ASPHYXIA: DEEP GREY MATTER INJURY - keywords
asphyxia deep grey matter
--> kernicterus
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
- 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
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asphyxia: deep grey matter injury: status marmoratus and dyskinetic CP
Differentiation from kernicterus is straight forward clinically and on imaging. Kernicterus displays a characteristic pattern of apoptotic injury to globus pallidus and subthalamic nucleus, best recognised in susceptibility weighted sequences in the acute stage.
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Human neuropathological evidence on asphyxia was crucial to understand damage to deep grey matter. Status marmoratus (“the marbled state”) refers to residual damage in deep grey matter as white streaks and whorls affect head of caudate, anterior dorsal putamen and dorsal thalamus. These streaks are due to - but microscopically normal - myelination within astroglial scars containing only encrusted (ferruginated) neurons (e.g. in thalamus). Primate models of acute total asphyxia, at two to nine days of recovery, revealed selective bilateral neuronal lesions. Cavitation is not seen in thalamus, in accord with the experimental finding that this is selective neuronal death and not tissue infarction. A distinct pattern of regional involvement of thalamus became apparent, subject to variation. Transsynaptic degeneration of thalamic neurons can be differentiated from primary thalamic injury by its absence of neuronal calcification and by predilection for the posterior region (pulvinar).
The children with pure basal ganglia and thalamus lesions tend to have dyskinetic CP but less pronounced cognitive deficits, whereas additional rolandic and especially hippocampal involvement lead to retardation of motor and cognitive development and severe bilateral spastic CP.
Hypoxia and cerebral hypoperfusion must be manifest to provoke neurological damage if separated. In combination they induce anaerobic metabolism in the brain with local acidosis (especially lactic acidosis): asphyxia is the term that covers such situation.
Neurons are more prone to asphyxia than glia. Only when neuronal necrosis is associated with endothelial necrosis and a disruption of the blood-brain barrier, the whole tissue may become infarcted. The clinical neurological picture following asphyxia is named hypoxic-ischaemic encephalopathy (HIE).
Intermediate steps in the chain of events are:
- energy failure with an increase of extracellular adenosine and triggering of oxidative phosphorylation;
- excessive release of glutamate in the synaptic cleft with depolarization of the postsynaptic neuron;
- increase of the intracellular calcium concentration;
- calcium induced production of enzymes degrading structural elements and cell enzymes;
- synthesis of arachidonic acid and free radicals.
asphyxia: deep grey matter injury: molecular cascades that lead to neuron death
scoring system
asphyxia: deep grey matter injury: imaging in vivo
posterior putamen only
atypical thalamus injury
injury to brainstem
behaviour of thalami in relation to event timing
hyperechoic thalami intrapartum antepartum recent. antepartum old
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day 1 no no yes
day 3 yes no yes
day 7-14 yes/no yes yes
diffusion MRI sequence
imaging changed by hypothermia
injury to striatum
Typical of changes to thalamus and striatum in asphyxia is that the injury is symmetrical.
CUS: Hyperechoic change due to cell response to neuronal injury starts in thalamus from day 2 on. Extensive changes may affect nearly all regions of thalamus in extreme asphyxia, but often a hyperechoic change in lateral thalamus is most striking. Thalamic hyperechoic change may subside in week two after an insult, to return in full after that time because of encrustation of neurons with iron and/or calcium.
MRI: DWI changes in thalamus may start on day 1 and persist for about 10 days. There can be progression in the extent of DWI change in the first week of life, with a tendency for thalamic changes to precede those in putamen. Long term changes leave a thalamic L-sign, likely a combination of primary injury to ventrolateral thalamus and of network injury to pulvinar.
luxury perfusion in veins
false negative ADC findings
conventional MR intensity changes
typical ADC changes
evolution in CUS
outcome based on imaging
echoic columns of injury
early haemorrhagic conversion
discrepancy
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asphyxia: deep grey matter injury: references
asphyxia: the complete asphyxia model in piglets
The hypoxia - complete asphyxia model (HI) in piglets is relevant to asphyxia in the full-term neonate (Brambrink et al. 1999, Maller et al. 1998, Johnston 1998, Roland et al. 1998). It combines systemic hypoxia followed by complete asphyxia as a model of worsening oxygenation. Airway occlusion of 7–8 min alone is not sufficient to produce significant brain damage, whereas longer durations of hypoxia produce asystoly and difficulties in resuscitating the heart. However, ventilation with 10% O2 for 30–45 min before 7–8 min of airway occlusion leads to reproducible regional brain damage.
In one-week-old piglets damage prefers primary sensory and forebrain motor systems (Martin et al. 1997). This is progressive. The cerebral cortex, thalamus and basal ganglia are specifically vulnerable. Based on electrophysiological mapping the neocortical area that is most vulnerable to HI corresponds to motor cortex and primary somatosensory cortex (Woolsey et al. 1946, Craner and Ray 1991). The most vulnerable region of piglet striatum (i.e. central putamen) appears to be the sensorimotor-recipient region, based on known corticostriatal connectivity in other mammals (Jones et al. 1977). In diencephalon, thalamic relay nuclei for somatosensory (ventral posterior nucleus), visual (lateral geniculate nucleus), auditory (medial geniculate nucleus), and motor (ventral anterior/lateral) systems are consistently damaged. In brainstem, visual (superior colliculus) and auditory (inferior colliculus) relay nuclei are predisposed to injury. This distribution of neonatal brain damage seems dictated possibly by regional connectivity, function, and mitochondrial activity (Martin et al. 1997). This theory is called the connectivity-metabolism hypothesis for brain damage in newborns.
Selective vulnerability of the basal ganglia in this model is striking (Martin et al. 1997). Putamen is most vulnerable and death of striatal neurons after HI in piglets is by necrosis (Martin et al. 2000). Damage to the Golgi apparatus and rough endoplasmic reticulum (ER) occurs at 3–12h, while most mitochondria appear intact until 12h. Mitochondria undergo an early suppression of metabolic activity, then a transient burst of activity at 6h after the insult, followed by mitochondrial failure. Cytochrome c is depleted at 6h after HI, failing to accumulate in the cytosol, and is not restored thereafter. Lysosomal destabilization occurs within 3–6 h after HI consistent with the lack of evidence for autophagy in striatum.
By 3-h recovery, glutathione levels are reduced in striatum (Golden et al. 2001). Peroxynitrite-mediated oxidative damage to membrane proteins occurs at 3–12 h after HI, and the Golgi apparatus and cytoskeleton are early targets for extensive tyrosine nitration. Striatal neurons sustain hydroxyl radical damage to DNA and RNA within 6h after HI. The early emergence of this injury coincides with elevated NMDA receptor phosphorylation, recruitment of neuronal NOS to the synaptic/plasma membrane, and oxidative damage by 5 min after reoxygenation (Mueller-Burke et al. 2008). This demonstrates that neuronal necrosis in the striatum after HI in piglets evolves rapidly and would be difficult to protect against in piglet. Early implemented interventions will thus be required to protect the basal ganglia region from HI.
In parasagittal sensorimotor cortex, neuronal cell death progresses more slowly than in basal ganglia in this model. Whereas some neuronal cell death can be detected between 6 and 24 h, the majority of the neurons die between 24 and 48 h. When delayed cell death in cortex is severe, the piglets develop clinical seizures between 24 and 48 h, a time of onset that is similar to that seen in human newborns with severe HIE. The occurrence of clinical seizures is associated with panlaminar necrosis in somatosensory cortex and augmented neuronal loss in hippocampus.
Martin et al. 1997: NN piglet selective vulnerability
- putamen, subthalamic nucleus, SNr, ventrolateral thalamus and geniculates, tectal nuclei
- somatosensory cortex (mainly IV/V, upper third convex and mesial, depth > crown); also cingular, insular and mesial occipital cortex (Azarelli et al. 1997)
hippocampal dentate gyrus control versus asphyxia d9
Myers 1969: parasagittal cortical necrosis and status marmoratus
inferior colliculus control versus asphyxia d9
asphyxia: neuropathology in the total asphyxia model in rhesus monkeys
Ranck and WIndle 1959
The clinical presentation after this total type of asphyxia was variable. Some developed acute bilateral rigidity and then alternating flaccidity and rigidity, indicative of pathology in descending motor pathways, including corticospinal, rubrospinal, and reticulospinal tracts (Lawrence and Kuypers 1968, Lawrence and Kuypers 1968, Sukoff and Ragatz 1980, Baker 2011, Cahill-Rowley and Rose 2014) and spinal pathology. They also exhibit attenuated vestibulo-ocular and pupillary light reflexes and oral motor dysfunction, consistent with brainstem pathology (Brandt and Dieterich 1994, Quattrocchi et al. 2016). Other monkeys showed acute inability to right with diminished appendicular tone, inactivity, and hypo-responsiveness, but by six days muscle tone reappeared with paretic and ataxic walking. Other monkeys display athetoid movements, inability to right and status epilepticus.
The neuropathology at two to nine days of recovery revealed microscopic bilateral lesions throughout the neuraxis (Ranck and WIndle 1959). A pattern of selective neuronal injury primarily involved 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. Similar brainstem and thalamic damage occurs in term human HIE (Schneider et al. 1975, Rutherford et al. 1996, de Vries and Groenendaal 2010). 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). 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 Purkinje neurons was largely restricted to the vermis. Damage to the cerebral cortex involved isolated necrotic degeneration of pyramidal neurons. Seizure presence correlates with the amount of cortical necrosis in humans (Clancy et al. 1989). The HIE monkeys also exhibited white matter damage. Myelin and axonal degeneration was found in a variety of white matter tracts, including the internal capsule. Oligodendrocytes in degenerating white matter showed cytopathology (Gilles and Murphy 1969).
Of interest in this model is that the duration of asphyxial insult necessary to produce microscopic brain injury increased dramatically with decreasing gestational age, ie, 12 minutes at term compared with 30 minutes at midgestation. These findings are in accord with all other subprimate species studied.
Faro and Windle in 1969 studied another cohort (n 12) of neonatal HIE monkeys survived for 10 months to 9 years of age. Again, these monkeys showed minimal delayed damage to hippocampus. Progressive pathology was not evident in the putamen, globus pallidus or cerebellum. In contrast, the spinal cord showed atrophy of the dorsal horns and intermediolateral columns, and the brainstem pathology evolved, particularly in cochlear nuclei. The thalamus had protracted secondary pathology including the anterior ventral, ventral anterior and centromedial nuclei and the pulvinar. The primary motor and somatosensory cortices underwent apparent transneuronal degeneration and atrophy. These monkeys underwent behavioral testing during their lifetime.
Ronald Myers and coworkers extended the work in monkey HIE on over 300 term fetuses during the 1960s and 1970s (Adamsons et al. 1971, Myers 1969 and 1972, Brann and Myers 1975). 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.
neuron surrounded by macrophages in thalamus
asphyxia: perfusion and acidosis in the total asphyxia model in rhesus monkeys
During this period, dramatic changes in acid base values of arterial blood are observed. Within 2.5 minutes, pO2 was maximally depressed; levels as low as 6 mm Hg being observed. Over 12.5 minutes of asphyxia, blood acidosis in a linear fashion from normal to levels as low as 6.80, and pCO2 increased in a similar fashion to ranges of 130 mm Hg. 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. Extending asphyxia to 25 min produced more extensive damage in brainstem and thalamus.
In 1959, Ranck and Windle asphyxiated five near-term (157–164 days’ gestation, term 166 days) Macaca mulatta fetuses (rhesus monkeys) by hysterectomy and waited 11–16 min before opening the amniotic sac and resuscitating with pulmonary insufflation with oxygen. A pattern of brainstem injury associated with total asphyxia was noted when respiratory gas exchange was completely stopped. Similar findings followed upon clamping of the umbilical cord, after catheterization of one femoral artery and placement of electrocardiographic leads, followed by placing a rubber sac over the head to prevent breathing.
An initial abrupt increase in blood pressure occurred when the umbilical 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, the fetus remained pulseless, and circulation stopped. Despite this, the fetal heart continued to beat 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 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.
Koehler et al. 2018
asphyxia: neuronal death during asphyxia
Necrosis. Central to ischaemic cell death is excitation of the cell by glutamate, elevation of iCa++ and formation of oxygen free radicals. Selective injury to putamen, thalamus and cerebral cortex isrelated to excessive activation of neuronal NMDA and AMPA type glutamate receptors, while brainstem injury may be related primarily to stimulation of neuronal AMPA/kainate receptors. Cells dies from overexcitation. A phase of subsequent mitochondrial impairment during the early recovery period, precedes deterioration (Leaw et al. 2017). Secondary energy failure concurs with oxidative stress and glutathion depletion. iCa++ rises acutely during the insult and again - after hours of delay - during secondary energy failure. The rise of iCa++ is slower and less pronounced in immature neurons.
Apoptosis. Cells may also die by apoptosis, depending on a pivotal role for the mitochondria without or with enough residual function (Hagberg 2004, Thornton and Hagberg 2015). Apoptosis is induced by events at the cell membrane or in the mitochondrion. More specifically mitochondrial respiration is suppressed and calcium signaling is dysregulated. At a certain threshold, mitochondrial permeabilization activates caspase-dependent apoptotic cell death. Ischaemia also induces inflammation, by release of TNF-α, TRAIL, TWEAK, FasL and Toll-like receptor agonists that activate death receptors on neurons and oligodendroglia.
Apoptotic cell death is also seen in epilepsy and hypoglycaemia.
In addition, cells in connected networks, not primarily directed to necrosis or apoptosis, may still wither in the hours to days following it, because of overexcitation by spreading epileptic acitvity, retrograde effects of axon destruction and loss of neurotrophic feedback from targets of their axons (Edwards et al. 1997, Nakajima et al. 2000, Northington et al. 2001).
McQuillen and Ferriero 2004: asphyxia
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- apoptotic-necrotic continuum in cortex and basal ganglia, apoptosis in thalamic sensory relay cells (VL thal and LG)
- selective vulnerability of striatal projection neurons that do not express NOSynthase activity
Hybrid types of cell death are well reported in the neonatal brain following HIE (Martin et al. 1998, Rocha-Ferreira and Hristova 2016). The term “apoptotic-necrotic continuum” refers to cells exhibiting typical programmed cell death features such as pyknosis, caspase-3 activation and nuclear condensation, along with non-programmed cell death characteristics (Rocha-Ferreira and Hristova 2016). The term necroptosis has been used to contain both processes. Northington et al. 2007 suggest that the predominant form of cell death following neonatal HI injury is necroptosis with partial activation of the caspase cascade, as well as transitional forms of cell degradation markers. This would explain why within 24 h following an ischaemic event brain markers of apoptosis such as caspases 3 and 9 are abundant, but there is no ultrastructural evidence of apoptotic cell death. Diffusion-weighted MRI agrees with the preponderance of necrosis or necroptosis, because injured cell clusters or nuclei have restricted diffusion which is unexpected in clean apoptosis (like in the acute stage of kernicterus where cell death in globus pallidus is not detected by diffusion weighted MRI).
A fourth cell death mode, autophagy may play an important role as well.
Because of these complexities the term selective neuronal death is more appropriate than selective neuronal necrosis. Clean apoptosis is seen in more immature brains and in deafferentiated neurons (loss of trophic support), but also in delayed cell death where neurons survived primary necrosis that affected neighbour cells. Apoptosis is rather typical of certain nuclei like the base of pons, the subiculum and the internal granular layer of cerebellar cortex (the imaging correlate of pontosubicular necrosis in relation to hypoxia, has not yet been defined). Non-neuronal cells, blood derived macrophages and leukocytes, also undergo apoptotic death in injured areas. In striatum and cortex necrosis seems to prevail, apoptosis being more dominant in thalamus.
Necrosis follows the maturation phenomenon, i.e. the more severe the insult the shorter the time course of cells in their necrotic process, but in cortex and striatum the necrotic cycle is complete in around three days. Apoptosis can follow a similar fast course, but in some instances it may also take up to one week for a neuron to slowly die. The delay between insult (often hours before delivery) and admission on the ward of an asphyxiated infant and the complexity of cell death in different brain regions, ongoing for several days, makes treatment difficult: actually the belief prevails that combining early neuroprotective drugs together with cooling may help some children with moderate asphyxia. Currently, therapeutic hypothermia is the only treatment available after severe intrapartum asphyxia.
enhanced expression of EAA receptors (NMDA, MGluR5) in immature brain cortex
Excitotoxicity is an important mechanism involved in perinatal brain injuries (Johrnston 2005, Kostandy 2012). Glutamate is the major excitatory neurotransmitter, and most neurons as well as many oligodendrocytes and astrocytes possess receptors for glutamate. The activities of certain ionotropic glutamate receptor/channel complexes are enhanced in the immature brain to promote activity-dependent plasticity. Excessive stimulation of glutamate receptor/ion channel complexes triggers calcium flooding and a cascade of intracellular events that results in apoptosis and/or necrosis. Elevated intracellular calcium will lead to mitochondrial dysfunction, activation of proteases, accumulation of reactive oxygen species and release of nitric oxide.
https://nl.wikipedia.org/wiki/NMDA-receptor
http://pittmedneuro.com/glutamate.html
asphyxia: NMDA receptor overactivation
Selective injury to the putamen, thalamus and cerebral cortex from near total asphyxia in term infants may be related to excessive activation of neuronal NMDA and AMPA type glutamate receptors, while brainstem injury may be related primarily to stimulation of neuronal AMPA/kainate receptors.
Interruption of the cascades of glutamate-induced cell death during ischemia may provide a way to prevent, or at least reduce, the ischaemic damage. Various therapeutic options are suggested: inhibiting the glutamate synthesis or release, increasing its clearance, blocking of its receptors or preventing the rise in intracellular calcium.
Friede 1989: karyorrhexis of subicular neurons in pontosubicular necrosis
asphyxia: necrosis versus apoptosis
asphyxia: neuronal death modes
after Truttmann et al. 2020
asphyxia: signal intensity changes on MRI following term birth asphyxia
Normal neonatal cortex intensity on MR (up to ≈ 3 mo):
- short T1 (brighter) and short T2 (darker), with longer white matter T1 and T2 → obvious cortex/white matter differentiation
- gradual prolongation of cortical values causes loss of differentiation near 3 months post term
- cortical highlighting by HIE and changes in white matter signal intensity were well documented in early research on this topic
- references to diffusion imaging in asphyxia: Soul et al. 2001, Barkovich et al. 2006, Swarte et al. 2009, Imai et al. 2018, Annink et al. 2020)
coronal scan with 4 columns of deep grey matter damage and extensive cortical necrosis: TBG 6, CWM 6
The Rotterdam score (n=80, Swarte et al. 2009), listed below, is a derived expansion of the Barkovich et al. 1995 score. Either MR (any sequence) or ultrasound with unequivocal findings can acknowledge damage to a brain part, day 3 after birth or later, only in term infants:
- in light blue: extensive deep grey matter injury
- in green: watershed subcortical injury
- in dark blue: leukomalacia at term
- in red: isolated cortical necrosis.
Other scores were compared with each other in Langeslag et al. 2022. It is logical that the extent of damage on imaging correlates with outcome, and that MR quality is paramount. How to use these scores in redirection of care, is for several reasons, not generalisable, but scoring damage on images is essential in such decisions.
asphyxia: Rotterdam scoring system
On MRI affected deep nuclei develop a higher than normal signal intensity on T1 from day 4 to the end of the first month (or permanently), accompanied by low signal intensity on T2.
Perirolandic and peri-insular cortical highlighting (high signal on T1 and low signal on T2, especially in the depths of the sulci) is variably associated with TBG scores 3 to 6.ADC values are low even within the first day, but exceptions exist where affected nuclei have normal ADC values. ADC values normalise around the end of the first week.
In asphyxia network effects in tracts cause diffusion changes in addition to local damage of axons and collateral effects of nearby cells in thalamus and putamen. Signal inversion refers to altered signal intensity on T1 MR.
CWM cortex and white matter
PLIC posterior limb of the internal capsule
TBG thalamus and basal ganglia
Thompson et al. 1997
moderate HIE 0.1 % - handicap in 25 %
severe HIE 0.1 % - handicap in 90 %
Clinical phenotypes are arbitrarily separated into subacute partial and acute near-total type, following insights from animal studies.
Sonographic changes other than brain swelling will, as a rule, not be found after asphyxia with mild encephalopathy (Sarnat grade 1).
The group for which imaging is most relevant consists of babies with moderate encephalopathy, usually presenting with hypotonia and clinical seizures.
Criteria have been suggested to withhold the diagnosis of intrapartum asphyxia (Hankins and Speer 2003):
4 major criteria are obligatory:
- severe metabolic acidosis
- HIE = hypoxic-ischaemic encephalopathy
- later development of CP
- exclusion of other causes than intrapartum asphyxia.
At least 3 of 5 minor criteria to retain the diagnosis “intrapartum”:
- a sentinel event before or during labour
- an abnormal CTG preceded by a normal recording
- Apgar score ≤ 3 at five minutes
- multi-organ failure/ 72 h of birth
- acute brain injury on imaging.
asphyxia: criteria and clinical scores
Sarnat and Sarnat 1976
management overview
An asphyxiating insult is often accompanied by a period of systemic and - when pronounced - subsequent brain hypoperfusion. If such change is gradual there is a temporary attempt to compensate for a deficit in perfusion by redistribution of flow from the neocortex to the deep nuclei and brainstem. This leads to (sub)cortical injury. In case of arrest of perfusion there is no compensatory redistribution and deep nuclei as well as brainstem nuclei are preferentially hit.
The primary insult in birth asphyxia occurs in utero and is therefore only detailed by experimental work. The fetus moves from a compensated to a decompensated state: when oxygen delivery drops to 25-50 % acidosis develops, the metabolic rate drops and there is a gradual decline of perfusion, with (dependent on the tempo of ischaemia) redirection of blood to brainstem and diencephalon and a total body diving reflex. When oxygen delivery drops below 25 % for over 5 minutes this is followed by bradycardia, acidosis, deep hypotension, further drop in perfusion, increased carotid vascular resistance and thus ischaemia in brainstem and diencephalon. The fetus becomes very acidotic (pH < 7.0, base deficit over 20 meq/L), apnoeic, with an inactive EEG and an elevated ST segment of the ECG. Brief (< 5 min) but repetitive insults also exhaust myocardial glycogen.
Damage is modulated by circumstances: (1) cause, extent and duration of the insult; (2) gestational age (the intensity of metabolic activity codetermines which zones are vulnerable and this sensitivity varies with maturation); (3) the pre-existence of fetal growth retardation; (4) the repetitive character of an insult; (5) timing and effectivity of postnatal treatment; (6) priming of neurons by transplacental drugs; (7) temperature in and ex utero in the hours to days surrounding the insult; (8) placental function; (9) seizure burden.
the 10 min rule
NMDA
the deep grey matter type
neuronal death
in vivo imaging
piglets
molecular chain
the complex human situation
all injury patterns
autophagy
mitochondrion
monkeys
causes
decelerations
stages and mechanisms
clinical phenotypes
dynamics
asphyxia: deep grey matter injury: perfusion dynamics and overview
clinical scores
asphyxia: evolution of fetal distress
after Gunn et al.
CFM traces (compressed and demodulated information from a few leads)
When confronted with a bad start at (near) term, there is a complicated diagnostic and therapeutic challenge for several days. Congenital anomalies and trauma are excluded by imaging and details of the clinical history. Total body hypothermia is started on immediate criteria and on a few hours of clinical and electro-encephalographic follow-up (Shah et al. 2025). Serial CUS end a day 4 or 5 MRI with diffusion sequences often provide clear views of regional injury.
Neither 36-h anesthesia nor 24-h hypothermia produced adverse effects at 4-day survival on a panel of neural death markers in newborn piglets (Gressens et al. 2015). This is in contrast with other findings in piglets (Wang et al. 2015) where apoptosis in piriform cortex was greater in hypoxic-asphyxic, rewarmed piglets than in naive/sham piglets. Caspase-3 inhibitor suppressed apoptosis with rewarming. Rapidly rewarmed piglets had more caspase-3 cleavage in cortex than did piglets that remained hypothermic or piglets that were rewarmed slowly. Cooling may also lead to disseminated intravascular coagulation, cardiac dysfunction and skin necrosis (Kumar et al. 2021). In addition there are drawbacks on the need to use mechanical ventilation and opioid use in many asphyxiated infants.
full EEG time-synchronised
aEEG (CFM or cerebral function monitoring) has become standard in brain monitoring until rewarming. This estimates extent of dysfunction, the need to remedy seizures and provides prognostic information that - coupled to imaging - is a basis for parental communication and in many cases an appropriate discussion about redirection of care.
asphyxia: dynamics of management
asphyxia: causes
cord knot
uterine rupture
tight cord
abruptio/solutio placentae
Although pure presentation phenotypes of asphyxia are observed in term human neonates, the picture is often more complicated than in animal models. But the subacute type with subcortical injury and the acute total type with injury to deep grey matter, certainly exist. Thalamic neurons start to die after 10 minutes of severe bradycardia or asystoly.
asphyxia: clinical phenotypes
Biological changes are separated in four stages with time from the insult on (Gunn et al. 2000).
after Gunn et al. 1997 in fetal sheep model
asphyxia: deep grey matter injury: biological stages
These studies suggest that a 30-minute time frame may be :
- too long in situations when there is (near) complete obliteration of blood flow to the fetus;- too short for the management of nonacute, progressive hypoxemia for which intrauterine resuscitation measures such as maternal oxygen administration, intravenous fluids, maternal positional changes, and discontinuation of uterine stimulation may prevent the need for surgical intervention. The ongoing debate about the value of electronic fetal monitoring has focused primarily on the fact that most variant fetal heart rate (FHR) patterns are poor predictors of fetal acid–base status (Fahey 2014, Parer and Ikeda 2007, Macones et al. 2008). Attention goes to FHR patterns classified as indeterminate: neither normal nor abnormal. Given that a majority of fetuses will have an FHR pattern considered indeterminate at some point in labor, this is an important topic. It is relevant for providers to be able to recognize those patterns that signal the presence of developing acidemia and those that signal the potential presence of an acute obstetric complication that can quickly lead to acidemia and fetal asphyxia, such as a placental abruption or uterine rupture. Early identification of these FHR patterns, and immediate intervention to improve oxygenation or expedite birth, may help improve outcomes.
asphyxia: the 10 minute rule
time scale of regional damage in a carotid occlusion model in fetal sheep (Williams et al. 1992)
For obstetricians the accepted decision-to-delivery interval in the most urgent cases is 30 minutes. The evidence is that this is too slow to avoid ischaemic brain damage in a number of fetuses. Human cases of acute profound hypoxic ischaemia in which the insult duration can be timed with precision remain rare and there is often uncertainty about the prior state of fetal health. While there is clear variability both in the fetal reserve and in the duration and degree of the insult, we think that that damage begins to accrue after 10 minutes of an acute profound hypoxic ischaemic insult (Rennie and Rosenbloom 2011).
In monkeys near term, anaesthetised with isoflurane, the umbilical cord was exteriorised and then clamped for 12–15 minutes. The animals were subsequently delivered by caesarean section, resuscitated with positive pressure ventilation, and studied with EEG and MRI in the neonatal period (Juul et al. 2007). After 15 minutes of clamping, the umbilical cord pH was 6.86 with a base deficit of 23 mmol/l and the animals took between 13–30 minutes to take their first breath. 12 Minutes did not produce a reliably severe insult using this model, whereas 15 minutes did. Results confirm the very short time between no damage and damage: after 15 minutes of clamping 100% of these animals had significant brain injury.
In a retrospective study of 106 human cases of uterine rupture between 1983 and 1992, fetuses exposed to prolonged deceleration could survive without asphyxia if they were delivered before 17 minutes had elapsed, but several babies developed neonatal morbidity after 10 minutes of a prolonged deceleration if there had been previous late decelerations (range 36–90 minutes)(Leung et al. 1993).
T
hyperechoic change in ventrolateral thalamus and dentate nucleus, day 16
term infant, before hypothermia era
dentate nucleus
P
Injury to thalamus is:
- easy to detect by serial US, lateral thalamus gradually becomes hyperechoic in the first days after acute total asphyxia
- as ventrolateral thalami are affected, two columns of echoic change emerge sparing mediodrodal thalamus; if putamen is affected, another two columns parallel to the thalamic ones, appear; PLIC stands out hypoechoic between these columns
- to read thalamic lesions, certainly in the cooling era, may be difficult in conventional MRI, but changes are often well seen on DWI, subdivision of affected thalamic nuclei is possible
- clear deep grey matter damage is often accompanied by the burst-suppression pattern on aEEG
- SSEP can be a useful adjunct to diagnosis.
complete injury
early injury to thalamus
asphyxia: columns of injury to thalamus and/or striatum
typical 4 column injury in coronal section
hyperechoic caudate head C, ventrolateral thalamus VL, putamen P and globus pallidus GP
hyperechoic caudate head C and mediodorsal thalamus MD associated with asphyxial leukomalacia during term birth asphyxia
C
MD
VL
asphyxia: injury to striatum
GP
Following an intrapartum insult, striatum starts to become hyperechoic on day 3 in infants where haemorrhagic conversion of the injured areas did not occur. The 4 injury columns PTTP start to become visible, also very clearly seen on proton density MRI and on diffusion weighted sequences. Putamen can be involved entirely or selective in its caudal part. Caudate head may or may not be affected in the process, the same goes for globus pallidus.
Caudate head and putamen may also change in imaging intensity in the context of network injury due to extensive damage to cortex and or white matter above it.
typical putamino-thalamic injury, exitus day 4, before the cooling era
I
I
same infant
I
I
day 4
evolution to a “bright" brain by extensive cortical neuronal death
Barkovich - Vigneron, AJNR 20069: serial diffusion weighted MRI and MRS: parameters deteriorate towards day 4-5 and then normalize —>
- crucial: interval insult to scan
changes in microstructure (average diffusion) may diverge from changes in metabolites
- PLIC signal inversion on T1 is not seen within 48h of insult
- on day 1-2 only DWI changes in thal VL and striatum; extensive changes in striatum and cortex day 3-5
- in routine care, it is exceptional since administration of hypothermia, to have a sequence of MR scans; often a decisive scan is performed on day 4 or 5 at the end of cooling
asphyxia: a sequence of changes in diffusion weighted MRI
day 1
HT
S
Injury to neurons is clearly demarcated by this haemorrhagic conversion, also in amygdala A, septum and rolandic cortex R. T2 MRI on day 4. Notice sparing of the caudate head.
vl
Term infant with second day scans demonstrating acute haemorrhagic conversion of deep grey matter injuries following uterine rupture. Typical hyerechoic change in striatum S, hypothalamus HT and thalamus T. The PLIC (posterior limb of the internal capsule) stands out by normal echopoor appearance in the absence of neuronal death, which is in contradiction with the use of the signal intensity of PLIC in MRI. Pulvinar is not affected. Ventrolateral and ventroposterior nuclei of thalamus are clearly affected.
A
R
vp
asphyxia: early haemorrhagic conversion
fetal distress, bad start, hypothermia, discontinuous EEG; day 6 scans with hyperechoic thalami (microconvex probe and high resolution linear probe) and normal ADC map
It has become the experience of many centres that hypothermia may not have changed the patterns of injury, but certainly delayed the changes at cell level and mitigated them. Especially intensity changes in thalamus, both aa CUS and MRI have become a challenge deciding whether or not to redirect care. More discrete imaging changes may correspond to subtler or even absent motor sequelae.
asphyxia: hypothermia and questionable signal intensity change of thalamus
day 3 ACA flow profile: no luxury perfusion
Absence of luxury perfusion in spite of deep grey matter and brainstem injury.
asphyxia: severe deep grey matter injury but absence of luxury perfusion
Term infant with clear intrapartum event, damage to thalamus and striatum but false negative findings on ADC map in day 5 MRI. Fetal bradycardia, followed by emergency caesarean section. Apgar scores 0/2 at 1 and 5 minutes. First postnatal pH 6.79 with lactate 17 mmol/L. First day EEG not discontinuous but with theta dominance. The conclusion must be that interpretation of ultrasound and conventional MR findings remains important in term asphyxiated infants that have been cooled.
asphyxia: discrepant ADC changes following hypothermia
asphyxia: injury to posterior putamen only
Term, premature rupture of the membranes, maternal fever, late bradycardia leading to emergency caesarean. Hypothermia. Clinical and electorgraphic seizures, burst suppression EEG after starting anticonvulsants. Subtle injury to posterior putamen, doubt about thalamus because not affected on MR.
asphyxia: typical damage in spite of cooling
bad start without sentinal event at term; burst suppression EEG; hypothermia; scans day 14; hyperechoic thalami and dentate nucleus
asphyxia: atypical injury to thalamus
A bad start at birth, in term infants, is not synonym to asphyxia. There may be different mechansims at play than during typical acute total or partial asphyxia. So it is not uncommon to observe imaging patterns that are not characteristic. This only means we need other data to understand such occurrences.
absent luxury perfusion
Term, uterine rupture, Apgar score 0/1 at 1 and 5 minutes. Flat EEG, clinical coma. Hypothermia.
Luxury perfusion in deep veins, not in the afferent artery. Deep grey matter damage, in the absence of cortical injury, is often not related to typical arterial luxury perfusion profiles, even when brainstem and dentate nucleus are also affected. High velocities in a deep vein do suggest some degree of overperfusion.
inconsistent luxury perfusion
asphyxia: luxury perfusion in the venous compartment
asphyxia: relatively subtle imaging findings in contrast with early sequelae
IUGR and finally fetal distress leading to emergency caesarean section. Metabolic acidosis. Clear sequelae within the neonatal period, suggestive of injury to brainstem and thalamus. Abnormalities on CUS and MRI on the contrary were relatively subtle.
typical late neonatal sequelae on T1 MRI with gliotic and calficied scars in thalamus and pallidum; dyskinetic CP and swallowing dysfunction; brainstem changes not diagnostic on T1 MR
<--
dystocia (uterine hypertonia), emergency caesarean, seizures at 12h, easily treated, T2 MR at 24 mo, athetoid quadriplegia, normal mental DQ; minimal changes in caudal putamen may delay the presentation of dyskinetic CP for a few years
mild injury to deep grey matter: 10-15 % CP
moderate injury: 60-75 % CP
severe injury: 98 % CP
comorbidities: epilepsy, learning problems, cerebral visual impairment
(Martinez-Biarge et al. 2011, Ferrari et al. 2011, Thoresen et al. 2021)
striatal connections
In many neonatal units, clinicians in charge try to present the parents a balanced prognostic analysis. This is the result of accumulated data: history, evolution of acidosis, seizure burden, evolution of the EEG background, results of SEPP and ABR, clinical response after cooling taking into account the influence of serum levels of sedatives and anticonvulsants, but especially serial CUS and a careful extensive MR analysis on day 4 to 6. There is ample evidence that a good review of the extension of damage can be made near the end of week one. Often the result of such analysis is discussed with the parents before deventilation. The introduction of hypothermia, along with other social trends, has changed the policy of redirection of care substantially. In addition there is a lack of growing insight due to near disappearance of neuropathological comparison with in vivo imaging.
Detailed description of prognostication is beyond the aim of this item chapter. The outcome feared with 4 column injury to thalamus VL and putamen, is dyskinetic CP. Even limited changes to putamen my lead to delayed onset of dyskinetic CP. On the other hand clear changes to putamen in the absence of extensive thalamic injury may not lead to CP. There is still room for clinical research in this field. Children surviving with brainstem injury often present with severe feeding problems, opthalmoplegia and motor disability with CP.
Hypothermia seems to reduce the likelihood of injury in deep gey matter, white matter and PLIC (Natarjan et al. 2016, Langeslag et al. 2022); it seems to delay by 2-3d the pseudonormalisation of diffusion restriction (Bednarek 2012). Isolated extensive thalamic injury is seen early (scans day 1-3), and focal thalamic and basal ganglia injury is seen later (day 4-7). On the early MRI, visual assessment underestimates abnormalities in the basal ganglia (59% abnormal vs. 90% abnormal on quantitative assessment), suggesting the need for quantitative assessment (Imai et al. 2018).
excitotoxic forebrain sensorimotor loop
asphyxia: prognostication based on imaging
asphyxia: luxury perfusion in the arterial compartment
It is unlikely for arterial perfusion indices to add substantially to prognostication, in individual cases, when the injury pattern has been well defined by imaging.
axial view of the mesencephalon with hyperechoic core
asphyxia: injury to brainstem
frontal
v4
axial
<----
uterine rupture; hypothermia; bust-suppression pattern on EEG; the hyperechoic dentate nucleus in frontal and axial mastoid section; hyperechoic thalamus and putamen
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 sonogrpahic finding that indirectly hints to brainstem damage. Interpretation of the clinical findings remains important in this context.
asphyxia: excitotoxic damage in sensorimotor forebrain systems
Dyskinetic cerebral palsy follows destruction of the pallidal and subthalamic functional stations in the striatum. A disinhibtion of thalamus by injury to striatum leads to hypertonia and dystonia, but injury to thalamus itself interferes with the clinical outcome in a manner not really understood in the era of hypothermia facing mitigated injury. The clinical presentation and motor consequences are no doubt complex due to a combination of loss of function but also acute uncontroled excitation.
In the acute stage at least three mechanisms interfere to disrupt the interaction between thalamus, cortex and striatum.
1. Following the insult OFR damage occurs in neurons of thalamus and cortex rich in mitochondria, this is the primary insult.
2. Cortical dysfunction and primary injury to striatal neurons will disinhibit thalamus that is normally inhibited by the striatum. There is a loop of thalamocortical inappropriate activation.
3. WIthin hours to days, neurons in thalamus that need trophic support from the cortex, will wither.
Dyskinetic cerebral palsy follows destruction of pallidal and subthalamic functional stations in the striatum.
A disinhibiton of thalamus by injury to striatum leads to hypertonia and dystonia, but injury to thalamus itself interferes with the clinical outcome, in a manner not really understood in the era of hypothermia facing mitigated injury of several components in the loops.
asphyxia: excitotoxic and trophic damage in sensorimotor forebrain systems
In the first 48 to 72 hours, children with moderate to severe asphyxia are often on a ventilator. A decision about deventilation is often made around day 4, when maturation of lesions can be appreciated with CUS and MR. A cluster of clinical, biochemical and neurophysiological (aEEG, sEEG, SSEP/VEP) information is gathered, in addition to lesions registered with imaging. Sonographic changes in the earlier phase, within 2 days of the insult, are indecisive because massive cell reaction and microvascular changes only develop over a period of at least 48 hours.
Early indicators hinting to the need for further imaging are (1) the fuzzy, swollen brain, (2) relative hypoechoic aspect of caudate, (3) appearance on day 2 or 3 of four hyperechoic columns in coronal section through deep grey matter, (4) luxury perfusion or reversed diastolic flow in large arteries, (5) early hyperaemic haemorrhage in ischaemic areas, (6) gyral core hyperechogenicity.
On days 3 to 5 injury to thalamus and striatum, if present, is clearly seen, in part because the unaffected (or at best oedematous) PLIC stands out between hyperechoic thalamus and striatum. Thalamus already becomes hyperechoic at the end of the first day following a severe insult, before hyperechoic change is seen in striatum. This argues for a primary necrotic process in thalamus, followed by striato-cortical necrosis, perhaps later superimposed by thalamic apoptosis.
ventricles may be small in the first 36 h after birth in neonates without injury, similar to asphyxia where a global faint hyperechoic change may be associated with slit ventricles and effaced lateral and interhemispheric fissures
asphyxia: deep grey matter injury: maturation of changes in CUS
It may take more days before cortical necrosis is reliably seen with US. Several neocortical/white matter patterns are seen in term birth asphyxia: best known is parasagittal cerebral injury or watershed injury, but other patterns are punctate periventricular haemorrhage, primary leukomalacia and isolated cortical injury not confined to watershed areas.
The effect of hypothermia on imaging has been well documented. Changes are delayed and mitigated. This means that in units where redirection of care was practiced after day 4 or 5 imaging, this attitude has been influenced by hypothermia. Whether this difficulty in prognostication has had an influence on the prevalence of CP is not yet clear (Weeke et al. 2018, DE Wispelaere et al. 2019, Langeslag et al. 2022, Parmentier et al. 2022, Alderliesten et al. 2025).
asphyxia: major injury patterns
SM
——>
Apoptosis and necroptosis pathways interweave after neonatal hypoxia-ischaemia (HI) (Thornton and Hagberg 2015). HI induces mitochondrial accumulation of calcium, production of reactive oxygen species, and rupture of the outer mitochondrial membrane. Changes in Bcl-2 family proteins induce the release of cytochrome c (cyt c) and apoptosis-inducing factor (AIF). Cyt c induces leads to caspase-3 activation, caspase-activated DNase (CAD) and DNA degradation. AIF forms a complex with cyclophilin A (CyA) which induces chromatinolysis and apoptotic cell death.
Concomitantly, microglia and astroglia release tumor necrosis factor-α (TNF-α) or other ligands (FasL, TWEAK, TRAIL and lipopolysaccharide, LPS) leading to the activation of death receptors, which in turn induce both apoptosis and necroptosis. Recruitment of TRADD and RIP1 lead to caspase-8 activation and cleavage of Bid leading to apoptosis. Under conditions when caspase-8 is inhibited, TRADD facilitates the activation of RIP1 and RIP3. RIP3 phosphorylates and recruits MLKL to the necrosome which can then be targeted to endoplasmic reticulum membranes triggering increased reactive oxygen species, fission and necroptosis.
Alternative non-mitochondrial mechanisms also play a role in the induction of necroptosis.
PET images are available from human newborns showing the pattern of brain glucose metabolism (Chugani et al 1986, 1987, 1991). Although there is relatively low glucose metabolism in most of the cerebral and cerebellar cortex, a number of regions appear to be metabolically active, including sensorimotor cortex SM, striatum S, thalamus T, brain stem, and cerebellar vermis. Amygdala and hippocampus are also prominent. Glucose metabolism reflects mitochondrial activity, hence regional vulnerability to lack of oxygen and glucose. Mitochondria are the nexus of pathways to offer energy as a primary site for converting glucose-derived pyruvate int ATP through oxidative phosphorylation. Hypoxic-ischaemic injury affects mitochondrial ATP production. Mitochondria can also be a cellular hub in inflammation.
Similar regional differences can be depicted with arterial spin labelling ASL MRI at term equivalent age (Tortora et al. 2017). Cingulate and calcarine cortex are also highly perfused.
asphyxia: role of the mitochondrion in cell death
asphyxia: decelerations on the CTG
<—— putamen
asphyxia: deep grey matter and cortical injury
cortical necrosis ——>
caudate head ——>
<—— thalamus
<—— cortical necrosis
<—— insular cortical necrosis
With severe asphyxia, both deep grey matter neuronal death and cortical necrosis may be seen in the second part of the week after the insult. The 4 columns of damage may include caudate. Cortical necrosis eliminates the relatively dark aspect of the normal cortical ribbon, changing all sulci into wide and blurred hyperechoic streaks.
P
L
I
C
asphyxia: early deep grey matter injury
Home delivery, tight nuchal cord and shoulder dystocy, inadequate resuscitation. Early hyperechoic change of thalami and clear signal intensity change of striatum on MRI.
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