ASPHYXIAL LEUKOMALACIA - keywords
asphyxial leukomalacia
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watershed injury references
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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
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
Insight into injury paradigms with asphyxia derives from the match of in vivo and postmortem findings in humans with large animal models (Painter 1995, Northington et al. 2007, Koehler et al. 2018). In general mixed patterns are common, because asphyxia in the human newborn starts as prolonged hypoxia, often climaxing by cardiovascular collapse with extreme bradycardia or asystoly, in some followed by hypoglycaemia and in many by seizures.
Biochemical changes lead to immediate cytotoxic edema, whilst triggering a chain of reactions provoking microvascular lesions and delayed primary neuronal death in specific areas, spread over hours to a few days. Correspondingly macrovascular phenomena follow a quadriphasic pattern: (1) initial hyperaemia (minutes), (2) no reflow (lasting hours) with lowered brain activity and low voltage EEG, (3) luxury perfusion (for a few days) and (4) late hypoperfusion.
As a first paradigm, deep grey matter injury to ventro- and ventroposterior relay nuclei in thalamus plus variable portions of striatum is associated with direct perirolandic/insular/ calcarine (sub)cortical injury.
A second paradigm consists of (multi)focal damage to cortex and white matter in inter-arterial border zones, often ascribed to hypoperfusion (Volpe and Herscovitch 1985). Subcortical white matter injury in this model is typical. Added to the above paradigms are focal arterial infarction and primary haemorrhage (for instance with haemostatic problems or due to congestion and vein rupture). Episodic hyperperfusion can transform ischaemic areas in haemorrhagic infarcts, a tableau of microvascular leaks through interrupted basal laminae.
There are other paradigms such as isolated cortical necrosis and primary leukomalacia following term birth asphyxia.
examples
the complex imaging situation
injury patterns in asphyxia
conventional MR intensity changes
White matter hyperechoic change:
bilateral- (birth) asphyxia
- preterm white matter injury
- medullary vein thrombosis
- viral encephalitis (rubella, enterovirus)
- bacterial encephalitis
- hypoglycaemia
- mitochondrial encephalopathy, organic aciduria
- pyridoxine dependent seizures
⁃ leukodystrophy
unilateral- medullary vein thrombosis
- sinus thrombosis
- bacterial encephalitis
- DVA
preterm PVL
asphyxia: causes
CUS white matter pattern
monkey model
partial asphyxia
ischaemic white matter injury in asphyxia
clinical scores
An ischaemic form of postasphyxial pure white matter injury exists that is not limited to perirolandic or border zones and affects deep as well as subcortical areas. High resolution CUS is needed for its description. Term children with cerebral palsy, developmental delay or epilepsy, who later have leukomalacia on MRI, may have suffered an in utero insult that in the end stage mimicks the acute peripartum injury described here.
cord knot
uterine rupture
tight cord
abruptio/solutio placentae
From the point of view of fetal well-being, the time spent in the second stage is to be limited (Defoort 1993). The deleterious effects of prolongation of the second stage can be due to interference with fetal oxygenation (acidosis) and to mechanical effects on the fetal head (pathological moulding). The mean pH of umbilical artery blood exceeds 7.31 when the second stage takes less than 15 minutes, but falls to 7.25 when 30 minutes are exceeded. A prolonged expulsion can make the moderate respiratory acidosis in the fetus, that normally resolves rapidly after birth, evolve into a potentially dangerous metabolic acidosis. The correlation between the increased risk for an untoward fetal outcome and the duration of the second, and also the first, stage cannot be considered as clearly defined. The period of risk is the perineal phase, being the interval between the presentation of the head at the pelvic floor and the completion of birth, or the duration of perineal 'bulging'. The duration of the phase of active bearing down has a three to seven times increased influence on fetal acid-base parameters compared to the whole duration of the second stage. When cord compression occurs this influence is much higher. Taking into account statistical exceptions to the general trend, a limit of 45 minutes is advisable. When monitoring, and in the presence of a normal heart frequency registration, an expectant attitude may be sustained longer.
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: subacute type, fetal distress during the second stage of labour
Most fetuses enter labor with a reserve of placental capacity. Contraction strength, frequency, and duration are the key factors that determine the rate at which fetal asphyxia develops during labor (Gunn and Thoresen 2019). Critically, the proportion of time the uterus spends at resting tone compared with contracting tone will determine the extent to which fetal gas exchange can be restored between contractions: any intervention that increases the frequency and/or duration of uterine contractions clearly places the fetus at increased risk of compromise.
A progressive fall in cerebral oxygen saturation sets in (studied with NIRS) when contractions occur more frequently than every 2.3 min (Peebles et al. 1994). Repeated hypoxia is more critical with preexisting placental insufficiency or fetal inflammation that sensitize the brain to hypoxia–ischemia. Conversely, even a fetus with normal placental function may be unable to adapt to tonic contractions or uterine hyperstimulation related to oxytocin infusion used for induction or augmentation or prostaglandin preparations for induction of labor.
+++ hyperechoic white matter
typical MR proton density
white matter collapse
diffusion restriction similar to watershed injury; network injury to caudate
white matter collapse
proton density images of term leukomalacia
evolution
+ caudate injury
<—— network injury to caudate
examples of leukomalacia due to term birth asphyxia
coronal details
DWI of leukomalacia
resembles cortical injury on MRI
Following asphyxia subcortical, periventricular and mixed forms of mild and moderate white matter injury are encountered. Often they present with ill-defined echodensities in white matter that do not lead to permanent damage, probably zones where ischaemia has not caused necrosis and echoic changes do not reflect infarction but congestion, increase in cellularity (microglia and astroglia) or punctate bleeding of limited significance. Reversal of the findings within days of birth will be a good prognostic sign. Hyperechogenicity of white matter increases its contrast with the normal hypoechogenicity of the cortex: the characteristic railroad track phenomenon, clearly observed in parasagittal sections around sulcus cinguli.
Diffuse, progressive and very marked hyperechogenicity of white matter is exceptional and may precede cyst formation or lead to early ventriculomegaly without cystic intermediary. For such severe white matter injury the name postasphyxial leukomalacia at term is appropriate. It is initially difficult to differentiate sonographically between necrosis in white matter and reversible changes. The CUS hallmark is a gradual and caricatural increase in echocontrast between relatively dark cortex and extremely bright subcortical and periventricular white matter in areas extending beyond the parasagittal border zones and perirolandic cortex. This pattern is seen early (on day 2) but increases over the next days, contrary to what one expects of congestion or erratic haemorrhage. This suggests an ongoing axonal or glial process, maturing over days. The hallmarks of the entity are subacute fetal distress, moderate encephalopathy within the first day of life, extensive white matter injury from ventricle to but not including cortex, sparing of thalamus and basal ganglia except for caudate nucleus, absence of T1 signal inversion in the PLIC, pronounced and persistent seizure activity within the first 3 days of life, in some resultant spasticity and epilepsy.
In a prospective cohort study of term infants with perinatal asphyxia the Hammersmith Neonatal Neurological Examination (HNNE) was compared with MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) plus general movement assessment at 3 months (Kivi et al. 2022). Of 50 infants, 33 suffered asphyxia without hypoxic-ischaemic encephalopathy (HIE), 17 with HIE. Almost all with HIE showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity.
In a rat model (Janowska et al. 2022) partial ischaemia stimulated oligodendrocyte proliferation in the subacute stage, but myelin remained impaired. In the in vivo model in P7 rats with MRI, ischaemia revealed changes in the volume of different regions, as well as changes in directional diffusivity of water that suggest altered myelinated fibers. Hypomyelination was at postmortem observed in the cortex, striatum, and CA3 region of the hippocampus. Severe changes to myelin ultrastructure were observed, including delamination of myelin sheets. Shortly after the injury, an increase in oligodendrocyte proliferation was observed, followed by an overproduction of myelin. In the first days after damage, OPCs intensively proliferate, and overexpress myelin proteins and oligodendrocyte-specific transcription factors. Despite this the production of functional myelin sheaths in brain tissue is impaired.
CUS of leukomalacia due to term asphyxia
Although our impression from US is that this is a specific entity, variation in outcome suggests white matter injury is heterogeneous. White matter changes are picked up by PD, DW and conventional MRI after 4 to 6 days, but may be less striking and less homogeneous compared with US. Lactate in white matter is high on MRS. This points to the existence of primary ischaemic leukomalacia following term asphyxia (Thornton et al. 1997, Petty and Wetstein 1999, Medana and Osiri 2003, Stys et al. 2004, Reddy 2022). In severe cases there may follow early tissue loss in the second week or even cavitation. The latter is also seen following laminar cortical necrosis and in some infants laminar cortical necrosis and leukomalacia coexist. In the first week several conventional MR studies also demonstrated postasphyxial white matter injury (Baenziger et al. 1993, Rutherford et al. 1995, Robertson et al. 1999, Robertson and Robson 2002). In the second week white matter may become brighter on T2 leading to a return or even increase of cortex/white matter differentiation. Some infants develop multicystic leukomalacia if demarcation between cortex and white matter is blurred on T2, testimony to the severity of the insult. They develop spastic quadriplegia and profound developmental delay. Delayed decreases in ADC have been observed in subcortical white matter from days 4 to 10 in patients with birth asphyxia. Late glial swelling is the hypothesis to explain this finding.
In neonates who were treated with hypothermia and developed brain injury, birth asphyxia impaired myelination in the regions that myelinate at or soon after birth (the posterior limbs of internal capsule, the thalami, and the lentiform nuclei), in the regions where the myelination process begins only after the perinatal period (optic radiations), and in the regions where this process does not occur until months after birth (anterior/posterior white matter)(Olivieri et al. 2021)
human term newborn asphyxia: major injury patterns
the monkey model of partial asphyxia with white matter injury
In contrast to partial asphyxia associated with acidosis, partial asphyxia without acidosis results in white-matter injury. Following the observation that in a number of last-trimester stillborn Rhesus fetuses, periventricular hemorrhage affecting hemisphere white matter primarily in the prefrontal and posterior parietal regions was present, the observation was made that a juvenile monkey who developed spastic quadriparesis following experimental production of placental insufficiency during midgestation showed paucity of white matter in both cerebral hemispheres. This pattern of injury appears when respiratory gas exchange of the fetus is diminished gradually and endures for long periods of time during which fetal arterial pO2 levels as low as 8-10 Torr are observed, but pH and pCO2 levels are virtually unaffected. These fetuses did not show clinical signs of distress. The neuropathological findings are similar to those noted in juvenile monkeys exposed to cyanide or carbon monoxide. Both processes impair cerebral oxidative metabolism without altering CO2 or pH.
healthy internal capsule
Partial Asphyxia With Acidosis. If instead of an acute total asphyxial event, the fetus is subjected to partial asphyxia by impairment of placental gas exchange in a chronic fashion, patterns of cerebral cortical injury with edema are noted. In eight Rhesus monkeys studied by Brann and Myers in 1975, five of eight fetuses showed significant cerebral edema after sustaining hemoglobin oxygen saturations below 50% between 4.33 and 5.58 hours. Three animals sustaining this degree of hypoxemia between 1.3 and 3.67 hours showed mild brain swelling. In about half the animals, dramatic asymmetry of cerebral injury was observed with the left hemisphere always the most affected.
Pale or hemorrhagic necrosis involving the entire cortex of both hemispheres or restricted to a parasagittal posterior parietal distribution was noted. Findings of tissue necrosis were observed microscopically, and these changes commonly affected the entire cerebral hemisphere sparing only the thalamus, portions of adjacent white matter, and medial aspects of the temporal lobe. Widespread cerebral necrosis was predictably associated with myocardial injury and cardiovascular collapse. Animals subjected to partial asphyxia of shorter duration tended to survive and later showed focal cortical injury with a predominance in the posterior parietal parasagittal regions. Occasionally neonatal monkeys with extensive cerebral injury have survived beyond the newborn period and when sacrificed later have demonstrated symmetrical bilateral porencephaly or cerebral necrosis with cystic degeneration of gray and white matter centered in the middle paracentral region.
myelin desintegration
Desintegration of myelin in the posterior limb of the internal capsule has been interpreted as secondary to neuronal necrosis (Ranck and Windle 1959). Primary leukomalacia was not a paradigm typically recorded in monkey experiments about apshyxia.
coagulation necrosis (Banker and Larroche 1962)
Pathologists (Virchow in 1867 early on, suggesting this was infectious) have extensively reported on pathological fatty change of white matter, mainly in the context of prematurity. The areas affected also harbor macrophages and swollen mineralised axons (stalactite shaped) (Parrot 1873, "steatosis, infarction, and hemorrhage in the periventricular white matter”- “diffuse interstitial steatosis"). The condition is now referred to as periventricular leukomalacia (PVL) after Banker and Larroche 1962. In acute specimen, coagulation necrosis is seen, with invading macrophages. Axons are affected as well as myelin. Severe variants lead to infarction which results in cystic PVL. Focal and diffuse forms exist, and ischaemia may play a role in the mechanisms (Schwartz 1961). Border zone fragility and oxygen toxicity were suspected cofactors.
Within the corpus callosum there is a complex relationship between the accumulation of sudanophilic lipids and gestational and postnatal age (Leech and Alvord 1974), on the basis of normal premyelin lipogenesis. Glia may demonstrate abnormalities in the absence of definitely necrotic lesions.Glial cells may respond in two ways, by an increase in the number of cells containing lipid droplets and by an increase in the total amount of histologically demonstrable lipid. Such glial fatty metamorphosis is a parameter of early injury to the immatutre premyelin glial cell at a moment of particular susceptibility.
There are no recent postmortem studies of the type of primary white matter damage that occurs in term infants with intrapartum asphyxia. Two 24-week-gestation infant brains were examined, who died at 33 and 46 weeks postmenstrual age MRI evidence of diffuse excessive high signal intensity (Parikh et al. 2016). Two others with PVL and two without injury were examined for comparison. Immunohistochemistry described reactive astrocytes, microglia, myelin, and axons. Infants with PVL demonstrated microscopic necrosis with spheroids, gliosis/microgliosis with reduction in stainable myelin and axons. Infants with diffuse excessive high signal intensity showed a different pattern with vacuolated regions that had increased reactive astrocytes and microglia, fewer oligodendroglial cell bodies/processes and a dramatic reduction in axon number.
glial fatty metamorphosis (of the corpus callosum)
typical PVL areas in preterm infants
fatladen macrophages in corpus callosum (oil red O staining, Leech and Alvord 1974)
axonal retraction balls (Banker and Larroche 1962)
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