patternstxt

2 - Two patterns of pathology and their causes
Miller and Myers (1970, 1972) examined the effects of
total asphyxia in adult monkeys subjected to periods of
cardiac arrest for twelve to twenty minutes [1, 2]. As
after asphyxia at birth, they found the inferior colliculus
to be the most severely involved structure in the
brain. Purkinje cell damage in the cerebellum was also
prominent. Note, as mentioned in chapter xx,
diminished numbers of Purkinje cells is a consistent
finding in neuropathological investigations of brains
from people with autism, and also in cases of
Wernicke's encephalopathy.

The finding of selective damage of brainstem nuclei in
adult monkeys was as puzzling as it had been in infant
monkeys. Miller and Myers demonstrated that the
inferior colliculus is as vulnerable to damage in mature
monkeys as in neonates. Figure xx from the paper by
Miller and Myers (1972) shows damage of the inferior
colliculi in an adult monkey caused by circulatory
arrest, which can be compared to figures xx and xx
showing the same damage caused by asphyxia at
birth. Circulatory insufficiency and hypoxia following
cardiac arrest resulted in damage to the cerebral
cortex as had prolonged partial hypoxia in fetal
monkeys.

Vulnerability of the inferior colliculus and other
brainstem nuclei to cardiac arrest in adult human
cases has also been described, for example by
Neubuerger (1954) and Adams et al (1966), but again
reported as a surprise finding [3, 4]. This is not
difficult to understand because circulatory arrest is
usually fatal, and a survival period of a week or two
following resuscitation is required before evidence of
brain damage becomes visible. However, it should
now be clear that the brainstem pattern of damage
caused by anoxia is not unique to fetal and infant
animals. Furthermore, it is a consistent finding and
should no longer be considered surprising.

Selective vulnerability of the inferior colliculi and other
brainstem nuclei to circulatory arrest and total
asphyxia can be understood in terms of the results of
research on blood flow and metabolism in the brain.
Conditions of partial oxygen insufficiency invoke
protective mechanisms that insure oxygen delivery first
to the brainstem nuclei of high metabolic rate and
leave areas of lesser metabolic activity like the
cerebral cortex more susceptible to damage. The
more frequent finding of cortical rather than selective
subcortical damage in cases of circulatory compromise
is because survival is more likely in instances of
oxygen insufficiency than when circulation and oxygen
delivery are totally blocked. A great deal of research
has gone into trying to understand mechanisms of
hypoxic brain damage, and it is of interest to review
some of the approaches taken.

Stafford and Weatherall (1960) subjected infant rats to
anoxia in experiments in which a constant flow of
nitrogen was maintained [5]. Total anoxia was thus
inflicted leading to blue color and rapid gasping before
cessation of respiratory effort. The animals died
unless quickly removed from the nitrogen atmosphere
and resuscitated, but brain damage was not produced
in the survivors. Intact circulation at least removes the
carbon dioxide that would otherwise accumulate and
hasten neuronal death.

Mutoh (1990) also used nitrogen in experiments to
study effects of neonatal anoxia on seizure
susceptibility in rats and like Stafford and Weatherall
did not find visible or microscopic damage within the
brain [6]. The rats subjected to anoxia did become
more susceptible to seizures induced by drugs like
bicuculline. Submicroscopic neurochemical changes
likely produced the increased susceptibility to the drug
induced seizures, which Mutoh attributed to diminished
function of monoamine neurons.

Levine (1960) initiated investigations of anoxic brain
damage first by placing laboratory rats in nitrogen or
nitrous oxide [7]. After twenty minutes in either of
these atmospheres, most animals died but brains of
the survivors were not visibly damaged. Levine then
adopted another method to study experimental oxygen
insufficiency, by tying shut the carotid artery on one
side of the animal’s neck. This also did not cause
visible brain damage. Finally, ligature of one carotid
plus use of nitrous oxide did produce damage of the
hippocampus, neocortex, thalamus, corpus striatum
and pyriform cortex, in decreasing order of frequency.
The Levine procedure produced damage more like
those of Myers (1972) findings following partial hypoxia
in which the brainstem nuclei of high metabolic rate
were spared [8]. The Levine method was used by
other investigators because the resulting pattern of
damage better matched what was expected; for
example Brown and Brierley (1968) adopted Levine’s
method for studying microscopic changes caused by
anoxia within cells [9].

The experimental procedures of Windle, Myers,
Stafford and Weatherall, Mutoh, and Levine, point out
that brain damage due to oxygen deprivation cannot
be precisely predicted. However, it appears that an
array of biochemical mechanisms go into action to
support and protect the strong drive for energy
production in the brainstem nuclei of high metabolic
rate. Factors such as the greater density of
capillaries, higher levels of glucose transport proteins,
and greater blood flow ensure continued function
under adverse conditions, unless oxygen, blood flow,
glucose, and essential nutrients like thiamine are
completely cut off.

Adjustments in blood flow, glucose transport, and
delivery of oxygen take place under abnormal
conditions. Many investigations in which blood flow
and glucose uptake are measured show an increase
of blood flow and/or glucose uptake in the inferior
colliculus; these increases are protective and
controlled by biochemical feedback mechanisms.

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.
Neubuerger KT (1954) Lesions of the human brain following circulatory arrest. Journal
of Neuropathology and Experimental Neurology 13:144-160.
Adams JH, Brierley JB, Connor RC, Treip CS. (1966) The effects of systemic
hypotension upon the human brain. Clinical and neuropathological observations in 11
cases. Brain 89:235-68.
Stafford A, Weatherall JAC (1960) The survival of young rats in nitrogen. Journal of
Physiology 153:457-472.
Mutoh F (1991) Effect of postnatal anoxia on seizure susceptibility in rats: bicuculline-
induced seizures and pretreatment with iproniazid. Life Sciences 48:2563-2569.
Levine S (1960) Anoxic-ischemic encephalopathy in rats. American Journal of Pathology
36:1-17.
Myers RE (1972) Two patterns of perinatal brain damage and their conditions of
occurrence. American Journal of Obstetrics and Gynecology 112:246-276.
Brown AW, Brierley JB. (1968) The nature, distribution and earliest stages of anoxic-
ischaemic nerve cell damage in the rat brain as defined by the optical microscope. Br J
Exp Pathol. 1968 Apr;49(2):87-106.