FLARING AND PVL - keywords
flaring and PVL
references to PVL and flaring
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premyelination gliosis
imaging of leukomalacia
primary axonal injury in PVL
subcentral location of flaring
de Vries classification
MR punctate white matter lesions
The problem of (transient) increased echogenicity of periventricular white matter in preterms has been examined by many since the suggestion by Trounce et al. in 1986 to use the term flaring if these changes were not as bright as clot, subsided only after two weeks and did not always regress with cavitation. A necessity of standardised gain and energy output setting was claimed. The majority of PVL in their experience had associated haemorrhage, suggesting they included some venous infarcts. Spongiosis and microcalcification were typical histopathological findings, adding haemorrhage in only 18 %. No doubt flaring was mostly pathological in this initial study.
There is a disturbing lack of cohesion in the subsequent CUS description of preterm white matter, as many assumed flaring to be a straightforward concept (Fawer et al. 1987, de Vries et al. 1988, Appleton et al. 1990, Levene et al. 1992, Jongmans et al. 1993, de Vries et al. 1993, Ringelberg and van de Bor 1993, Fazzi et al. 1994, Lai et al. 1999, Sie et al. 2000). Although critics of the concept claim that machine settings affect appreciation, this has rarely been documented. Grant et al. 1983 stated that echogenicity did not vanish with change in power or gain setting. Contrary to this, Paneth et al. 1990 thought assessment was influenced by minor changes in gain setting. Few mentioned texture of white matter. DiPietro et al. 1986 described a flame-shaped fine blush of echogenicity, not visible from the posterior fontanel due to different orientation of insonated fibers. Pidcock et al. 1990 referred to retrotrigonal white matter in a parasagittal section as homogeneous and striated. For Paneth et al. 1990 the normal was an alternation of interlaced gracile echogenic and echo-poor lines.
Whether higher resolution affected subjective interpretation of hyperechogenicity was not examined, but more detail might enhance lesion detection but may also add shades between normal and abnormal. Echogenicity increases by the presence of cells, vessels, calcium and fat. Not only leukomalacia but also normal premyelination gliosis explains this periodic increase of echogenicity around 28-34 w PMA.
the problem of hyperechogenicity
relation to optic radiation
relation to corticospinal tract
>
typical patterns
mechanisms of leukomalacia
In the early eighties of the 20th century the value of ultrasound in the description of GMH-IVH was recognized. It became clear that haemorrhage was not always found at autopsy in preterms with hyperechoic change in white matter suggestive of bleeding. The early stages of haemorrhagic and purely ischaemic white matter injury seemed sonographically indistinguishable at the time (Hill et al. 1982, Levene et al. 1983, Nwaesei et al. 1984, Dolfin et al. 1984, Delaporte et al. 1985, Rushton et al. 1985, Tamisari et al. 1986). The hyperechoic aspect could be due to clot, but also to necrosis with cellular reaction (astroglial scars and macrophages holding fat and/or hemosiderin) from the subacute stage on.
Venous infarction due to GMH/IVH is invariably haemorrhagic, rarely bilateral and if so most likely asymmetrical (Gould et al. 1987, Govaert and de Vries 2010). It affects defined drainage areas: terminal, longitudinal caudate, septal, inferior ventricle vein. In the hours preceding infarction one observes hyperechoic change in white matter, probably due to severe congestion of medullary veins. This is one of the reasons why mild WMD cannot be differentiated with certainty from congestion only. Transience within hours to days possibly attests of congestion, and even some low grade cellular response in white matter might also disappear in days. Because PVL and GMH/IVH co-occur in a substantial number of preterms it is incorrect to dismiss hyperechoic white matter as just congested. Conversely, congestion
exists in the absence of GMH/IVH.
We have since learnt that preterm leukomalacia is a bilateral and fairly symmetrical disease with predilection for the posterior frontal to parietal peritrigonal white matter, involving anterior frontal, temporal or occipital regions if more extensive (Volpe 1995, Levene 2000, Govaert and de Vries 1997, Agut et al. 2020). There is some evidence that isolated anterior frontal PVL exists but only rarely (Shuman and Selednik 1986, Fawer et al. 1987). Frank bleeding into PVL is uncommon, punctate, short linear or serpiginous haemorrhage is not.
timing of cystic lesions
significance of white matter injury
diffuse white matter disease
the concept of flaring to describe preterm leukomalacia
axonal retraction balls (Banker and Larroche 1962)
glial fatty metamorphosis: premyelination gliosis or PVL
Pathologists (Virchow in 1867 early on, suggesting this was infectious) have extensively reported pathological fatty change of white matter, mainly in preterm infants. The areas affected harbor macrophages and swollen mineralised axons (stalactite shaped) (Parrot 1873: "steatosis, infarction and haemorrhage in periventricular white matter” - “diffuse interstitial steatosis”)(references in Larroche 1977). The condition is further developed as periventricular leukomalacia (PVL) by Banker and Larroche 1962. In acute PVL specimens, coagulation necrosis is seen, with invading macrophages. Axons are affected. Severe variants lead to infarction which results in cystic PVL. Focal and diffuse forms exist (Schwartz 1961). Border zone hypoperfusion and oxygen toxicity were early suspected cofactors.
Within the corpus callosum as it normally develops there is a complex relation between the physiological accumulation of sudanophilic lipids and postmenstrual age (Leech and Alvord 1974, Larroche 1977), on the basis of normal premyelin lipogenesis. The presence of fat in and around glial cells is therefore to some extent normal. Similar findings (e.g. for the stratum sagittale) were done elsewhere, where in general this physiological fat deposition precedes formation of mature myelin.
But glia may also demonstrate abnormalities in the absence of definitely necrotic lesions. Glial cells 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 excessive glial fatty metamorphosis is therefore also a parameter of early injury to the immature premyelin glial cell at a moment of particular susceptibility. This combination of normal and abnormal cell reactions explains the challenge of flaring.
Leech and Alvord 1974, Larroche 1977: sudan black positive glial cells in normal white matter along the atrium (top) and in corpus callosum (bottom): density peaks between 30 and 36 w PMA, prior to deposition of myelin starting at 38w PMA; myelination glia is unrelated to GFAP + radial glia (as in reactive gliosis); myelin as it is produced spreads the premyelinating cells, so they are less densely concentrated (Roback and Scherer 1935, Tuthill 1938)
fatladen macrophages in corpus callosum (oil red O staining, Leech and Alvord 1974)
coagulation necrosis (Banker and Larroche 1962)
white matter hyperechogenicity: initial papers
1 Grant et al. 1983
2 DiPietro et al. 1986
3 Fawer et al. 1987
4 de Vries et al. 1988
5 Appleton et al. 1990
6 Pidcock et al. 1990
7 Paneth et al. 1990
8 Levene et al. 1992
9 Jongmans et al. 1993
10 de Vries et al. 1993
The absence of consistent sonographic description, some of it due to technical differences between machines and their settings, is the cause of the current impopularity of the concept of flaring. In similar preterm cohorts (before 2006) prevalences of white matter injury range from 20 to 90 %, and MRI has presented us with the same problem as CUS in that respect.
to hyperechogenicity
11 Ringelberg and van de Bor 1993
12 Fazzi et al. 1994
13 van Wezel-Meijler et al. 1999
14 Sie et al. 2000
p personal practice at Sophia Children's Hospital Rotterdam
normal? was normal aspect of white matter reported
relation to plexus: where sick areas compared with plexus echogenicity
texture: was (in)homogeneity discusses
prolonged: was serial avaluation attempted
If you add to this that cystic PVL has almost disappeared in 2026, there are several reasons to rethink the concept of flaring. In a cohort of below 32w GA preterms (n =163) in Sophia Children’s hospital Rotterdam we recorded pathological flaring in 9 % and questionable flaring in 45 %, GMH/limited IVH in 15 % and extensive IVH and/or venous infarction in 8 % (2000 to 2005, acuson sequoia scanning)
typical gliotic PVL
extensive haemorrhagic PVL
flaring to gliotic nodules
CUS of normal white matter: periventricular leukomalacia
29 w to term MRI
caesarean at 32w for solutio placentae, neonatal seizures and RDS; spastic quadriplegic at 1 year of age
frontal cystic PVL
flaring to cystic PVL
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subcortical leukomalacia affecting pulvinar
moderate cystic PVL
moderate gliotic PVL
degrees of gliotic PVL
severe cystic PVL
NEC induced PVL
normal versus abnormal flaring
The duration of flaring is important. Transient hyperechogenicities disappear within a week without cyst formation or ventricular dilatation. Dammann and Leviton 1997 proposed a classification of hyperechogenicities into brief (1 to 6 days), intermediate (7 to 13 days) or prolonged (14 days or more). It has been reported that the duration of periventricular hyperechogenicities correlates with outcome, even without cyst formation (Cooke et al. 1985, Appleton et al. 1990, Jongmans et al. 1993, Aziz et al. 1995). Prolonged hyperechogenicities have also been found to predict white matter abnormalities on MRI (Maalouf et al. 2001). Data regarding prognostic significance of persisting hyperechogenicities remain conflicting (Bennett et al. 1990, Horsch et al. 1992). Therefore, the use of the terms flaring and ‘grade I PLV’ can be problematic, as it may falsely suggest an association with motor or cognitive impairment.
We recommend (Agut et al. 2020) the descriptive term ‘persistent hyperechogenicities’ or ‘pathological flaring'. It is important to try to look for signs of pathological “flaring" as described above, note the duration of the hyperechoic changes and monitor for subsequent sings of white matter volume loss. Homogeneity versus heterogeneity of white matter echogenicities is important to assess. Inhomogeneous or patchy hyperechogenicities are likely to represent non-cystic WMI and commonly correlate with MRI abnormalities (Sie et al. 2000).
Increasingly higher resolution probes are likely to detect subtler white matter abnormalities. Linear hyperechoic changes perpendicular to the ventricle margin often follow deep venous anatomy and have a haemorrhagic component, globular and coalescing nodules under the central groove above the sulcus circularis superior of the insula correlate more with gliotic changes.
white matter echogenicity: the problem of hyperechogenicities/flaring
historical description
The sequential CUS interpretation of preterm WMI, including both cystic and non-cystic forms, is biased by a lack of objectivity in interpretation of the early changes. Generally the presenting feature is increased periventricular echogenicity (often named flaring). These hyperechoic changes can disappear withing days or persist for several weeks. When they disappear, they can do so without leaving any abnormality (premyelination gliosis, congestion, low grade cell response) or they can evolve into gliotic and even cystic changes and/or ventriculomegaly with other features of brain volume loss and dysmaturation.
In the early eighties it became possible to diagnose cystic PVL with CUS (Hill et al. 1982). Ten years later de Vries and collaborators described a grading system for PVL that has been used until now (de Vries et al. 1992). There is evidence of the correlation between this system and prognosis (Pierrat et al. 2001). However, several limitations in using it are encountered in the clinical practice.
Assessment of mild (grade I) WMI remains difficult because periventricular hyperechogenicity is a subjective finding. The interobserver agreement on this has been remarkably low in some studies (Pinto et al. 1988, Hintz et al. 2007). Overdiagnosis is problematic. Choroid plexus echogenicity was used as a reference for differentiating between grade I PVL and normal periventricular blush. However cPVL can be observed following flaring that never exceeded the brightness of plexus. CUS findings, in addition to periventricular hyperechogenicity, that support grade I PVL include patchy appearance, extension of echogenicity beyond the peritrigonal area and bilateral but asymmetric periventricular distribution (Govaert and de Vries 2007).
Homogeneous symmetrical hyperechogenicities are normal around the anterior frontal horns and the parieto-occipital junction of the lateral ventricles, representing parts of the anterior limb of the internal capsule and the optic radiation, respectively (Boxma et al. 2005, Leijser et al. 2009).
complete classification
objective analysis
Infection/inflammation together represent the other major upstream mechanism of preterm WMI (Khwaja and Volpe 2008). Systemic upregulation of pro-inflammatory cytokines and diffuse activation of microglia within white matter lead to pre-OL injury or death. Thus, both intrauterine and postnatal infections as well as necrotizing enterocolitis are known risk factors for preterm WMI and adverse outcome (Wu and Colford 2000, Yoon et al. 2000, Shah et al. 2008). Back and colleagues described the late progenitor OL in human brains between 23 and 32 weeks of gestation and believe that cell type to be in a “developmental window of vulnerability” in the OL lineage. In tissue culture late progenitor OLs are exquisitely vulnerable to toxic effects (Back et al. 2002), far more than early OL progenitors and more mature OLs, which are resistant to damage. It was shown in a culture model that glutamate is highly toxic to differentiating oligodendroglia (Oka et al 1993). Back et al. demonstrated in human postmortem material that injury to oligodendrocyte precursors is mainly due to selective lipid peroxidation and not due to protein nitration (Back et al. 2005). In that hypothetic frame ischaemia is still the most accurate model of generating these lesions, with glutamate excitotoxicity further down the cascade. The culprit is the oligodendroglial cell in diffuse and focal white matter injury, with focal gliosis as one of the consequences.
to mechanisms
three major players for preterm PVL
The pathophysiology of WMI of prematurity is extensively reviewed (Khwaja and Volpe 2008, Back 2017). WMI is related to a confluence of maturational factors that render preterm white matter susceptible to injury.
Ischaemia and infection/inflammation are upstream mechanisms that activate two critical downstream mechanisms - excitotoxicity and free radical attack by reactive oxygen and nitrogen species - which in turn lead to death of the vulnerable pre-oligodendrocyte (pre-OL). The maturational state of the cerebral vessels adds to the susceptibility to ischaemia.
Hypoperfusion of the brain with ischaemia in the zones between the most important arterial irrigation areas (‘border zones’) was initially considered to be the common denominator. For the third trimester this area is mainly found between ventriculofugal (striatal) and ventriculopetal (cortical) branches of the middle cerebral artery, showing necrosis in a band of white matter located in the coronal axis of the lateral ventricle at a distance of about 1 cm from its lateral wall (at least 3 mm from the ependyma)(Takashima and Tanaka 1978, Rorke 1992). Often the most damaged areas are found at the junction between the parietal and the occipital lobe and within the frontal lobe in front of the foramen of Monro because those are border zones between major cerebral arteries. But the existence of ventriculofugal and ventriculopetal arteries has been dsiproved (Nelson et al 1991), as high power stereomicroscopy suggested that ventriculofugal arteries were in fact transcerebral venous channels. This challenged the ischaemia theory. The juxtaventricular area is nevertheless an area devoid of small arteries, a border zone between distal branches from perforators and pial arteries (penetrating from the surface in the direction of the ventricle).
In addition brain perfusion of the sick preterm infant often has impaired autoregulation (Greisen and Borch 2001, Soul et al. 2007). The consequential inability to maintain flow in the presence of even minor falls in systemic blood pressure can induce ischaemia. Hypotension and hypocarbia (through cerebral vasoconstriction) are the main preventable risk factors for decreased cerebral blood flow, as there is an association between severe hypotension or hypocarbia and WMI (Okumura et al. 2001, Martens et al. 2003, Shankaran et al. 2006).
Back et al. 2012: cerebral blood flow under conditions of basal flow; 3d reconstruction of fluorescence images of 0.65 gestation ovine control brain
pseudocolor basal blood flow images show higher blood flow (arrows) in the pons (image 1) and subcortical gray matter (image 2), and lower flow (dark blue) in periventricular white matter (PVWM) (arrowheads)
- cystic leukomalacia is the best predictor of major handicap, usually cerebral palsy (Rennie and Roberton 2000)
- normal neonatal sonograms: major handicap in up to 5 % (often mental retardation and visual handicap)
leukomalacia grading system based on ultrasound (de Vries et al.) versus outcome
- uncomplicated subependymal/intraventricular haemorrhage (no venous infarction, no hydrocephalus): major handicap in 10-15 %
- moderate to severe ventriculomegaly without parenchymal infarction: major handicap in 34 %
- shunted hydrocephalus: major handicap in 60 %
- cystic leukomalacia: major handicap in 90 %.
preterm periventricular leukomalacia at postmortem
diffuse telencephalic leuko-encephalopathy
Focal frontal cPVL is very uncommon, usually the focal cystic variant affects the subrolandic area at the fronto-parieto-occipital transition. The diffuse type of white matter injury without cyst formation has been originally referred to as telencephalic leukoencephalopathy.
cystic lesions are characteristically located in the periventricular area in the preterm infant; with maturation, the sensitive area moves to the cortex;
mixed periventricular and subcortical variants are not common (Sie 2005); fluid within white matter cysts is eventually absorbed by surrounding white matter, giving rise after some time to a gliotic scar zone with locally disturbed myelination
extensive cystic PVL
the typical patterns of preterm white matter injury
typical "white spots against an ivory background" = focal PVL areas in preterm infants with abnormal fatty metamorphosis and coagulation necrosis (Banker and Larroche 1962): lesions are PAS positive, the areas carry granular or sticklike disintegrating axons (Cajal’s retraction balls), calcium deposition and iron in microglia; the end result is “sclerosis of the white matter” with loss of volume and decreased myelin content; an area of 2 mm separates the lesions from the ependyma, the temporal lobe is least affected; the ventricle wall is intact; the lesions are bilateral but not strictly symmetrical
early preterm MRI scan around 30w PMA, registered with the ultrasound section; flaring with some excess lateral to and above the atria; hyperintense globular change on proton density MR
focal cystic PVL
normal white matter
haemorrhagic preterm periventricular leukomalacia at postmortem
x
PVL and arterial watershed zones
The border zone theory of periventricular leukomalacia. The interarterial or border zone hypothesis claims that periventricular leukomalacia is the result of infarction in hte watershed area between ventriculopetal cortical branches of the middle cerebral artery and ventriculofugal striatal branches of the anterior, middle cerebral and anterior choroidal arteries.
Top: power doppler images of pre-atrial white matter, demonstrating a vessel-poor area halfway between pia and ependyma; observe the highest level of a perforator artery at the lateral ventricle wall.
Middle: arterial barium-injected specimen of a coronal brain section at 24 weeks (Pape and Wigglesworth 1979). Notice poor perfusion of the periventricular white matter compared with the deep nuclei and subcortical area.
Bottom: the difference between a genuine stroke within the distal area of a perforator artery and PVL can be subtle. Strokes are very rarely bilateral and nearly symmetrical.
Bottom: parafrontal germinolysis is found in a plane below the lateral ventricle point, contrary to PVL.
periventricular area devoid of small medullary arteries (courtesy JS Wigglesworth Hammersmith Hospital, barium injection)
In practice, white matter hyperechogenicities are considered important if they match or exceed plexus density. Soft symmetrical radial echodensities are normal around the frontal horns and the parieto-occipital junction of the lateral ventricle. Perinatal white matter is relatively echogenic due to an increased water content, active late glial migration and early myelination (fat laden oligodendroglia).
In case of doubt, insonation through the posterior fontanelle allows for easier differentiation from ischaemia or haemorrhage because the sound beam runs parallel to the axons in the ‘blush’.
This assessment is always a surrogate of the histopathological reality; cellularity with cell death and congestion may mislead into predicting cystic PVL; this is the main reason for deferring interpretation of flaring into the third week after birth or after a severe inflammatory or ischaemic event that occurs before PMA 34 w.
possibility and problem of the concept of flaring
There can be a clear impression of white matter pathology in preterm infants of similar gestational age, when one has built up experience with similar appropriate machine settings. Echoreflections that are (nearly) as echodense as choroid plexus, a tissue often used as a reference for diagnosing leukomalacia, are abnormal. This approach is not without problems: (i) plexus is highly perfused in this age group and furthermore there are varying degrees of congestion or haemorrhage; and (ii) the more preterm the child is, the more prominent and echoic the plexus appears to be, and consequently its property as a calibrant is questionable in the very immature baby.
When evaluating periventricular white matter echogenicities it is important to look for signs of pathological flaring (persistent hyperechogenicities), note the duration of the changes and monitor for subsequent signs of white matter volume loss.
Homogeneity versus heterogeneity of white matter echogenicities is important to assess: inhomogeneous or patchy hyperechogenicities are likely to represent non-cystic WMI and commonly correlate with MRI abnormalities.
High-resolution ultrasound probes and wider angles of insonation are likely to detect subtler white matter abnormalities.
The best way to detect white matter lesions is with a wide sector angle (≥ 90 degrees) and high frequency transducer (≥ 7.5 MHz, preferably ≥ 9 MHz). Appropriate time gain compensation should be set so subcortical white matter appears isoechoic throughout, both near and distant to the fontanel. Coronal images from the anterior fontanel are better than parasagittal for studying WMI, because the most vulnerable area (which is lateral and superior to the lateral ventricle at the fronto-parietal transition) is more easily seen on coronal views.
Linear hyperechoic changes perpendicular to the ventricle margin often follow deep venous anatomy and have a haemorrhagic component, globular and coalescing nodules under the central groove correlate more with gliotic changes.
leukomalacia grading system based on ultrasound (Agut et al. 2020)
Ultrasound analysis of secondary white matter volume loss or dysmaturation of the central nervous system at term equivalent age (Leijser et al. 2007, Hagmann et al. 2011)
A. Size of frontal horns of lateral ventricles in a coronal section at the foramen of Monro
1. Lateral ventricle index > 13 mm
2. Short axis of the frontal horn > 3 mm
B. Size of ventricle midbody (> 10 mm) and thalamo-occipital distance (> 24 mm) as indirect sign of parietal (peritrigonal) and occipital white matter volume loss, measured in the parasagittal view
C. Width of the interhemispheric fissure, measured in a coronal view at the level of the foramen of Monro as a mean distance between hemispheres >3 mm (between gyral crests above sulcus cinguli)
D. Sino-cortical width in the coronal view > 4 mm at the level of the foramen of Monro
E. Thickness of the body of corpus callosum in a mid-sagittal view < 1.5 mm
F. Complexity of gyral folding inappropriate for gestational age (Inder et al. 2003, Woodward et al. 2006)
To depict cysts, serial ultrasound scans should be performed at least weekly due to the relatively late appearance and change over time of lesions. Serial ultrasound imaging is crucial in preterm infants with antenatal, intrapartum or postnatal risk factors for WMI. If information from CUS performed beyond the first weeks of life is not taken into account, the sensitivity of this neuroimaging tool has been proven to be low compared to conventional MRI for predicting CP and other long-term neurological morbidities. A CUS scan should be obtained at TEA (late CUS), looking for signs of cerebral atrophy. Signs of impaired brain growth or brain atrophy are related to adverse neurodevelopmental outcome.
In recent years, the de Vries et al. I-IV classification has been adapted, to make sure some entities are well described and included, to stress the rarity of subcortical cystic leukomalacia, and to accomodate the general decrease in prevalence of cystic PVL. This adaptation needs validation with outcome, although mild (I), moderate (II) and severe (III and IV) are similar to the de Vries classification.
Mildbilateral hyperechoic change in WM dorsal and lateral to the external angle of the lateral ventricle, most pronounced in posterior frontal to occipital areas; gradually disappearing over days
Moderate- hyperechoic changes in WM persisting beyond the second week with heterogeneous appearance (patchy), typically subrolandic
- localized cystic change adjacent to the external angle of the lateral ventricle, typically subrolandic
- homogeneous hyperechoic changes in WM followed by one or two of signs of white matter volume loss in serial scans
Severe- persistent and widespread periventricular density (patchy) associated with more than two signs of white matter volume loss in serial scans
- extensive cysts in frontoparietal and occipital periventricular white matter or extensive cysts in subcortical white matter (cystic periventricular leukomalacia)
The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischaemia and systemic infection/inflammation, both of which are common in premature infants. Cofactors are partial-pressure passivity of the cerebral circulation and postnatal acute hypocarbia. In animal models inflammation (e.g. induced by LPS) potentiates the effects of hypoperfusion. The potentiation has caused subthreshold ischaemic insults to still lead to white matter injury.
Chronic hypoxia reduces sirtuin 2 (Sirt2) function in mice: this increases proliferation but limits differentiation of the OL precursor -> rarefied neuropil in white matter, vacuoles in OLs (Wei et al. 2025). Dysmaturation is not an optimal term for this, as it is not specific for alteration in oligodendroglial development.
3 major players
risk factors
the fragile OL precursor
In a postmortem report the presence of NMDA receptors in human control brains was compared with 10 instances of white matter injury (some with typical PVL around 30w PMA) (Jantzie et al. 2015).Increased NMDAR-mediated vulnerability was suggested during early brain development due to an upregulation of receptor subunits, in particular highly calcium permeable NR2B-containing and magnesium-insensitive NR3A NMDARs.
Preterm fetal sheep (0.6 gestation) received either sham-asphyxia or asphyxia by cord occlusion for 30 min, and recovered for either 3 or 35 days. The 35 day recovery groups received either intraventricular insulin-like growth factor-1 (1 µg/24 h) or vehicle, from 3 to 14 days after asphyxia (Wassink et al. 2024). Asphyxia was associated with loss of frontal and parietal white matter, reduced myelin basic protein and oligodendrocyte transcription factor 2, persistent inflammation and caspase-3 activation. Four of eight fetuses developed cystic lesions in white matter. Prolonged infusion with insulin-like growth factor-1 restored frontal white matter, improved numbers of oligodendrocyte transcription factor 2-positive and mature oligodendrocytes, reduced astrogliosis and microgliosis after 35 days recovery.
border zones
the cascade of events
Elucidation of these factors lead to experimental (and limited clinical) study of early treatment of white matter injury (Butts et al. 2008, Volpe et al. 2011, Murugan et al. 2013, Kuhn et al. 2019). Although these lost pre-oligodendrocytes may be replaced in focal circumscript lesions by new cells from the subventricular zone and/or by abundant local proliferation, the latter seem not to follow the normal trajectory to produce mature myelin.
NEC
hypocarbia
Schneider and Miller 2019, Leijser and de Vries 2019, Agut et al. 2020
risk factors for PVL
sulcus centralis
registration of the area of flaring with coronal T1 MRI to compare diffusion characteristics
Although parasagittal images used in the early reports invariably show sections through trigonum and retrotrigonal white matter, one can see on a coronal image with planes of section indicated, that the area of interest superior and lateral to the ventricle cavity is lateral to choroid plexus in parasagittal view. The only reasonable section to estimate pathological flaring is around the choroid plexus in a symmetrical coronal plane. In parasagittal sections, the (aligned) nodules of gliotic PVL can be best seen above and slightly medial to the posterior and superior insular angle, in the area below the sulcus centralis; nodules extending in front of sulcus centralis may interfere directly with the corticospinal tract.
abnormal flaring in the subcentral location
insula
parasagittal section
gliotic nodules aligned ->
pre-cystic PVL
9 instances of preterms around PMA 30w with severe extensive hyperechoic change preceding cystic PVL: these examples illustrate the appropriate use of the concept of flaring; notice the bilaterality with some asymmetry, and the variable extension of the hyperechoic change into the temporal lobe
optic radiation versus flaring
An elliptoid hyperechoic area, appearing bilaterally adjacent to the lateral ventricle on coronal ultrasound images, is almost invariably seen in preterm infants. There is no difference found in the mean grey-value ratio of the region of interest between infants with a gestational age of 26 or 31 weeks. The acoustic behaviour of the area does not seem to change with time. The prevalence (83.7%), the symmetrical nature and the unchanged character of the region of interest between 26 and 31 weeks argue in favour of the hypothesis that these para-atrial spots are not part of any white matter disorder (Boxma et al. 2005) .
optic radiation anatomy
flaring versus optic radiation
The question arises why this structure is visible on coronal ultrasound scan taken through the anterior and disappears on images obtained through the posterior fontanel. Given that myelination of the optic tract is largely postnatal, it is too simple to attribute the hyperechoic character to premyelination gliosis. The orientation of the optic radiation might explain hyperechoic change due to perpendicular insonation of a crowded axonal bundle. In a coronal ultrasound section through the anterior fontanel, the upper part of the optic radiation is insonated almost perpendicularly. In this area, acoustic interfaces are maximal, the beam is well focused and this probably causes the hyperechoic band. From the posterior fontanel the fibers are insonated at an angle of 45°. The optic fibers are now oriented more parallel to the interrogating ultrasound beam, explaining the different echoic nature. The axons of the optic radiation probably serve as a specular reflector, a phenomenon that is angle-dependent. Which disposition of fibers is needed to produce the hyperechoic aspect is not known.
It is conceivable that PVL may in its extensive variant cover the para-atrial upper part of the optic radiation and mask the optic radiation.
By comparing ultrasound with neuro-anatomical and MR images a likely structure adjacent to the lateral ventricle that can match the region of interest is the upper part of the optic radiation. The fact that the hyperechoic band can also be pursued in the direction of the occipital area argues in favour of this hypothesis. Another argument is that preterm infants with PVL often have visual impairment, which is more pronounced in the inferior visual field. PVL causes lesions in brain areas crossed by the corticospinal tract, but axons of the upper part of the optic radiation are also located in this area.
Pierrat et al. 2001: first cyst day in infants with cPVL: light grey bars are infants with focal (minimal) PVL (n=32) dark grey bars are infants with extensive PVL (n=39).
Paneth 1994: early cystic change following coagulation necrosis; cyst coalesce into bigger cavities; the lost tissue leads to local hydrocephalus ex vacuo; eventually the cavities disappear as surrounding surviving neuropil obliterates them
As PVL may develop antenatally, for example following TTTS with or without the death of the co-twin, an early, first day ultrasound examination is crucial in timing the injury. In these situations fully developed cysts can be seen on the scan made shortly after birth. Leukomalacia is considered antenatal when the cysts are present at birth, or when cysts are clearly evolving from echogenic areas during the first 10 days after birth.
With a perinatal insult, it usually takes two to three weeks to develop extensive cystic PVL, even longer: the median date of cyst formation is 18 days but the range was 10-39 days (Kubota et al. 2001). The shortest event to first sonographic cyst interval we observed was 13 days. There is a relation between the severity of cystic PVL and the time it takes for the cysts to develop, i.e. the smaller the cysts, the more time for them to develop (Pierrat et al 2001, de Vries 2004). Sometimes the initial echogenicity develops several weeks after birth following an acute clinical deterioration like septicaemia or necrotising enterocolitis which is referred to as late-onset PVL (de Vries et al. 1986).
timing of cystic PVL studied at its peak of occurrence
In very low birthweight infants (<1500g) there has been a reported 15–25% overall prevalence of sonographic leukomalacia (before 2000). The cystic variant prevailed in around 3 % of VLBW infants, whereas the non-cystic variant reached three to five times this figure. With ultrasound cystic PVL was more common between 1000 and 1500 g than below 1000g. Cystic leukomalacia was the best predictor of major handicap, usually cerebral palsy [normal neonatal sonograms: major handicap in < 5 %; uncomplicated GMH/IVH (no venous infarction, no hydrocephalus): major handicap in 10-15 %; moderate to severe ventriculomegaly without parenchymal infarction: major handicap in 34 %; shunted hydrocephalus: major handicap in 60 %; cystic leukomalacia: major handicap in 90 %].
In contrast to GMH/IVH, which mostly occurs during the first 72 hours and rarely beyond the first week , in preterm infants leukomalacia can occur until term.
types of preterm PVL: Agut et al. 2020
Three overlapping neuropathological variants have been described: cWMI with macroscopic focal necrosis evolving to cysts; non-cystic WMI with mutliple focal areas of necrosis that evolve into glial scars; and diffuse astrogliosis without focal necrosis (1,10,Khwaja and Volpe 2008, Back et al. 2017). To some extent, these variants correlate with distinct clinical outcomes.
Hypoxic-ischaemic and toxic injury to the metabolically active oligodendroglia (OL) are now considered to be important. Back and colleagues describe the late progenitor OL in human brains between 23 and 32 weeks of gestation and believe that cell type to be in a “developmental window of vulnerability” in the OL lineage.
Several groups found an association between ascending intrauterine infection, production of proinflammatory cytokines and white matter injury (Leviton & Gilles 1984, Perlman, Risser, & Broyles 1996, Verma et al. 1997)(measuring proinflammatory cytokines in amniotic fluid, fetal plasma and cord blood). TNF alpha, interleukin (IL)-1 beta and interleukin-6 have been shown to be raised in the amniotic fluid of pregnant women with chorioamnionitis. Others studied the in situ expression of proinflammatory cytokines and found a high expression of TNF alpha, a myelinotoxic factor, in the brains of newborns with PVL (Kadhim et al. 2001). The relationship between chorioamnionitis and cerebral palsy was evaluated in a meta-analysis and chorioamnionitis was found to be a risk factor for both cerebral palsy (RR 1.9; 95% CI 1.5-2.5) and cystic PVL (RR 2.6; 95% CI 1.7-3.9) (Wu and Colford 2000). It was recently shown that chorioamnionitis is not only associated with raised IL-1 beta and IL-6 but also with a decrease in mean and diastolic blood pressure after birth (Yanowitz et al. 2002). It is possible that these inflammation-induced haemodynamic disturbances make the newborn more susceptible to perinatal brain injury.
the fragile oligodendrocyte precursor
Major maturation-dependent factors underlying the three downstream mechanisms in PVL (Volpe et al. 2011)
Free radical attack: abundant production of both ROS and RNS in PVL (by pre-OLs, microglia, astrocytes); delayed development of antioxidant defenses in pre-OLs; acquisition of Fe2+ by pre-OLs
Excitotoxicity: exuberant expression of major glutamate transporter (source of glutamate) by pre-OLs; exuberant expression on soma of pre-OLs of AMPA receptors, which are deficient in the GluR2 subunit and therefore are Ca2+ -permeable; exuberant expression on neurites of pre-OLs of NMDA receptors, which also are Ca2+ -permeable; likely mechanism of excitotoxicity is receptor dependent generation of ROS/RNS and non-receptor dependent glutathion depletion
Microglial activation: microglia are especially abundant in PVL; potent sources of ROS/RNSPresence of TLRs on microglia; activation results in release of free radicals; maturation-dependent concentration of microglia in normal cerebral white matter; microglial activation releases potentially injurious cytokines; TNFalpha derived from microglia in diffuse PVL, potentiates the maturation-dependent toxicity to pre-OLs by interferon gamma (interferon gamma expressed in astrocytes in diffuse PVL and its receptor expressed in pre-OLs); microglial activation impairs glutamate transport and accentuates excitotoxicity
Gilles and Murphy 1969: hypertrophic binuclear eosinophilic astrocyte in white matter
Gilles and Murphy 1969: amphophilic or basophilic globules near capillaries and small veins
With the increasing use of MRI attention was drawn to a diffuse form of white matter disease, not well identified with ultrasonography. This diffuse white matter involvement, injury without infarction or focal gliosis, was first reported by Gilles and Murphy (1969) as telencephalic leuko-encephalopathy.
It is a histological diagnosis, based on abundance and hypertrophy of astroglial cells and/or glial cell injury (karyorrhexis). Other features are glial fatty metamorphosis (increase of glial cells karying fat droplets in an increased amount) and the presence of amphophilic globules (perivascular exsudates with mineral deposition).
A limited amount of sudanophilic staining (oil red O positive) is present in the normal preterm brain within small, irregular, often spindle-shaped cells where it probably reflects an immature stage of myelin precursor turn-over (myelination gliosis). The normal accumulation of this lipid starts around 25 weeks of gestation and is found up to 3 months post term; premyelin lipid would not be expected in corpus callosum in the late second trimester.
This entity is clinically less well defined than cystic PVL, but is possibly similar to the so-called DEHSI (diffuse excessive high signal intensity) seen on T2 MRI (Counsel 2003). This diffuse degree of white matter disease may lead to ventriculomegaly without preceding cystic lesions (Kuban 1999) and may have a relation with imapired growth of the corpus callosum in the early postnatal period (Anderson et al. 2005).
Selective neuronal necrosis in cortex or brainstem is also common in infants with astroglial cell injury. That pulvinar is often co-affected (Yokochi et al. 1997) may help to predict mental retardation and oculomotor disturbances needs confirmation with MRI and histopathological examination.
Paneth et al. 1994: diffuse white matter astrogliosis (GFAP staining)
diffuse white matter disease in the preterm infant
score 4
A clinically relevant classification for early MR scoring has been reported by Sie et al. 2005. Extension of injury from rostral to caudal and ventricle to cortex is as important is the development of cysts. Early diffusion weighted MR (first week) picks up restricted diffusion in affected white matter (Fu et al. 2009)
score 2
score 5
(punctate) white matter lesions in an MR scoring system
many infants with hyperechoic change in white matter do not develop cysts;
in the early stages there are foci of coagulation necrosis, but cell loss is often accompanied by petechial bleeding; the latter causes high T1 and low T2 signal characteristic of many acute PVLs (Cornette et al. 2001);
many acute PVL cases remain purely ischaemic
prevalence and clinical significance of PVL
Although, in VLBW survivors, severe neurologic disability mainly defined by cerebral palsy (CP) and intellectual disability, is reported at a lower rate than previously, such outcomes are still observed in 5%–15% of VLBW survivors (Hamrick et al. 2004, Robertson et al. 2007, van Haastert et al. 2011, Moore et al. 2012, Cheong et al. 2017, Pierrat et al. 2017). Milder cognitive disabilities, learning difficulties and behavioral problems detected at (pre)school age are observed in 25%–50% of VLBW and represent a significant public health burden (Marlow et al. 2005, Larroque et al. 2008, Cheong et al. 2017). The focal necrotic lesions observed in cPVL classically precede a clinical picture of bilateral spastic CP (BSCP)
and visual dysfunction, as well as
moderate-to-severe cognitive impairment
and learning disability (van Haastert et al.
2011). Epilepsy may affect around 20 % of
spastic diplegic children.
Some pronounced non-cystic forms may also lead to CP and cognitive dysfunction (Ment et al. 1999, Pappas et al. 2018). The relatively recent shift to less severe WMI explains a shift to milder forms of impairment predominantly in cognition and behaviour, often without motor involvement or CP (Larroque et al. 2008, Hutchinson et al.2013, Schneider and Miller 2019). Specific deficits affecting former preterms with normal IQ influence executive functions (Johnson et al. 2016), motor coordination and visuomotor processing, attention and hyperactivity (Anderson et al. 2011), language and learning (Grunau et al. 2002, Johnson et al. 2016, Joseph et al. 2016), and mental health (autism spectrum disorder and internalizing symptoms) (Grunau et al. 2004).
The growing brain adapts to the
lesions with a myriad of options.
There are plenty of indications that CUS and MRI do not pick up all changes in the brain of preterms with PVL. The focal lesions are destructive, but also interrupt developmental pathways, affecting areas proximal or distal, but distant to the focal lesions:
- periventricular leukomalacia complex (Grunnet 1982, Paneth 1990 and 1994)
- late neuronal migration disorders
/cortical dysplasia (Marin-Padilla 1997,
1999 and 2000)
- cytokines in cortical neurons in acute stage (Kadhim et al. 2003)
- APP in pyramidal neurons (Deguchi et al. 1999)
- reduced cortical grey matter volume in ex-VLBW on MR (Inder et al. 1999 and 2005)
- reduced glucose metabolism in rolandic area.
The incidence of preterm WMI (white matter injury) varies among reports, partly due to definitions based on different imaging techniques (CUS or MRI) and their particular timelines and diagnostic roles. A systematic review concluded that the prevalence of preterm WMI, including both cystic and non-cystic, is 14.7% based on ultrasound diagnosis and 32.8% based on MRI (Romero-Guzman et al. 2017). The prevalence is 39.6% in infants born below 28 weeks GA; 27.4% below 32 weeks and 7.3% below 37 weeks.
In very low birth weight infants (VLBW< 1500 g) there is a reported 20-50% overall incidence of some degree of white matter injury.There is a peak incidence at 27-28 weeks.
Different groups used different classifications in different cohorts. Often only infants with extensive cystic lesions are included, and sometimes a unilateral porencephalic cyst, usually due haemorrhagic venous infarction, is lumped with cases of bilateral cystic PVL and then referred to as “echolucencies”. Even in the interpretation of echolucencies interobserver agreement has been remarkably low.
Most studies in the eighties reported an incidence of 3 to 10% for bilateral cystic leukomalacia (de Vries et al. 1988a, Fawer et al. 1985, Trounce, Rutter, & Levene 1986, Lemons et al. 2001). When non-cystic PVL (“flare”) was included an incidence of 26% has been found (Trounce, Rutter, & Levene 1986). A survey in Japan, where many units have access to MRI, revealed an incidence of 5% (in babies less than 33 weeks gestation) using ultrasound, and 8% when MRI was used to make the diagnosis (Fujimoto et al. 1998).
Leukomalacia, in its classic form, evolving from coagulation to later cystic necrosis has become less common (Hamrick 2004). In the unit in Utrecht the incidence in VLBWs has dropped from 4% in the early nineties to about 1% over the last couple of years. It has become clear that other forms of brain injury account for the majority of neurodevelopmental outcomes in VLBW infants. In a centre with a high prevalence of cPVL (17 % below 33 w of gestation) pre- and perinatal factors like indomethacin tocolysis and low Apgar scores have been found as risk factors (Murata et al. 2005). Hypocarbia may cause PVL (Okumura et al. 2001), but spontaneous hyperventilation with hypocarbia may also be one of the only clinical signs in preterms with extensive white matter injury, together with irritability (a clinical feature difficult to quantify).
objective analysis of flaring
Baraldi and Parmiggiani 1995, Barr et al. 1996, Simaeys et al. 2000, Stippel et al. 2001 and 2005
Together with researchers at TELIN (department of telecommunication and information at Gent University Hospital in Belgium) we developed an ultrasound segmentation tool that measures the size of an hyperechoic area within a region of interest lateral to and above the lateral ventricle. Speckle generated by the sound beam is the reason why there is texture in a sonogram and not in MR image. Speckle results from an interference pattern built up by echoes backscattered from Rayleigh scatterers, not from simple cytology (cell size << wavelength). Lateral speckle size depends on focal length, depth, transducer diameter, frequency (at 7.5 to 10 MHz in the near field lateral resolution is of the order of 1 mm). Axial speckle size depends on bandwith of transducer and can be of the order of 0.4 mm at 7.5 to MHz. Fully developed speckle size (high scatter density) only depends on transducer characteristics.
To measure within the image a co-occurrence matrix is applied, creating a two-dimensional histogram of the image: two parameters are taken into account: distance and angle. From the matrix, parameters can be computed that describe texture of the image. Using prior statistics of the grey value and texture data in a boxed region of interest, we developed a filter to prepare images, compensated for gain and time gain settings, of healthy and sick white matter for segmentation of flares. Image processing includes thresholding (using grey mean value of choroid plexus), a closing operation (dilation and erosion to homogenize the area) and a morphological gradient. Segmentation is based on mathematical morphology and textural information, is independent of ultrasound machine variation and is fast. The process of segmentation comes down to classifying a pixel in the flare-class or in the background-class. If a standard section is used in the same anatomical plane, the surface within this contour of standardized 'flare' is an indicator of the extent of white matter damage.
Size in pixels of the segmented hyperechoic area in one hemisphere in 10 infants with cystic PVL, 11 with haemorrhagic PVL and 43 normal scans. All images were first week sonograms of preterms below 32 weeks gestation, in the cystic PVL cases preceding cavitation. Normals were chosen because there was a subjectively normal scan, with either a normal MRI and/or a normal outcome at 2 years.
An advantage of ultrasound is that texture relies on speckle, itself relying on tissue characteristics and sound beam physics. Texture is absent in MR images (below right).
disappearing OR
Gradual disappearance of the optic radiation spots in a 32 weeks preterm infant with birth asphyxia that developed cystic leukomalacia in the first two weeks of life.
typical PVL examples
The pre-OL disturbance consists acutely of cell death, followed subacutely and chronically by failure of pre-OL differentiation and, as a result, hypomyelination (Back 2017, Volpe et al. 2011). Axonal maturation studies suggest that immature axons are also susceptible to injury (Haynes et al. 2005, Alix et al. 2012). Neuronal/axonal disease frequently accompanies preterm WMI and is characterized by degeneration and volume loss of nuclei in the brainstem, basal ganglia, thalamus, cerebral cortex and/or cerebellum, for which the term ‘encephalopathy of prematurity’ has been proposed (Volpe 2005). Thus, WMI is often associated with secondary trophic gray matter injury that leads to disturbances in cortical and thalamic development (Ball et al. 2012). As a consequence of WMI, diminished volumes of cerebral cortex and deep gray nuclei, delayed cortical folding and impaired myelination are frequent findings at TEA (Ajayi-Obe et al. 2000, Peterson et al. 2003, Inder et al. 2005, Srinivasan et al. 2007).
PVL imaging
postmortem, haemorrhagic type
linear versus nodular
eurUS.brain classification
typical precystic stage
(ab)normal flaring
postmortem, ischaemic type
evolution to first cysts
acute prolonged hypcarbia
hypocarbia
Wiswell et al. 1996
acute brief hypocarbia
Resistance index in the pericallosal artery was significantly lower (higher relative diastole) in infants with PVL and hypocarbia during the first 72 h of life (Okumura et al. 2002), which is suggestive of vasoparalysis at the level of large arteries. This seems at odds with the idea that hypocarbia causes vasoconstriction as a mechanism leading to PVL.
The role of autoregulation disturbances in promoting WMI is partly elucidated (Pryds et al. 1989, Greisen 2009). Most preterms have periods of pressure passive perfusion by impaired autoregulation (Soul et al. 2007, Verhagen et al. 2014) or conditions like sepsis or necrotizing enterocolitis (Schat et al. 2016, van der Laan et al. 2016).
In children going on to develop severe GMH-IVH pressure-flow autoregulation seen to be impaired (Pryds et al. 1989). In these children it was found that the CBF-CO2-reactivity was reduced. This may express maximal vasodilatation prior to haemorrhage, related to abnormal changes in setpoint for CBF-CO2 reactivity.
Certainly acute prolonged hypocarbia (as for instance during oscillation ventilation (Wiswell et al. 1996, Greisen and Vannucci 2001, Resch et al. 2012) can contribute to the onset of cystic PVL.
On the other hand infants with PVL also seem to hyperventilate themselves. So timing of the hypocarbia in relation to imaging is relevant for retaining a low CO2 as a causal factor (Kubota et al. 1996, Stenzel et al. 2020).
typical example
venous infarction
Necrotic white matter, even if it has not been superimposed on GMH, may suffer haemorrhagic conversion due to hyperperfusion, microvascular damage due to free radical formation and disturbed haemostasis. Differentiation is therefore necessary between venous infarction of white matter associated with GMH/IVH (right hemisphere) and PVL (left hemisphere).
Near the frontal horn, venous infarction creates a triangular hyperechoic area pointing to the compressed vein in the lateral ganglionic eminence. This triangular appearance is not seen with PVL.
IPL (venous infarction) usually unilateral
together with ipsilateral (large) IVH
fan shaped echodensity
sharply delineated
almost half develop hemiplegia
15-20% require shunt
focal gliosis on later MRI
posthaemorrhagic ventriculomegaly regular shape
signs of increased pressure (ballooning)
no signs of atrophy (no widening of interhemispheric fissure)
cPVL (cystic leukomalacia)mainly bilateral
no/only small IVH or hyperechoic germinolysis
patchy appearance
irregular border
outcome almost invariably CP
even with unilateral cysts bilateral gliosis on later MRI
ventriculomegaly due to leukomalacia
irregular shape
no signs of increased pressure (ex vacuo)
signs of atrophy
(widening of interhemispheric fissure)
More than 4/5 of venous infarcts are unilateral, most if not all cases of PVL are bilateral. Near the temporal horn of the lateral ventricle, PVL usually leaves a less affected area near the ventricle, whereas venous infarction sticks to the ventricle wall matrix area in the roof of the temporal horn. The vast majority of venous infarcts is in terminal vein area, not in the frontal lobe. At the outer margin of a venous infarct there is interdigitation of veins draining slightly deeper and not; this creates the feathered appearance where involved veins stand out against adjacent less involved veins. This venous differential drainage pattern has not yet been visualised in the normal newborn brain.
PVL versus venous infarction
PVL ——>
PVL
to significance
developing white matter neuropil: normal axons
PVL
leukomalacia: disintegrating axons in the acute stage
cortex above a white matter lesion
Marin-Padilla 1997
three axotomized pyramidal neurons transforming into interneurons
normal
Marin-Padilla 1997, 1999 and 2000: the cortex (above a chite matter lesion) without efferents to deep grey matter and brainstem/cord, survives with many cellular changes: some axotomized pyramidal neurons become interneurons, some develop abundant local collaterals and hypertrophy, …
Sensorimotor cortex in infancy, above the lesion, uses less glucose in PET scans (Higuchi et al. 1997).
GABA-A receptor binding potential is focally increased in red coloured areas (decreased in blue areas) at 12 year of age in children with spastic diplegia of perinatal origin
damage in red coloured tracts, by tract based spatial MR statistics, at 12 year of age in children with spastic diplegia of perinatal origin
corticospinal fibers interrupted by typical subcentral white matter lesions (red)
Studied at 12 years of age with diffusion MRI and with GABA-receptor PETscan, descending motor tract injury along with overlying cortical volume reduction and reduced functional connectivity appear to be leading mechanisms of motor dysfunction in patients with periventricular leukomalacia that caused spastic diplegia (Lee et al. 2011). Increased regional γ-aminobutyric acid(A) receptor binding potential appears to result from a compensatory “plasticity" response after perinatal injury.
spastic diplegia
plasticity following injury
Preterm white matter injury destroys axons, which leads to reorganisation of connected neuronal networks that survive the insult, e.g. in overlying isocortex. In this case lesions are bilateral but asymmetrical and occur in third trimester of pregnancy.
Focal and extensive cystic PVL differ significantly in prognosis (Pierrat et al. 2001). In focal cPVL the upper limb (fibers running more anterior and lateral than lower limb fibers) are typically spared.
——>
The corticospinal fibers to the arm course more anterior and lateral than the fibers to the leg. Gliotic PVL thus tends to spare the upper limb motor control.
corticonuclear tract
Staudt et al. 2003: outcome in spastic children is best associated on MRI with involvement of corticospinal fibers, more so than with white matter volume (loss).
<—— corticospinal tract
corticospinal tract lesions
NEC to leukomalacia
flaring versus optic radiation
the optic radation, dorsal part
six week old preterm: gliotic changes
nodular gliotic versus linear haemorrhagic
Schwartz 1964 : early on pathologists recognized linear microhaemorrhagic changes in atrial white matter, different from nodular and serpiginous lesions.
preterm day 6: bilirubin containing stripes with some haemorrhage
A systematic analysis summarized nine studies of punctate white matter lesions in preterm infants (PWML) with a total of 1655 patients (de Bruijn et al. 2023). Mean incidence of isolated PWML was 22.1%. All studies showed a relationship between PWML and motor delay. Two studies found a significant correlation between cognitive and behavioral outcomes and PWML. Number and location of lesions are related to severity and type of impairment. Only studies with imaging around TEA were included, and studies were heterogeneous in design and quality.
Different patterns of punctate white matter lesions exist (Kersbergen et al. 2014): a linear appearance associated with signal loss on SWI, and a cluster appearance associated with restricted diffusion on DWI on the preterm MRI. Cluster and mixed lesions on the preterm scan changed in appearance in over 50% on the near term scan, whereas linear lesions generally kept their appearance. Lesions were only visible on the early scan in 33%, and were only seen at term equivalent in 20%.
MR versus CUS
In most preterm infants with normal CUS at TEA, it is uncertain whether MRI adds clinically relevant information (Horsch et al. 2010). The impact on outcome of mild white matter abnormalities seen on MRI at TEA, missed on CUS, is still unknown. High negative predictive values in the absence of major CUS abnormalities for CP at 2 years of age have been reported (de Vries et al. 2004, van Wezel-Meijler et al. 2011). Mild white matter abnormalities seen on MRI at term age are unlikely to change decision-making or parental information. In addition, the appearances of WMI change over time, and this change has so far been best documented by serial CUS rather than by serial MRI (Pierrat et al. 2001, Sarkar et al. 2015, Martinez-Biarge et al. 2016).
Performing a single MRI at TEA in preterm infants with WMI may underestimate the severity of injury, particularly in case of focal cystic PVL, in which cysts - only seen for a few weeks - often are no longer present at term.
A number of MRI evaluation scales are developed to categorize the severity of preterm WMI (Miller et al. 2003, Sie et al. 2005, Woodward et al. 2006, Kidokoro et al. 2013, Martinez-Biarge et al. 2016). Often MRI scoring is based on findings of one scan performed at around term age. This allows little comparison with serial CUS. The more recent classification published by Martinez-Biarge et al. 2016 takes into account the timing of MRI in relation to postnatal age (or the age after the time of the insult), which makes it more exchangeable with categorization of WMI based on sequential CUS.
coronal section at the foramen of Monro demonstrating colour changes around medullary veins, explaining the linear aspect of some white matter lesions in the absence of frank haemorrhage
linear and globular lesions
The combination of prolonged acute hypocarbia and chorioamnionitis preceding cystic PVL.
2 different examples of how posterior caudate veins drain to the terminal vein in a position lateral to the typical focus of globular gliotic PVL
Although the terms linear and punctate “punctate white matter lesions” have emerged from the MR literature, this remains confusing; short linear and globular patterns are observed with CUS; the globular types are located lateral to the typical posterior medullary draining veins (suggesting the globular type of PVL is independent of venous architecture).
linear and nodular PWML
beta-APP deposits in swollen axons (Meng et al. 1997)
Thirteen ELBW infants of 85 infants with PVL, born at 23 to 27 weeks of gestation, showed a widespread type of distribution of PVL from deep to intermediate white matter (Deguchi et al. 1997). Immunohistochemistry demonstrated glial fibrillary acidic protein (GFAP)-positive astrocytes had increased in the deep white matter, often spreading to the intermediate white matter, in all cases of PVL. Tumor necrosis factor-alpha (TNF-alpha)-positive cells were found in the deep to intermediate white matter in 69% of PVL cases and appeared earlier, from 23 weeks of gestation, than in controls. beta-Amyloid precursor protein (beta APP)-positive axons were found around PVL in the deep to intermediate white matter in 85% of the cases. In age-matched control ELBW infants, GFAP-, TNF-alpha-, or beta APP-positive cells were never found.
In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages,
diffuse axonal damage in PVL was detected by fractin (an apoptosis marker) in white matter sites
surrounding and distant from acute and organizing foci of necrosis (Haynes et al. 2008). Using
beta-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages. GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. Diffuse axonal injury thus occurs in PVL.
Axonal retraction balls have been an early compagny of acute PVL descriptions. Primary injury is not only to pre-oligodendrocytes, but also to axons.
Human beta-amyloid precursor protein immunoreactivity was demonstrated in axonal swellings (spheroids) around periventricular leukomalacia (Arai et al. 1995). beta-Amyloid precursor protein immunoreactivity was homogeneous in damaged axons at the early stage with microglia, concentrated at the center of axonal swellings at the subsequent stage with astrogliosis, and undetectable at the terminal stage of cavitation or neovasculation. Immunostaining for beta-amyloid precursor protein is useful in localizing PVL lesions at their early stages.
In 16 cases of prenatal-onset periventricular leukomalacia (PVL), beta-APP positive axons were found in the early stage, which included coagulation necrosis, microglial activation, axonal swelling or
astrogliosis, but were not detectable in the late stage of prenatal PVL (Meng et al. 1997).
Beta-APP immunoreactive neurons were also observed in the fifth layer of pyramidal neurons of the cerebral cortex, corresponding to the beta-APP positive axons in PVL.
an area with APP spheroids in white matter (Haynes et al. 2008)
axonal injury in PVL
fractin + axons
fractin + astrocyte
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