A pattern of brainstem injury associated with total asphyxia in rhesus monkeys (Ranck and Windle 1959) was noted when gas exchange of the fetus was completely stopped. Similar findings followed clamping of the umbilical cord. An initial abrupt increase in blood pressure occurred when the cord was clamped because of an increase in vascular resistance, and within 90 seconds, bradycardia ensued. Within 20 seconds after bradycardia onset, blood pressure fell. At 60 seconds, systolic and diastolic pressure showed a secondary prolonged rise that peaked at 3 to 4 minutes and then gradually fell again, reaching a nadir at 12 to 15 minutes. Unless resuscitated at this point, circulation stopped. The fetal heart continued to beat without force at a rate of 60 to 70 beats per minute until the monkey was resuscitated (up to 35 minutes after insult). The anesthetized fetus displayed a short series of breathing movements during the second or third minute followed by apnea and then a long series of gasps beginning at the end of 4 minutes and continuing into the 12th to 14th minute of asphyxia. During this period, dramatic changes in acid base values of arterial blood were observed. Within 2.5 minutes, pO2 is maximally depressed; levels as low as 6 Torr being observed. Over 12.5 minutes of asphyxia, blood pH declined in a linear fashion from normal to levels as low as 6.80, and pCO2 increased in a similar fashion to ranges of 130 Torr. Accompanying these changes, base deficit increases linearly to levels as high as 16 mEq/L. The monkey may be resuscitated and show good myocardial response to epinephrine, cardiac massage, and oxygen, despite periods of total asphyxia lasting 30 to 35 minutes, but despite these early responses, total asphyxia lasting beyond 20 minutes resulted in eventual death of the fetus. Resuscitation before 20 minutes increased the likelihood of survival, and in this model, 12 to 13 minutes of total asphyxia were required to produce the first evidence of brain injury. Beyond 12 to 13 minutes, the extent of injury increased with increasing durations of asphyxia, but the risk of fatality also increased.
Ronald Myers extended the work in monkey HIE on over 300 term fetuses (Adamsons et al. 1971, Myers 1972, Brann and Myers 1975, Myers and Brann 1976, Myers 1977) and confirmed their findings. Total asphyxia caused brainstem pathology; partial asphyxia led to severe edema and neocortical damage; partial asphyxia without any major increase in PCO2 or decrease in pH caused white matter injury; and partial followed by total asphyxia, as might occur during breech delivery or prolapse of the umbilical cord, induced basal ganglia damage.
Brainstem Injury Due to Asphyxia
Brainstem structures affected
Human neuropathological evidence and primate models were crucial to understand damage to deep grey matter following asphyxia. Necrosis in striatum and thalamus are discussed elsewhere. Brainstem and cerebellum are often involved. Primary hits are in nuclei listed here. Tegmentum of mesencephalon to medulla is often involved; cranial nerve nuclei, reticular formation and other nuclei. The lesions are almost never haemorrhagic. Tract degeneration in the subsequent days to weeks is expected in the corticospinal tract and perhaps also in the central tegmental tract, which may have an additional influence on imaging. Primary injury to the dentate nucleus on ultrasound is a surrogate marker for injury to brainstem nuclei. Some of these primary lesions can be detected with acute MRI (diffusion and susceptibility weighted sequences especially).
Pontosubicular necrosis is linked to intensive care with hypoxia, hypo- and hypercarbia, not to intrapartum asphyxia (Friede 1972). It can coexist with leukomalacia in preterms. The imaging correlate of pontosubicular necrosis has not been reported yet.
necrosis of the tegmentum of the medulla oblongata (left) and the pons (right), after Schneider et al. 1975 in the human neonate; in this series colliculus superior was the only nucleus often sparedcolumnar tegmental necrosis of the brainstem, after Schneider et al. 1975
Schneider et al. 1975, Sylvester 1960: humans — frequently affected (40–80 per cent): reticular formation, cerebral cortex, thalamus, caudate, dentate nucleus, cranial nerve nuclei, lateral geniculate, cerebral white matter, substantia nigra, cerebellar granular layer and Purkinje cells, subthalamus.
claustrum necrotic in some
obvious predilection for the inferior collicles, but superior collicles also involved in cardiac arrest (Gilles 1963)
regional involvement of thalamus: injury prominent in ventro- and dorsolateral nuclei, often sparing pulvinar and typically absent in mediodorsal nucleus, centre médian and intralaminar nuclei
necrosis in the superior colliculi, after Friede 1989: cardiac arrest encephalopathy
Asphyxia: Hindbrain Involvement
Typical Brainstem Asphyxia
Extending asphyxia to 25 min caused extensive damage to brainstem and thalamus in the monkey model. The neuropathology at two to nine days of recovery revealed microscopic bilateral lesions throughout the neuraxis. A pattern of selective neuronal injury primarily involved primary sensory nuclei, including inferior colliculus, superior olive, medial geniculate nucleus, ventral posterior thalamus, gracile and medial cuneate nuclei, vestibular nuclei, the principal sensory and motor nuclei of the trigeminal nerve. The HIE monkeys also exhibited white matter damage. Myelin degeneration was found in a variety of white matter tracts, including the internal capsule, and appeared to coincide with axonal degeneration. Individual oligodendrocytes in degenerating white matter showed cytopathology.
Similar brainstem and thalamic damage occurs in the term human neonate with HIE (Gilles 1963, Schneider et al. 1975, Friede 1959, Rutherford et al. 1996, de Vries and Groenendaal 2010, Quattrocchi et al. 2016). Some of the reduced motor activity, hypotonia, flaccidity, and depressed or absent deep tendon reflexes can be due to spinal cord injury in the human infant (Sladky and Rorke 1986). Basal ganglia damage was found in globus pallidus, the caudal half of the putamen, similar to term human HIE (Rutherford et al. 1996, de Vries and Groenendaal 2010, Martin and Barkovich 1995, Barkovich et al. 1995, Miller et al. 2005). Minor neuronal loss was evident in the monkey dentate gyrus, but most of the hippocampus appeared normal (unlike the vulnerability of the neonatal human hippocampus, particularly after clinical seizures (Schiering et al. 2014)). Loss of cerebellar Purkinje neurons was largely restricted to vermis.
Asphyxia: Injury to Brainstem (Imaging)
axial view of the mesencephalon with hyperechoic core
It is notoriously difficult to clearly show injury to brainstem tectum or tegmentum with CUS. Even with MRI there is a limit to fine description of structures involved in a process of neuronal death. Hyperechoic change in dentate nuclei is one readily available sonographic finding that indirectly hints to brainstem damage. Interpretation of the clinical findings remains important in this context.
uterine rupture; hypothermia; bust-suppression pattern on EEG; the hyperechoic dentate nucleus in frontal and axial mastoid section; hyperechoic thalamus and putamen
Asphyxia: Injury to Pallidum and Subthalamus
Involvement primarily of pallidum and subthalamus, with dentate nucleus. This is similar to kernicterus although hyperbilirubinemia was not an issue in this infant cooled after asphyxia due to uterus rupture.
SWI sequences, with appropriate windowing, can be helpful to describe areas affected by deep grey matter asphyxia. Fetal distress with meconium staining, followed by cooling.
Asphyxia: Injury to Tegmentum Mesencephali
Unexplained fetal distress, followed by cooling. Pronounced hyperperfusion of several deep gray matter structures, including subthalamus and colliculi. Changes in tegmentum appear to affect tracts as well as neuronal nuclei.
Asphyxia: Hyperperfusion
Asphyxia: Injury to Corticospinal Tract
Immediate encephalopathy from birth, after uneventful delivery (IUGR). MRI day 6, after cooling. Clear diffusion changes in PLIC and CST at brainstem level. (courtesy E Bonafiglia, Verona)
Kernicterus versus Asphyxia
A pallido-subthalamic pattern of injury is different than the thalamo-striate pattern that is typical of acute total asphyxia (Leech and Alvord 1977, Larroche 1977, Hayashi et al. 1991).
Comparison of lesion distribution: asphyxia vs. kernicterus
acute stage, seizures, TSB > 700 µmol/L
von Kossa positive nuclei, not recognized in H&E staining (Changaris et al. 1984)
Differential diagnosis: altered signal of pallidum on MRI
∆∆ altered signal of pallidum on MRI
asphyxia
CO intoxication
manganese storage
polycythaemia (T1 shortening = hypersignal)
PRES
hypoglycaemia
organic acidaemias like glutaric aciduria
mitochondrial disorder
cupper storage (Wilson disease)
neurofibromatosis I
succinic semialdehyde dehydrogenase deficiency
Pontosubicular Necrosis
Characteristic neuronal necrosis (probably programmed cell death by its microscopic signs) in base of pons and subiculum has been repeatedly reported in sick preterm to near term infants (Friede 1972, Takashima et al. 2009). This was linked to hyperoxia (inducing lipid peroxidation in a rat model, Ahdab-Barmada et al. 1986) and to parenteral calcium administration (Changaris et al. 1984). It has male predilection and can coexist with other typical preterm conditions like kernicterus and leukomalacia. Cells appear shrunken with pyknotic or karryorhectic nuclei, with limited astroglial reaction in the acute stage, mild gliosis and microglial reaction in the chronic stage. Lesions extend around subiculum. The pons looks normal on section at postmortem and atrophy without cavitation is the end stage. Cell eosinophilia is not obligate. Some cells suffer from calcium precipitation in the nuclei and cytoplasm, only to be recognized by special stains (van Kossa and alizarin red S). This precipitation seems to depend on the amount of parenteral calcium gluconate administered. The interpretation of pathologists was that this was not due to trophic damage, but a primary hit on these cells.
calcium gluconate precipitates in the nucleus of an inferior olive neuron (electron microscopy, Changaris et al. 1984)a mixture of normal neurons in the base of pons, with shrunken cells that have pyknotic (dark collapsed) or karryorhectic (fragmented) nuclei (Friede 1989)
Karyorrhexis is characterized by loss of definition of the nuclear membrane and disintegration of the nucleus into basophilic granules, including complete loss of basophilic material, typical of apoptosis, with little astroglial reaction. In very low birth weight infants delivered before GA 28 w the distribution spreads to the inferior olivary nucleus, basal ganglia, thalamus and cerebral cortex.
References to Brainstem Asphyxia
Adamsons K, Mueller-Heubach E, Myers RE: Production of fetal asphyxia in the rhesus monkey by administration of catecholamines to the mother. Am J Obstet Gynecol 1971; 109:248-262.
Ahdab-Barmada M, Moossy J, Nemoto EM, Lin MR. Hyperoxia produces neuronal necrosis in the rat. J Neuropathol Exp Neurol. 1986 May;45(3):233-46.
Barkovich AJ, Westmark K, Partridge C, et al. Perinatal asphyxia: MR findings in the first 10 days. Am J Neuroradiol 1995; 16: 427–438.
Brann AW Jr. and Myers RE. Central nervous system findings in the newborn monkey following severe in utero partial asphyxia. Neurology 1975; 25: 327–338.
Clancy RR, Sladky JT and Rorke LB. Hypoxic-ischemic spinal cord injury following perinatal asphyxia. Ann Neurol 1989; 25: 185–189.
de Vries LS and Groenendaal F. Patterns of neonatal hypoxic-ischaemic brain injury. Neuroradiology 2010; 52: 555–66.
Friede RL (1972) Ponto-subicular lesions in perinatal anoxia. Arch. Path. 94, 343–354.
Friede RL (1989) Developmental neuropathology. Berlin: Springer-Verlag. Ch 7. Perinatal lesions of gray matter and Ch 9. Kernicterus.
Gilles FH (1963) Selective symmetrical neuronal necrosis of certain brainstem tegmental nuclei in temporary cardiac standstill. J Neuropath Exp Neurol 22: 318.
Hayashi M, Satoh J, Sakamoto K (1991) Clinical and neuropathological findings in severe athetoid cerebral palsy: a comparative study of globo-Luysian and thalamo-putaminal groups. Brain Dev 13:47-51.
Larroche J-Cl (1977) Developmental pathology of the neonate. North-Holland : Elsevier.
Leech RW, Alvord EC (1977) Anoxic-ischemic encephalopathy in the human neonatal period. Arch Neurol 34:109-113.
Martin E and Barkovich AJ. Magnetic resonance imaging in perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 1995; 72: F62–F70.
Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005; 146: 453–460.
Myers RE: Atrophic cortical sclerosis associated with status marmoratus in a perinatally damaged monkey. Neurology 19:1177-1188, 1969
Myers RE. Two patterns of perinatal brain damage and their conditions of occurrence. Am J Obstet Gynecol 1972; 112: 246–276.
Myers RE and Brann AW Jr. Abruptio placentae in rhesus monkey causing brain damage to the fetus. Am J Obstet Gynecol 1976; 126: 1048–1049.
Myers RE. Experimental models of perinatal brain damage: relevance to human pathology. In: Gluck L (ed.) Intrauterine asphyxia and the developing fetal brain. Chicago: Year Book Medical, 1977, pp.37–97.
Quattrocchi CC, Fariello G and Longo D. Brainstem tegmental lesions in neonates with hypoxic-ischemic encephalopathy: magnetic resonance diagnosis and clinical outcome. World J Radiol 2016; 8: 117–123.
Ranck JB Jr. and Windle WF. Brain damage in the monkey, macaca mulatta, by asphyxia neonatorum. Exp Neurol 1959; 1: 130–154.
Rutherford M, Pennock J, Schwieso J, et al. Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child Fetal Neonatal Ed 1996; 75: F145–F151.
Schiering IA, de Haan TR, Niermeijer JM, et al. Correlation between clinical and histologic findings in the human neonatal hippocampus after perinatal asphyxia. J Neuropathol Exp Neurol 2014; 73: 324–334.
Schneider H, Ballowitz L, Schachinger H, et al. Anoxic encephalopathy with predominant involvement of basal ganglia, brain stem and spinal cord in the perinatal period. Report on seven newborns. Acta Neuropathol 1975; 32: 287–298.
Sladky JT and Rorke LB. Perinatal hypoxic/ischemic spinal cord injury. Pediatr Pathol 1986; 6: 87–101.
Takashima S, Itoh M, Oka A. A history of our understanding of cerebral vascular development and pathogenesis of perinatal brain damage over the past 30 years. Semin Pediatr Neurol. 2009 Dec;16(4):226-36.