency (hypoxia) and total oxygen cutoff (asphyxia) is not a matter of degree. That brainstem damage is sometimes seen in human cases of circulatory arrest or suffocation has been a puzzle and topic of discussion in the medical literature [111-117].

Neubuerger (1954) investigated neuropathology in cases of cardiac arrest during surgery; most resulted in damage to the cerebral cortex, but Neubuerger expressed surprise that the location of lesions showed more variety than expected [111]. He made special note of one case in which there was, "...involvement of centers usually affected in Wernicke's disease, especially the mammillary bodies and posterior colliculi..." This was a person who died, at age 72, of respiratory failure during surgery. Artificial respiration and heart massage were performed with spontaneous heart beats obtained after eight minutes and spontaeous respiration after eighteen minutes. The patient, however, remained in a coma until death one week later. This can be viewed as a case of sudden catastrophic asphyxia, comparable to asphyxia at birth as produced in the experiments begun five years later by Ranck and Windle 1959 [26].

Gilles (1963) described symmetrical damage of brainstem nuclei in three individuals who survived episodes of cardiac arrest but later succumbed [113]. In two of the cases, normally expected damage was found in the cerebral cortex, thalamus, and cerebellar cortex. In addition, brainstem lesions of sensory and motor nuclei of several cranial nerves including the third (oculomotor), the inferior colliculi, cell groups in the reticular formation, and the lateral cuneate nuclei were found. The third case was an eighteen-month-old child who drowned but was resuscitated. In this case, the cerebral and cerebellar cortex remained intact.

Gilles noted the similarity of the brainstem pattern of damage to that found after experimental asphyxia of newborn monkeys and in human cases of kernicterus (bilirubin staining, or jaundice, of subcortical nuclei), and he suggested that brainstem "aphasias," such as in Moebius syndrome [242] might be related to temporary cardiac arrest in the prenatal or perinatal period. Moebius syndrome is another condition associated with Autism [243, 244], and it appears to be related to brainstem pathology [245-248], caused in some cases by prenatal exposure to the drug misoprostol [249].
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(2) Wernicke-like or "circulatory arrest" encephalopathy
Brierley (1961) described, "Wernicke-like" lesions in the mammillary bodies as well as severe cell loss and gliosis in the inferior colliculi" in the brain of a two-year old child who suffered cardiac arrest of ten to fifteen minutes duration from anesthesia used for repair of a hernia [112]. Brierley also noted the striking similarity of this pattern of damage to that reported by Ranck and Windle.

Gilles (1969) reported three more cases of brainstem damage: In a 17-month-old boy who suffered cardiac arrest during a high fever, a nine-year-old child resuscitated after suffocation under a collapsed earthen bank, and a 22-year-old man who suffered cardiac arrest following a bullet wound to the abdomen [116]. Gilles referred to these cases as examples of "hypotensive brainstem necrosis." Janzer and Friede (1980) suggested "cardiac arrest encephalopathy" as a better term, and reported the brainstem pattern of damage in eight infants and seven adults for all of whom a well documented episode of cardiac arrest had occurred [117].

When circulation and oxygen delivery are completely cut off, metabolism within the brainstem nuclei of high circulatory rate comes to a sudden halt. This clearly happens far less often with survival than circulatory insufficiency or partial disruption of aerobic metabolism. Damage from both partial and total asphyxia can happen, with both cortical and brainstem patterns evident in the brain of any victim of an accident that interferes with respiration.

Asphyxia is not a more severe degree of hypoxia; asphyxia is a different kind of insult. Protective mechanisms go into effect in situations of reduced blood flow or oxygen insufficiency (hypoxia). Expansion of blood vessels (vasodilation) happens with exposure to toxic substances [233-236], and in alcohol intoxication [24]. Increased blood pressure can lead to bursting of capillaries; the "whiskey nose" of some alcoholics is a visible sign of this kind of process. Figure 19 (below) shows "flea-bite" size hemorrhages in the brainstem caused by alcohol intoxication. The "corpus quadrigeminum post" (posterior quadrigeminal body, or inferior colliculus) is indicated as a primary site in which this kind of damage occurs.
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Wernicke's encephalopathy
Figure 19: Wernicke's encephalopathy: Flea-bite size hemorrhages in the brainstem from dilated blood vessels that burst (from Kant 1933, with permission from Springer-Verlag).

30 – Wernicke's Encephalopathy

(1) Hemorrhagic (or vascular) cause?
Brainstem damage caused by alcohol intoxication has long been known as Wernicke's encephalopathy [237-241]. Wernicke (1881) observed this pattern of damage in the brains of two alcoholic men and a young woman who had swallowed sulfuric acid [251]. An English translation of part of Wernicke's paper can be found in the article by Brody and Wilkins (1968) [253].


Wernicke described the damage as hemorrhagic, consisting of pin-point size burst capillaries as shown in the photograph above. Whether Wernicke's encephalopathy is always hemorrhagic has been controversial. Rosenblum and Feigin (1965) reported 41 cases of which 17 had no hemorrhages [252]. Visible petechial hemorrhages were recognized in 5 cases, and 19 revealed hemorrhages only under the microscope; five of these 19 were old hemorrhages recognized only by hemosiderin laden macrophages. Thus only 60 percent of their 43 cases showed any evidence of a hemorrhagic process.

Wernicke cited a paper by Gayet (1875) who described hemorrhagic brainstem damage in a man who survived several months following scalding of his airways in a boiler explosion [250]. Figure 20 predates use of photography, but is a drawing in color showing the areas of hemorrhagic damage in Gayet's patient.

(2) Brain structures involved
The mammillary bodies are usually noted as most severely affected in Wernicke's encephalopathy. But damage in the inferior colliculi is also often prominent [237-241].

Location and severity of the damage is variable because protective mechanisms have time to go into effect whenever a toxic insult does not immediately or totally disrupt aerobic metabolic systems.


Drawing of hemorrhagic brainstem damage (from Gayet 1875)

Figure 20: Drawing of hemorrhagic brainstem damage found by Gayet (1875) in a patient who survived eight months following scalding of the airway in a boiler explosion.

Note the involvement of the cerebellum in Wernicke's encephalopathy [254, 255]. Similar cerebellar pathology is prominent in the few investigations of brains from individuals with autism.

Damage caused by asphyxia at birth should probably be recognized as a variant of Wernicke's encephalopathy. Windle reported that the brainstem lesions caused by asphyxia at birth were not hemorrhagic in origin, which may be why he did not consider the damage caused by asphyxia at birth to be a variant of Wernicke's encephalopathy. But the brainstem structures affected are comparable.
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31 - Suffocation at the Molecular Level
Circulatory arrest and suffocation have an immediate and catastrophic effect on respiratory gas exchange and thence aerobic metabolism. In these circumstances brain structures of high metabolic rate are most vulnerable, evident from experiments on asphyxia in monkeys (newborn and adult) and case reports of damage following resuscitation after cardiac arrest and accidents like drowning [1-2, 29, 111-117]. The same metabolically active brain nuclei are also susceptible to damage or impaired function by chemical substances many of which may selectively disable aerobic metabolic pathways.

(1) Selective disruption of aerobic metabolism:
Troncoso et al. (1981) introduced the substance pyrithiamine as a tool for simulating thiamine deficiency, producing Wernicke's encephalopathy, and as a shortcut for mimicking the effects of chronic alcohol consumption in laboratory animals [256]. Pyrithiamine displaces thiamine (vitamin B1) from the enzyme that activates it as a cofactor for the major (Krebs cycle) pathway of glucose metabolism. Neurological impairment and neuropathology are produced more quickly with pyrithiamine than by administering alcohol to experimental animals [257-261].

Pyrithiamine causes suffocation at the molecular level. Protective mechanisms can have no effect. Hakim (1986) found dramatic increases in cerebral circulation following pyrithiamine administration – a protective response doomed to failure [259]. Blood flow returned to normal levels following administration of thiamine except in the inferior colliculi, mammillary bodies, and thalamic nuclei – an early sign of permanent impairment in these metabolically most active brain nuclei.

Glucose metabolism is blocked by pyrithiamine, thus carbon dioxide is not produced as a stimulus for hemoglobin to release oxygen. Chen et al. (1997) found the inferior colliculi sustained damage before the mammillary bodies or any other of the brainstem nuclei of high metabolic rate in laboratory rats injected with pyrithiamine [261]. The blocking of glucose metabolism by pyrithiamine is one step beyond that of carbon monoxide or cyanide, which displace oxygen on the hemoglobin molecule [33, 34].
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(2) Fast-acting anesthesia:
Roth and Barlow (1961) used an autoradiographic technique modeled after that used for measuring blood flow to investigate distribution of anesthetic agents in the brain [122]. They found distribution in the brain of fast-acting thiopental was different from that of barbiturates, which are slow to take effect but of longer duration. Thiopental was quickly distributed to the inferior colliculi and other nuclei of high blood flow. This finding lends support to the idea of Denny-Brown (1962) that the midbrain tectum (auditory and visual colliculi) is involved in maintaining the conscious state [119].

If the action of thiopental is on a specific neurotransmitter system, it would appear to be one of special importance for consciousness, and one closely coupled to aerobic energy production – the reason for high aerobic metabolism to have evolved in brain nuclei that maintain vigilance for environmental change.

(3) Brain-damaging intoxicants:
Damage of the inferior colliculus has been reported following exposure to several toxic chemicals [262-267]. Fumes from dry-cleaning fluids may reduce oxygen available to the lungs, or like thiopental be quickly distributed to areas of the brain with high blood flow. A confusional delirium afflicting two pressers in a dry-cleaning establishment was described by Bini and Bollea (1947) as comparable to alcohol intoxication [262]. Chronic intoxication lead to coma and death with focal lesions typical of Wernicke's encephalopathy found in the mammillary bodies, floor of the fourth ventricle, and inferior and superior colliculi.

Franken (1959) reported the case of a 28-year-old man exposed over a two-year period in his work filling fire extinguishers with methyl bromide [263]. He developed transient alterations in consciousness and involuntary jerking of his legs; he died two days after acute intoxication by a large amount of methyl bromide. Franken described brain lesions of the Wernicke-encephalitic type involving both posterior quadrigeminal bodies (the inferior colliculi). Goulon et sl. (1975) and Squier et al. (1992) reported additional cases of disability and death following acute exposure to methyl bromide, with Wernicke-like patterns with prominent involvement of the inferior colliculi [264, 265].

Cavanagh (1992) commented on the paper by Squier et al. and pointed out other toxic substances (6-amino-nicotinamide, misonidazole, metronidazole, and mono- and dinitro-benzene) that act by disabling the biochemical pathways of energy generation and produce symmetrical brainstem damage similar to that caused by methyl bromide [266]. Cavanagh and Nolan (1993) described the same pathology in laboratory rats caused by alpha-chlorohydrin, which was under investigation for use as a male anti-fertility agent [267]!
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(4) Selective what?
Terms such as "Selective serotonin re-uptake inhibitors" have become part of the common vernacular, and are used to promote sales of drugs touted to improve mental well-being. Caution is warranted. There may be drugs, and even herbal remedies, that impair aerobic metabolism without causing visible damage; unlike alpha-chlorohydrin they may be out there on the market.

Alzheimer dementia as well as autism is on the rise. It might seem prudent to require that all pharmaceutical products be tested for their effects on the brain. The autoradiographic methods for blood flow and deoxyglucose uptake are ideally suited to investigation of metabolic effects of substances that do not produce visible damage. Auditory system and aerobic metabolic impairments have been detected in Alzheimer patients [14, 268].

(5) Mercury and lead poisoning:
Bertoni and Sprenkle (1989) used the deoxyglucose method to investigate how lead compounds affect the brain. They found decreased glucose uptake throughout the brain seven hours after administration of lead acetate, but this was most pronounced in structures of the auditory system: Inferior colliculus, superior olive, cochlear nucleus, lateral lemniscus, and auditory cortex [18]. Bertoni and Sprenkle proposed that lead may poison the energy-activating enzyme Na,K-ATPase.

Oyanagi et al. (1989) reported auditory system involvement as part of the neuropathology of mercury poisoning in 14 victims of Minamata disease (or Hunter-Russell syndrome), a condition that includes impairment of hearing and speech [102]. The evidence that mercury and lead affect the auditory system suggests that they may be disruptive to aerobic metabolism or a neurotransmitter system dependent upon a steady energy supply. How heavy metals interfere with aerobic metabolism is not as clear-cut as in the case of pyrithiamine.

The mercury preservative (Thimerosol) in vaccines is widely claimed to be a cause of autism [97-101]. The mercury theory is controversial because it has been formulated largely by parents who report having seen regression into autism following vaccination of their child. Lead poisoning has been reported as a co-morbid condition in some children with autism[174-176].
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(6) Mitochondrial damage:
Aerobic metabolism takes place within the mitochondria of cells. Any substance disruptive to any component of mitochondria (cell walls, cristae, enzyme complexes, ribosomes, or DNA) will impede aerobic metabolism. Mitochondria have their own double stranded circular DNA similar to that of primitive bacteria [274, 276]. Mitochondria are thought possibly to have been a primeval infecting organism that turned out to be symbiotic for multicellular life forms because of the efficiency of their aerobic pathways for energy production [270, 277].

Mitochondrial genes encode RNA sequences for ribosomes, where peptides are assembled to become components of the enzymes that catalyze oxidative metabolism [274, 276]. Genes within chromosomes of cell nuclei encode additional RNA and peptide sub-units for the mitochondrial enzyme system. Mitochondria are duplicated from the maternal egg because sperm cells do not contain mitochondria [277]. Chromosomal genes are derived from both parents, and are far less vulnerable to mutations because protective enzymes that repair chromosomal DNA evolved later in cells with nuclei.

Mitrochondrial DNA is especially susceptible to mutagenic agents, and antibiotic drugs can damage mitochondria because of their similarity to bacterial organisms [271, 275]. Antibiotics are less and less effective against bacteria, which mutate and produce resistant strains. But damage to mitochondria may be a more urgent reason to avoid overuse of antibiotic medications. Mutations of mitochondrial DNA can lead to serious mitochondrial disorders. The kidneys and auditory system are most susceptible; nephrotoxicity and ototoxicity are common side effects of many drugs.

Matrilineal transmission of deafness induced by widespread use of streptomycin has been reported [272, 273]. Toxic chemicals used as herbicides and pesticides have long been known to cause neurodegenerative disorders; methyl bromide was used for this purpose as well as in fire extinguishers. DeJong (1944) reported the neurotoxicity of methyl bromide [269], which later was found to cause a brainstem pattern of damage similar to that caused by asphyxia [262-265]. Other chemical substances have been found to be mutagenic to mitochondrial DNA and are known to cause symptoms similar to those of Parkinsonism and Huntington’s chorea [271, 275]. [Top]

32 - Thiamine Deficiency
Suffocation at the molecular level also occurs in cases of severe thiamine (vitamin B1) deficiency. Beriberi is an illness that developed in countries where rice was a dietary staple after whole-grain rice was replaced by refined white rice [282, 284].

Causes ranging from infection, toxic contamination of water, dietary deficiency of protein, to racial predispositions were sought, but adding back to rice "polishings" containing the germ removed during refining was found to immediately ameliorate the symptoms of this illness. Diligent research finally led to isolation of thiamine as the essential molecular component that would prevent illness [281].

Thiamine is an essential cofactor for enzymes that catalyze glucose metabolism, and is now therefore classified as a vitamin. Thiamine is needed only in small amounts but it has a high turnover rate and needs to be replaced at least daily. Neurological signs gave evidence of brain involvement in beriberi. Peripheral "polyneuritis," disorders of eye movements, staggering gait, disorientation, and drowsiness were noted to be similar to the problems of chronic alcoholics, and thiamine deficiency was found to produce the same bilaterally symmetric lesions of brainstem nuclei characteristic of Wernicke's encephalopathy [283].


Inferior colliculus damage caused by thiamine (vitamin B1) deficiency
Figure 21: Damage to the inferior colliculi in a human patient maintained on prolonged parenteral feeding lacking vitamin B1 (from Vortmeyer et al. 1992).

Calingasan et al (1994) measured distribution of the major thiamine-dependent enzyme, alpha-ketoglutarate dehydrogenase, and found the highest amounts in regions of the brain that are predilection sites for Wernicke’s encephalopathy [12].

Brain damage in alcoholism is widely regarded as due to thiamine deficiency in part because alcohol damages the gastro-intestinal system, which disrupts absorption of nutrients. Thiamine is used in detoxification treatment of alcoholics, and an analogue of thiamine appears to be helpful to some children with autism. Its use should perhaps be considered in autistic children with gastrointestinal disorders. One pilot study with thiamine tetrahydrofurfuryl disulfide appears to have helped some children [285].


Figure 21 shows severe damage to the inferior colliculi in a terminally ill patient maintained on total parenteral nutrition (TPN) in which thiamine was lacking [286], and this was not a unique case [287]!

The damage in figure 21 is hemorrhagic but otherwise strikingly similar to the pattern of damage caused by asphyxia at birth. Wernicke's encephalopathy has been observed in animals inadvertently maintained on diets lacking thiamine [288, 290] and in experimental thiamine deficiency [289, 291]. Damage to the inferior colliculi was found most prominent in animals, in contrast to more severe involvement of the mammillary bodies in human cases of chronic alcohol use.

Damage caused by long-term escalating abuse of alcohol is serious, but not as catastrophic as sudden total deprivation of the essential aerobic coenzyme thiamine. Protective mechanisms spare the inferior colliculus and leave the mammillary bodies more vulnerable to repeated damage during the lifespan of a person addicted to alcohol.
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33 - Brain-Gut Relationship
Chronic alcohol use damages the esophagus, intestinal tract, and liver. Liver encephalopathy or cirrhosis is the terminal stage of alcoholism. Alcohol in excess directly damages these organs. But considering the speed with which mental changes and inebriation occur following use of alcohol, it seems clear that alcohol's first target is the brain.

Toxic impairment of the brain involves brainstem centers, and involuntary functions such as intestinal peristalsis depend upon intact brainstem circuits that control the autonomic nervous system [292]. Thus the gut is as dependent upon integrity of brainstem function as the brain is on absorption of essential nutrients like thiamine.

Myers referred to the brainstem pattern of damage by asphyxia at birth as a "monotonous rank-order of brainstem nuclei." This pattern of damage did not produce cerebral palsy, but it is a pattern of damage no less serious. Impaired autonomic function caused by brainstem damage should be investigated as possibly contributive to the gastrointestinal problems of some children with autism.

Korsakoff (1889) observed the signs of neurological impairments (oculomotor, ataxia, and mental confusion) described by Wernicke not only in cases of chronic alcoholism, but also during the course of infections and cancerous cachexia (or wasting which may also have involved thiamine deficiency) [293]. Korsakoff provided description of 14 cases of non-alcoholic origin. Among these were post-partum illnesses, typhoid, tuberculosis, tapeworm, diabetes, pneumonia, jaundice, and intestinal disorders. In addition to early acute symptoms similar to those reported by Wernicke, Korsakoff is best remembered for describing the long-term course leading to memory impairment.

Neubuerger (1937) discussed the possibility that "auto-toxic" substances could be produced in senile and diseased organs, and that these auto-toxins were the reason Wernicke's encephalopathy developed in the brain [294]. The brain-gut relationship continues to be described [295-298].

Morley (2003) has noted that immediate clamping of the umbilical cord at birth can leave the infant in a state of hypovolemic shock, which in turn triggers generalized vasoconstriction that shifts blood flow from less vital organs to the heart and brain [299]. Hankins et al. (2002) provided evidence that asphyxia from placental abruption or umbilical cord prolapse during labor results in injury to the liver, kidneys, and heart as well as the brain [300]. Autism is associated with complications at birth, and some children with autism may then begin life with multiple organ injury as well as damage of brainstem autonomic centers.
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. . . .

VI. REFERENCES

34 - Bibliography

Asphyxia and Hypoxia at Birth
  1. Windle, W. F. (1969). Brain damage by asphyxia at birth. Scientific American, 221(#4), 76-84.
  2. Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence. American Journal of Obstetrics and Gynecology 112:246-276.
    Back to: Variable vulnerability, Molecular suffocation, [Top]

    Cerebral Blood Flow
  3. Landau WM, Freygang WH, Rowland LP, Sokoloff L, Kety SS (1955) The local circulation of the living brain; values in the unanesthetized and anesthetized cat. Transactions of the American Neurological Association 80:125-129.
  4. Kety SS (1962) Regional neurochemistry and its application to brain function. In French, JD, ed, Frontiers in Brain Research. New York: Columbia University Press, pp 97-120. Back to: Figure 1, [Top]
  5. Reivich M, Jehle J, Sokoloff L, Kety SS (1969) Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. Journal Of Applied Physiology 27:296-300.
  6. Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L (1978) Measurement of local cerebral blood flow with iodo-14-C-antipyrine. American Journal of Physiology, 234, H59-H66.

    Measures of Aerobic Metabolism (Deoxyglucose Uptake)
  7. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. Journal of Neurochemistry 28:897-916.
  8. Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Casella V, Fowler J, Gallagher B, Hoffman E, Alavi A, Sokoloff L (1977) Measurement of local cerebral glucose metabolism in man with 18F-2-fluoro-2-deoxy-d-glucose. Acta Neurologica Scandinavica. Supplementum 64:190-1

    Correlates of High Deoxyglucose Uptake
  9. Gross PM, Sposito NM, Pettersen SE, Panton DG, Fenstermacher JD. Topography of capillary density, glucose metabolism, and microvascular function within the rat inferior colliculus. J Cereb Blood Flow Metab. 1987 Apr;7(2):154-60.
  10. Rahner-Welsch S, Vogel J, Kuschinsky, W (1995) Regional congruence and divergence of glucose transporters (GLUT1) and capillaries in rat brains. Journal of Cerebral Blood Flow and Metabolism 15:681-686.
  11. Zeller K, Rahner-Welsch S, Kuschinsky W (1997) Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. Journal of Cerebral Blood Flow and Metabolism 17:204-209.
  12. Calingasan NY, Baker H, Sheu KF, Gibson GE (1994) Distribution of the alpha-ketoglutarate dehydrogenase complex in rat brain. Journal Of Comparative Neurology 346:461-479.
    Back to: Thiamine Deficiency, [Top]

  13. Hovda DA, Chugani HT, Villablanca JR, Badie B, Sutton RL (1992) Maturation of cerebral oxidative metabolism in the cat: a cytochrome oxidase histochemistry study. Journal of Cerebral Blood Flow and Metabolism 12:1039-1048
  14. Gonzalez-Lima F, Valla J, Matos-Collazo S (1997) Quantitative cytochemistry of cytochrome oxidase and cellular morphometry of the human inferior colliculus in control and Alzheimer's patients. Brain Research 752:117-126.
    Back to: Molecular Suffocation, [Top]

    Research on Blood Flow and Glucose Uptake
  15. Sokoloff L (1981) Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. Journal of Cerebral Blood Flow and Metabolism 1:7-36.
  16. Hakim AM and Pappius HM (1981) The effect of thiamine deficiency on local cerebral glucose utilization. Annals of Neurology 9:334-339.
  17. Vingan RD, Dow-Edwards ML, Riley EP (1986) Cerebral metabolic alterations in rats following prenatal alcohol exposure: a deoxyglucose study. Alcoholism, Clinical and Experimental Research 10:22-26.
  18. Bertoni JM and Sprenkle PM (1989) Lead acutely reduces glucose utilization in the rat brain especially in higher auditory centers. Neurotoxicology 9:235-242.
    Back to: Molecular Suffocation, [Top]

  19. Nehlig A, Pereira de Vasconcelos A, Boyet S (1989) Postnatal changes in local cerebral blood flow measured by the quantitative autoradiographic [14C]iodoantipyrine technique in freely moving rats. Journal of Cerebral Blood Flow and Metabolism 9:579-588.
  20. Dow-Edwards DL, Freed LA, Fico TA (1990) Structural and functional effects of prenatal cocaine exposure in adult rat brain. Brain Research Developmental Brain Research 57:263-268.
  21. Kusumoto, M., Arai, H., Mori, K., & Sato, K. (1995). Resistance to cerebral ischemia in developing gerbils. Journal of Cerebral Blood Flow and Metabolism, 15, 886-891.
    Back to: Variable Vulnerability, [Top]

  22. Chugani HT, Hovda DA, Villablanca JR, Phelps ME, Xu, W-F (1991) Metabolic maturation of the brain: a study of local cerebral glucose utilization in the developing cat. Journal of Cerebral Blood Flow and Metabolism 11:35-47.
  23. Burchfield DJ, Abrams RM (1993). Cocaine depresses cerebral glucose utilization in fetal sheep. Developmental Brain Research 73:283-288.
  24. Grünwald F, Schröck H, Biersack HJ, Kuschinsky W (1993) Changes in local cerebral glucose utilization in the awake rat during acute and chronic administration of ethanol. Journal of Nuclear Medicine 34:793-798.
    Back to: Variable Vulnerability, Patterns of Damage, [Top]

  25. Antonelli PJ, Gerhardt KJ, Abrams RM, Huang X. Fetal central auditory system metabolic response to cochlear implant stimulation. Otolaryngol Head Neck Surg. 2002 Sep;127(3):131-7.

    Early Research of Windle and Coworkers
  26. Ranck JB, Windle WF (1959). Brain damage in the monkey, Macaca mulatta, by asphyxia neonatorum. Experimental Neurology 1: 130-154.
  27. Jacobson HN & Windle WF (1960) Responses of foetal and new-born monkeys to asphyxia. The Journal of Physiology (London) 153:447-456.
    Back to: Patterns of Damage, [Top]

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    Neurofibromatosis
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    Phenyhlketonuria
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    Fragile X Syndrome
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    Leber's Congenital Amaurosis
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    Adenylosuccinate Lyase Defect
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    Lactic Acidosis
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    Mitochondrial Disorders
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  211. Fetal to Postnatal Adaptation Mercer JS, Skovgaard RL. Neonatal transitional physiology: a new paradigm. J Perinat Neonatal Nurs. 2002 Mar;15(4):56-75.

    Infant Anemia
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    Hierarchy of Human Needs
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    Biochemistry Textbooks
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    Polycythemia
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    Autism in Twins
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    Neonatal Asphyxia in Laboratory Rats
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    Categories of Mental Disorders
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    Adjustments Under Adverse Conditions
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    Neuropathology in Alcoholism (Wernicke's Encephalopathy)
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    Moebius Syndrome (Bilateral Facial Palsy)
  242. Moebius PJ (1888) Ueber angeborenen doppelseitige Abducens-Facialis-Laemung. Münchener Medizinische Wochenschrift. 35: 91-94.
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    Wernicke-Gayet Encephalopathy
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    Pyrithiamine Enzyme Poison
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    Toxic fumes, Methyl Bromide, and Alpha-chlorohydrin
  262. Bini, L. & Bollea, G. (1947). Fatal poisoning by lead-benzine (a clinico-pathologic study). Journal of Neuropathology and Experimental Neurology, 6, 271-285.
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    Auditory System Impairment in Alzheimer Dementia
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    Mitochondria and their vulnerability
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    Disruption of Mitochondrial Function
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    Thiamine Deficiency
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    Thiamine Treatment
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    Thiamine Deficiency in Total Parenteral Nutrition
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    Thiamine Deficiency in Animals
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    Brainstem Control of Autonomic Functions
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    Wernicke's Encephalopathy in Gastrointestinal Disorders
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    Hypovolemic Shock at Birth
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. . . .

SUMMARIES


V. BRAINSTEM DAMAGE

28 - Variable Vulnerability
Protective mechanisms increase blood flow to the inferior colliculus in any circumstance that leads to impairment of aerobic metabolism. This has been revealed in several experiments with toxic chemicals. Total catastrophic disruption of aerobic metabolism damages the rank order of brainstem nuclei of high metabolic rate. Partial interference with aerobic metabolism spares the inferior colliculus and leads to damage of less metabolically active brain centers.

29 - Patterns of Damage
Circulatory insufficiency most often leads to damage of the cerebral cortex. Brainstem damage with or without involvement of cortical areas has been reported in people resuscitated after drowning, suffocation, or cardiac arrest. Brainstem damage has often been compared with that found in monkeys asphyxiated at birth and also in Wernicke's encephalopathy.

30 - Wernicke's Encephalopathy
Gayet (in 1875) and Wernicke (in 1881) described damage restricted to the brainstem in cases of airway damage, alcoholism, and ingestion of sulfuric acid. This pattern of damage is associated most often with alcoholism and thiamine (vitamin B1) deficiency.

31 - Suffocation at the Molecular Level
An increasing array of toxic substances has been found to interfere partially or catastrophically with aerobic metabolism. Brainstem nuclei are affected in varying degrees.

32 - Thiamine Deficiency
Thiamine (vitamin B1) is an essential cofactor for enzymes of aerobic metabolism. Deficiency of thiamine in the diet or because of malabsorption in gastrointestinal disorders leads to Wernicke's encephalopathy or variants of this pattern of damage.

33 - Brain-Gut Relationship
Autonomic functions such as intestinal peristalsis are controlled by brainstem centers. Damage to these autonomic centers can impair intestinal function. Intestinal dysfunction in turn leads to malabsorption and/or absorption of digestional fragments that should be excluded. Toxic fragments of digestion may be toxic to the brain and further compound the effects of earlier damage.


END

January 20, 2023 06:44 PM

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