- Ranck JB, Windle WF (1959). Brain damage in the monkey, Macaca mulatta, by asphyxia
neonatorum. Experimental Neurology 1:130-154.
- Sechzer JA, Faro MD, Barker JN, Barsky D, Gutierrez S, Windle WF. Development behaviors:
delayed appearance in monkeys asphyxiated at birth. Science. 1971 Mar 19;171(976):1173-
5.
- Sechzer JA, Faro MD, Windle WF. Studies of monkeys asphyxiated at birth: implications for
minimal cerebral dysfunction. Semin Psychiatry. 1973 Feb;5(1):19-34.
- Neubuerger KT (1954) Lesions of the human brain following circulatory arrest. Journal of
Neuropathology and Experimental Neurology 13:144-160.
- Neubürger K (1937) Wernickesche Krankheit bei chronischer Gastritis. Ein Beitrag zu den
Beziehungen zwischen Magen und Gehirn. Zeitschrift für die gesamte Neurologie und
Psychiatrie 160:208-225.
- Gilles FH (1963) Selective symmetrical neuronal necrosis of certain brain stem tegmental
nuclei in temporary cardiac standstill. Journal of Neuropathology and Experimental
Neurology 22:318-318.
- Gilles FH (1969) Hypotensive brain stem necrosis: selective symmetrical necrosis of
tegmental neuronal aggregates following cardiac arrest. Archives of Pathology 88:32-41.
- Gellner L (1959) A Neurophysiological Concept of Mental Retardation and Its Educational
Implications. Chicago, IL: The Dr. Julian D. Levinson Research Foundation for Mentally
Retarded Children, Cook County Hospital.
- Kanner L (1943) Autistic disturbances of affective contact. Nervous Child 2:217-250.
- Moebius PJ (1888) Ueber angeborenen doppelseitige Abducens-Facialis-Laemung.
Münchener Medizinische Wochenschrift. 35: 91-94.
- Gillberg C, Steffenburg S (1989) Autistic behaviour in Moebius syndrome. Acta Paediatrica
Scandinavica 78:314-316.
- Miller MT, Stromland K. (1999) The mobius sequence: a relook. Journal of AAPOS 3:199-208.
- Lipson AH, Webster WS, Brown-Woodman PD, Osborn RA (1989) Moebius syndrome:
animal model--human correlations and evidence for a brainstem vascular etiology.
Teratology 40:339-50.
- Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence.
American Journal of Obstetrics and Gynecology 112:246-276.
- Miller JR, Myers RE (1970) Neurological effects of systemic circulatory arrest in the monkey.
Neurology 20:715-724.
- Miller JR, Myers RE (1972) Neuropathology of systemic circulatory arrest in adult monkeys.
Neurology 22:888-904.
- Zimmerman HM and Yannet H (1933). Kernicterus: jaundice of the nuclear masses of the
brain. American Journal of Diseases of Children, 45, 740-759.
- Rozdilsky B and Olszewski J (1961). Experimental study of the toxicity of bilirubin in newborn
animals. Journal of Neuropathology and Experimental Neurology, 20, 193-205.
- Lucey JF, Hibbard E, Behrman RE, Esquival FO, Windle WF (1964) Kernicterus in
asphyxiated newborn monkeys. Experimental Neurology 9:43-58.
- Carpenter KJ (2000) Beriberi, White Rice, and Vitamin B: A Disease, a Cause, and a Cure.
Berkeley: University of California Press.
- Bini L and Bollea G (1947). Fatal poisoning by lead-benzine (a clinico-pathologic study).
Journal of Neuropathology and Experimental Neurology 6:271-285.
- Franken L (1959) Étude anatomique d'un cas d'intoxication par le bromure de méthyle. Acta
Neurologica et Psychiatrica Belgica 59:375-383.
- Goulon M, Nouailhat R, Escourolle R, Zarranz-Imirizaldu JJ, Grosbuis S, Levy-Alcover MA
(1975). Intoxication par le bromure de methyl: Trois observations, dont une mortelle. Etude
neuro-pathologique d'un cas de stupeur avec myoclonies, suivi pendent cinq ans. Revue
Neurologique (Paris) 131:445-468.
- Squier MV, Thompson J, Rajgopalan B. (1992) Case report: neuropathology of methyl
bromide intoxication. Neuropathology and Applied Neurobiology 18: 579-584.
- Oyanagi K, Ohama E, and Ikuta F (1989). The auditory system in methyl mercurial
intoxication: a neuropathological investigation on 14 autopsy cases in Niigata, Japan. Acta
Neuropathologica (Berlin). 77:561-568.
- Cavanagh JB, Nolan CC (1993) The neurotoxicity of alpha-chlorohydrin in rats and mice: II.
Lesion topography and factors in selective vulnerability in acute energy deprivation
syndromes. Neuropathology and Applied Neurobiology 19:471-479
- Leigh D (1951) Subacute necrotizing encephalomyelopathy in an infant. Journal of
Neurology, Neurosurgery, and Psychiatry 14:216-221.
- Cavanagh JB, Harding BN (1994) Pathogenic factors underlying the lesions in Leigh's
disease. Tissue responses to cellular energy deprivation and their clinico-pathological
consequences. Brain 117(Pt 6):1357-1376.
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to damage to inferior olivary nuclei? Neuropathology and Applied Neurobiology 1994 20:599-
603.
7 - Vulnerability to metabolic disruption
Ranck & Windle (1959) noted with surprise that the
primary damage caused by asphyxia at birth in
monkeys was in the inferior colliculus, and they looked
long and hard for signs of the expected damage to
motor systems of the cerebral cortex [1]. It also came
as a surprise that the asphyxiated monkeys did not
develop cerebral palsy, only a delay in gaining motor
control with poor manual dexterity as a residual defect
[2, 3].
Ranck and Windle did not discuss the similarity of
bilaterally symmetric damage of brainstem nuclei to
Wernicke's encephalopathy as had Neubuerger
(1954) five years earlier in describing neuropathology
observed after cardiac arrest [4]. But, as noted in the
previous section, Neubuerger began his career in
Germany where he had long been interested in
Wernicke's encephalopathy not only in alcoholism but
in other medical conditions [5]. It could be said that
Ranck and Windle started a new tradition in America,
although it never gained as much attention as it
should have, perhaps because they regarded
brainstem damage as minor compared with the major
involvement of cortical motor systems associated with
cerebral palsy that they had sought to produce in
monkeys by means of sudden, total asphyxia at birth..
Gilles (1963) reported pathology similar to that
observed by Ranck & Windle in an 18-month-old
infant who died a few weeks following resuscitation
from drowning [6]. Six years later (Gilles 1969) noted
the same pattern of damage in a nine-year-old child
resuscitated after being rescued from under a
collapsed earthen bank [7]. Gilles (1963) was the first
to suggest that the brainstem pattern of damage with
prominent involvement of the inferior colliculi might
lead to developmental language delay. Gellner
(1959) had however discussed how trauma at birth
could damage the inferior and superior colliculi, thus
might impair sensory function and lead to autistic
isolation as described by Kanner [8, 9].
Gilles did not compare the findings of Ranck and
Windle to those of Wernicke, but he did suggest that
the lesions caused by anoxia in the perinatal period
might result in developmental language disorders
such as those observed in ocular-facial diplegia
syndrome described in the German literature by
Moebius 1888. [10] Gillberg & Steffenburg (1989) and
Miller & Stromland (1999) have since reported a high
frequency of autistic behaviors in children with Moebius
10 syndrome, and suggested that there may be a
common site of dysfunction within the brainstem [11,
12]. Lipson et al. (1989) also suggested a brainstem
etiology for Moebius syndrome [13].
Myers (1972) discovered that it was prolonged partial
insufficiency of oxygen that produced damage of
cortical motor systems and led to cerebral palsy [14].
Miller & Myers (1970, 1972) investigated the effects of
total and partial oxygen deprivation on adult monkeys
and found the same patterns of damage that occurred
in infant monkeys; a brief period of total asphyxia
(induced by cardiac arrest) damaged brainstem
nuclei, primarily the inferior colliculus, and longer
periods of partial circulatory insufficiency led to
damage of motor centers in the cerebral cortex [15,
16].
Brainstem nuclei are often the primary locus of
bilirubin staining following perinatal jaundice;
Zimmerman & Yannet (1933) observed this in human
cases [17]. Rozdilsky & Olszewski (1961) and Lucey
et al. 1964) found the inferior colliculi to be most
vulnerable to damage in investigations of kernicterus
produced in experimental animals [18, 19]. Lucey et
al determined that bilirubin only caused damage if
preceded by an asphyxic insult. A major consequence
of metabolic disruption is impairment of the
blood-brain barrier, with increased vulnerability to
higher than normal levels of common but potentially
toxic metabolites. Zimmerman and Yannet pointed
out, "This differs in no way from the well known fact
that any intravital dye will localize in zones of injury,
and will leave unstained tissues which are not
damaged."
Many toxic substances also cause symmetric bilateral
damage of the brainstem nuclei of high metabolic rate.
Carpenter (2000) pointed out that one theory of
causation of beriberi had been exposure to toxic
contaminants of rice because the polyneuritic
symptoms were similar to those caused by arsenic
poisoning [20] . Neubürger (1937) compared similarity
of Wernicke's encephalopathy to damage caused by
lead poisoning [5]. Following are some examples of
Wernicke-like patterns of damage caused by toxic
substances:
Bini and Bollea (1947) reported bilateral brainstem
damage in two people who inhaled dry-cleaning fluid
fumes [21]. Franken (1959), Goulon et al. (1975),
and Squier et al (1992) found bilateral damage in the
brainstem with most severe involvement of the inferior
colliculi in people who inhaled methyl bromide fumes
[22-24]. Oyanagi et al. (1989) noted prominent
damage in brainstem nuclei of the auditory system in
victims of methyl mercury poisoning [25]. Cavanagh
and Nolan (1993) reported damage to the brainstem
nuclei of high metabolic rate in experimental poisoning
of laboratory rats and mice with alpha-chlorhydrin, a
substance under consideration as a male anti-fertility
agent [26]. These chemical substances would appear
to be directly toxic to enzymes of aerobic metabolism
because of the sudden and catastrophic disability that
follows exposure.
Enzymes of the aerobic metabolic pathway are located
in the mitochondria of cells, and disorders of
mitochondrial energy metabolism have been found to
lead to Wernicke-like damage of the same subcortical
sites. Leigh (1951) described this pattern of
brainstem damage in an infant who died after failure to
thrive [27]. Leigh's syndrome, as it is now known, is
thought to be a disorder of mitochondrial enzyme
structure. Cavanagh and Harding (1994) investigated
neuropathology in 20 victims of Leigh's syndrome and
found the brainstem nuclei of high metabolic rate to be
the primary sites of damage, especially the inferior
colliculi [28]. Cavanagh (1994) reported cerebellar
Purkinje cell loss that appeared to be secondary to
damage of the inferior olives in 10 of the Leigh
syndrome cases [29].
- Ranck JB, Windle WF
(1959). Brain damage in the
monkey, Macaca mulatta, by
asphyxia neonatorum.
- Sechzer JA et al. (1971)
Development behaviors:
delayed appearance in
monkeys asphyxiated at
birth.
- Sechzer JA et al. (1973),
Studies of monkeys
asphyxiated at birth:
implications for minimal
cerebral dysfunction.
- Neubuerger KT (1954)
Lesions of the human brain
following circulatory arrest.
- Neubürger K (1937)
Wernickesche Krankheit bei
chronischer Gastritis. Ein
Beitrag zu den Beziehungen
zwischen Magen und
Gehirn.
- Gilles FH (1963) Selective
symmetrical neuronal
necrosis of certain brain
stem tegmental nuclei in
temporary cardiac standstill.
- Gilles FH (1969)
Hypotensive brain stem
necrosis: selective
symmetrical necrosis of
tegmental neuronal
aggregates following
cardiac arrest.
- Gellner L (1959) A
Neurophysiological
Concept of Mental
Retardation and Its
Educational Implications.
- Kanner L (1943) Autistic
disturbances of affective
contact.
- Moebius PJ (1888) Ueber
angeborenen doppelseitige
Abducens-Facialis-
Laemung.
- Gillberg C, Steffenburg S
(1989) Autistic behaviour in
Moebius syndrome.
- Miller MT, Stromland K.
(1999) The mobius
sequence: a relook.
- Lipson AH et al. (1989)
Moebius syndrome: animal
model--human correlations
and evidence for a
brainstem vascular etiology.
- Myers RE (1972) Two
patterns of perinatal brain
damage and their
conditions of occurrence.
- Miller JR, Myers RE (1970)
Neurological effects of
systemic circulatory arrest
in the monkey. Neurology
20:715-724.
- Miller JR, Myers RE (1972)
Neuropathology of systemic
circulatory arrest in adult
monkeys.
- Zimmerman HM, Yannet H
(1933). Kernicterus:
jaundice of the nuclear
masses of the brain.
- Rozdilsky B, Olszewski J
(1961). Experimental study
of the toxicity of bilirubin in
newborn animals.
- Lucey JFet al. (1964)
Kernicterus in asphyxiated
newborn monkeys.
- Carpenter KJ (2000)
Beriberi, White Rice, and
Vitamin B: A Disease, a
Cause, and a Cure.
- Bini L, Bollea G (1947).
Fatal poisoning by lead-
benzine (a clinico-
pathologic study).
- Franken L (1959) Étude
anatomique d'un cas
d'intoxication par le bromure
de méthyle.
- Goulon M et al. (1975).
Intoxication par le bromure
de methyl: Trois
observations, dont une
mortelle. Etude neuro-
pathologique d'un cas de
stupeur avec myoclonies,
suivi pendent cinq ans.
- Squier MV et al. (1992)
Case report:
neuropathology of methyl
bromide intoxication.
- Oyanagi K et al. (1989). The
auditory system in methyl
mercurial intoxication: a
neuropathological
investigation on 14 autopsy
cases in Niigata, Japan.
- Cavanagh JB, Nolan CC
(1993) The neurotoxicity of
alpha-chlorohydrin in rats
and mice: II. Lesion
topography and factors in
selective vulnerability in
acute energy deprivation
syndromes.
- Leigh D (1951) Subacute
necrotizing
encephalomyelopathy in an
infant.
- Cavanagh JB, Harding BN
(1994) Pathogenic factors
underlying the lesions in
Leigh's disease. Tissue
responses to cellular
energy deprivation and their
clinico-pathological
consequences.
- Cavanagh JB (1994) Is
Purkinje cell loss in Leigh's
disease an excitotoxic event
secondary to damage to
inferior olivary nuclei?