Periventricular Leukomalacia 

Periventricular Leukomalacia 

Description

• Periventricular leukomalacia is an ischemia-reperfusion injury of periventricular white matter in premature infants^(1,2,3)

Also Called

•  PVL
•  periventricular leucomalacia

Epidemiology

Who Is Most Affected

•  premature infants, especially < 32 weeks gestation^(1,2,3)
•  infants with birth weight < 1,500 g^(1,2,3)

Incidence/Prevalence

• periventricular leukomalacia may be detected in^(1,3)
  • 3%-20% of very low-birth-weight infants (500-1,500 g)
    •  higher rate with evaluation by magnetic resonance imaging compared to ultrasound
    •  higher rate in more premature infants
  •  20% of infants born < 32 weeks gestation
  •  50% of neonates requiring extracorporeal circulatory support during repair of congenital heart lesions

Likely Risk Factors

• risk increases with decreasing gestational age and birth weight⁽³⁾
• complications of postnatal stress, including^(1,2,3)
  •  hypoxia
  •  hypotension
  •  hypocarbia
  • cumulative exposure to hypocarbia (but not to hyperoxia) associated with risk of periventricular leukomalacia
    •  in prospective study of 778 low-birth-weight infants, of whom 21 had periventricular leukomalacia (PVL)
    •  Reference – Pediatrics 2006 Oct;118(4):1654
• infection, including maternal chorioamnionitis^(1,3)
  • chorioamnionitis may increase risk of cystic periventricular leukomalacia in preterm infants
    •  based on meta-analysis of 30 studies
    •  chorioamnionitis associated with increased risk for PVL in preterm infants (risk ratio 3, 95% CI 2.2-4)
    •  Reference – JAMA 2000 Sep 20;284(11):1417, commentary can be found in JAMA 2000 Dec 20;284(23):2997
•  complex congenital heart disease⁽³⁾
•  prolonged cardiac surgery, including in term infants^(1,2)
•  chromosome abnormalities⁽³⁾

Factors Not Associated With Increased Risk

• gender not associated with risk of periventricular leukomalacia (PVL) in very low-birth-weight (VLBW) infants despite higher incidence of intraventricular hemorrhage (IVH) and severe IVH in boys
  •  based on retrospective cohort study
  •  104,847 preterm VLBW infants were assessed for diagnoses of IVH, severe IVH, and PVL
  • comparing boys vs. girls
    •  IVH in 15.9% vs. 13.6% (adjusted odds ratio [OR] 1.15, 95% CI 1.11-1.19)
    •  severe IVH in 38% vs. 32.7% (OR 1.18, 95% CI 1.06-1.32)
    •  PVL in 0.38% vs. 0.43% (not significant)
  •  Reference – Pediatrics 2010 Feb;125(2):e333
•  genetic polymorphisms of hemostasis genes (factor V Leiden, prothrombin G20210A, factor VII-323 del/ins, factor XIII-Val34Leu) were not associated with frequency of intraventricular hemorrhage or periventricular leukomalacia in 2 prospective cohorts with 1,181 very low-birth-weight infants (Pediatrics 2006 Aug;118(2):683full-text)

Associated Conditions

• respiratory distress syndrome (hyaline membrane disease)
• apnea of prematurity
• necrotizing enterocolitis

Etiology and Pathogenesis

Causes

• hypoperfusion of periventricular white matter due to^(1,2,3)
  •  failure of arteriolar autoregulation of cerebral perfusion
  •  poorly developed penetrating arteries in premature infants
  •  lower cerebral blood flow velocities in first day after birth found in 8 of 67 low-birth-weight infants who had periventricular leukomalacia with cyst formation on ultrasound (Pediatrics 2006 Jan;117(1):1)
•  inflammation may also contribute to development of periventricular leukomalacia^(1,3)

Pathogenesis

•  decreased systemic blood pressure, hypocarbia, or cytokines from chorioamnionitis or other infection result in reduced cerebral blood flow and periventricular ischemia^(1,3)
• ischemia damages immature oligodendroglia resulting in^(1,2,3)
  •  activation of microglia cells in telencephalic periventricular and subplate regions
  •  accumulation of glutamate, free radicals, and proinflammatory cytokines
• damage to oligodendroglia and subsequent reaction reduce myelin production and may result in^(1,2)
  •  poor growth/formation of periventricular white matter of cerebral cortex
  •  impaired neuronal myelination causing diminished axonal diameter and/or delayed maturation
  •  reduction in mature thalamocortical connections
  •  loss of subplate neurons
  •  pyramidal tract damage (leads to cerebral palsy)
• extent of injury may vary with gestational age⁽³⁾
  •  diffuse injury more likely < 26 weeks with white matter atrophy, ventriculomegaly, and cortical underdevelopment
  •  focal injury more likely ≥ 26 weeks with cyst formation

History and Physical

History

Chief Concern (CC)

•  infants are usually asymptomatic when periventricular leukomalacia is detected⁽¹⁾
• symptoms develop slowly over time and may include^(1,2,3)
  •  delayed motor development and spastic diplegia
  •  delayed cognitive development and intellectual disability
  •  visual or hearing impairment
  •  learning disorders
  •  seizures

Past Medical History (PMH)

• ask about^(1,2)
  •  gestational history
  •  perinatal history
  •  attainment of developmental milestones

Physical

General Physical

• measure and plot
  •  head circumference
  •  length/height and weight

Neuro

• assess^(1,2,3)
  •  neurocognitive development
  •  muscle strength and tone (spasticity)
  •  vision and hearing

Diagnosis

Making the Diagnosis

• diagnosis is made by abnormal findings in and adjacent to cerebral ventricles on neuroimaging including⁽¹⁾
  •  diffuse periventricular white matter echodensity
  •  focal or diffuse white matter cysts

Differential Diagnosis

• neonatal hypoxic-ischemic encephalopathy (HIE)
• perinatal stroke

Testing Overview

•  neuroimaging studies such as ultrasound and magnetic resonance imaging required for diagnosis⁽¹⁾
•  electroencephalogram is also useful for diagnosis⁽¹⁾

Imaging Studies

• ultrasound
  • neuroimaging findings of periventricular leukomalacia (PVL)^(1,2,3)
    •  periventricular white matter echodensity (increased echogenicity) with or without cystic abnormalities confirms diagnosis
    •  may include germinal matrix hemorrhage that extends into ventricles and periventricular cysts
    •  cystic abnormalities usually detected 1-2 weeks postnatally, but other changes may be present in first 24-48 hours and occasionally on fetal ultrasound
    •  cysts are absorbed and disappear within 2-3 months
    •  development of white matter necrosis, atrophy, resorption, and gliosis
    •  ventriculomegaly
    •  normal findings at 1 week and 1 month rule out PVL
  • cranial ultrasound readings have poor interobserver agreement for periventricular leukomalacia
    •  based on study of 326 premature infants
    •  Reference – J Pediatr 2007 Jun;150(6):592.e1
• magnetic resonance imaging (MRI)
  • MRI is more sensitive than cranial ultrasound for detecting^(1,2,3)
    •  diffuse periventricular white matter abnormalities
    •  atrophy of telencephalic gray matter
    •  long tract degeneration
    •  gyral underdevelopment
    •  enlarged subarachnoid spaces

Biopsy and Pathology

• pathology findings may include^(1,2)
  •  degeneration of periventricular white matter with inflammatory cells within foci of degeneration
  •  periventricular clustering of cysts
  •  axon disruption
  • white matter changes by immunohistology such as
    •  depletion of immature oligodendroglia
    •  astrogliosis
    •  microglial activation
    •  accumulation of proinflammatory cytokines and products of lipid peroxidation
•  placental evaluation may show abnormalities suggestive of dysfunctional placental circulation (Pediatrics 2002 Apr;109(4):650full-text)

Electroencephalogram (EEG)

• EEG findings may include^(1,3)
  •  excess frontal and occipital rolandic sharp waves
  •  paroxysmal discharges (increases risk of infantile spasms)

Management

Management Overview

• no specific treatment available for periventricular leukomalacia

Complications

• permanent neurological deficits may include^(1,2,3)
  • cerebral palsy (CP)
    •  usually spastic diplegia or quadriplegia
    •  periventricular leukomalacia is most common known cause of CP
  •  other significant motor defects
  •  cognitive deficits and learning disabilities
  •  visual, hearing, and other sensory deficits
  •  behavioral problems
  •  refractory complex partial seizures
  • infantile spasms
•  ventriculomegaly and/or hydrocephalus^(1,2,3)

Prognosis

• risk of poor neurodevelopment outcome from periventricular leukomalacia (PVL) increases with decreasing birth weight and gestational age, and presence of cysts^(1,2,3)
  •  permanent neurological deficits may occur in 33% of premature infants < 32 weeks gestational age with PVL
  • in infants with birth weight < 1,500 g
    •  5%-10% will have significant motor defects
    •  additional 25%-50% may have sensory, cognitive, and behavioral deficits
  • occipitoparietal cystic changes increase the risk of
    •  cerebral palsy – develops in 60%
    •  permanent neurological deficits
    •  refractory complex partial seizures
  •  isolated frontal cysts associated with a better prognosis⁽³⁾
• risk of neurodevelopmental impairment at 18-26 months may be similar among very preterm infants with disappeared or persistent cystic periventricular leukomalacia at 36 weeks postmenstrual age
  •  based on retrospective cohort study
  •  7,063 infants born at ≤ 26 weeks gestation who had cranial imaging at < 28 days chronological age and again at or near 36 weeks postmenstrual age were evaluated for neurodevelopmental impairment at 18-26 months corrected age by standardized history, neuromotor examinations, and Bayley Scales of Infant Development testing
  • 433 infants had cystic periventricular leukomalacia (PVL)
    •  18% had cystic PVL on first imaging that disappeared by second imaging (disappeared PVL)
    •  20% had cystic PVL on first imaging that persisted through second imaging (persistent PVL)
    •  62% had cystic PVL that appeared only on second imaging (late PVL)
  • rates of neurodevelopmental impairment at 18-26 months (no significant differences)
    •  52% with disappeared PVL (not significant vs. persistent PVL; p = 0.06 vs. late PVL)
    •  54% with persistent PVL
    •  56% with late PVL
  • rates of death at > 36 weeks postmenstrual age
    •  7% with disappeared PVL (not significant vs. persistent PVL; p = 0.06 vs. late PVL)
    •  9% with persistent PVL
    •  16% with late PVL
  •  no significant differences among cystic PVL groups in risk of moderate or severe cerebral palsy, or rates of mental or psychomotor developmental index scores < 70
  •  Reference – J Pediatr 2018 Apr;195:59.e3
• term MRI lesions in corona radiata above posterior limb of internal capsule on coronal view predict abnormal motor development in preterm infants with periventricular leukomalacia
  •  based on cohort of 289 preterm infants who had term magnetic resonance imaging (MRI) and were followed for 3-5 years
  •  62 (21.5%) had T1 hypersensitivity or cystic lesions in periventricular white matter
  •  none of 227 infants without lesions developed cerebral palsy
  •  normal motor development in all 17 infants with T1 hypersensitivity that spared corona radiata related to corticospinal tract
  •  among 45 children with T1 hypersensitivity or cystic lesions in corona radiata related to corticospinal tract, 37 (82%) had spastic motor defects
  •  cystic lesions had 62% sensitivity, 87% specificity, 38% positive predictive value, and 94.7% negative predictive value for abnormal motor development
  •  T1 spotty hypersensitivity without cystic lesions in corona radiata related to corticospinal tract had 78% sensitivity, 96% specificity, 56% positive predictive value, and 98.5% negative predictive value for abnormal motor development
  • Reference – Pediatrics 2007 Jul;120(1):e10

Prevention and Screening

Prevention

• prevention of preterm labor and preterm birth is best way to prevent periventricular leukomalacia (PVL)⁽³⁾
• risk of PVL may be reduced by^(2,3)
  •  close monitoring and maintenance of blood pressure
  •  avoiding hypoxia and carbon levels below 35 mm Hg
  •  inhalation of low concentrations of nitric oxide
•  limited evidence that antibiotic use before premature delivery prevents periventricular leukomalacia⁽³⁾
• treatment guided by cerebral oximetry monitoring for first 72 hours after birth does not reduce composite risk of death and severe brain injury at postmenstrual age 36 weeks compared to usual care in extremely preterm infants (level 1 [likely reliable] evidence)
  •  based on randomized trial
  • 1,601 extremely preterm infants (gestational age < 28 weeks) were randomized within 6 hours after birth to treatment guided by cerebral oximetry monitoring for first 72 hours vs. usual care and followed until postmenstrual age 36 weeks, death, or discharge to home, whichever came first
  • in treatment guided by cerebral oximetry monitoring for first 72 hours group
    • probe with near-infrared light sources and sensors was fixed to head of infants
    • signal mainly indicated hemoglobin oxygen saturation from veins in cortex and subcortex directly beneath probe
    • interventions for normalizing cerebral oxygenation were considered if cerebral oxygenation dropped below hypoxic threshold of 55%
  • primary outcome was composite of death and survival with severe brain injury assessed on cerebral ultrasonography at postmenstrual age 36 weeks
  • severe brain injury was defined as ≥ 1 of grades 3-4 intraventricular hemorrhage, cystic periventricular leukomalacia, posthemorrhagic ventricular dilatation, cerebellar hemorrhage, and cerebral atrophy
  • 1,579 infants (98.6%) (median gestational age 26 weeks, 53% male) were included in primary outcome analysis
  • median age at initiation of monitoring in cerebral oximetry monitoring group was 3 hours
  • comparing cerebral oximetry monitoring vs. usual care at postmenstrual age 36 weeks
    • primary outcome in 35.2% vs. 34% (not significant)
      • death in 21.2% vs. 19.8% (relative risk [RR] 1.07, 95% CI 0.89-1.28)
      • severe brain injury in 24.2% vs. 23.6% (RR 1.02, 95% CI 0.85-1.21)
    • death or bronchopulmonary dysplasia in 65.8% vs. 67.9% (RR 0.96, 95% CI 0.89-1.02)
    • death or retinopathy of prematurity in 30.4% vs. 28.3% (RR 1.08, 95% CI 0.94-1.24)
    • death or late-onset sepsis in 73.2% vs. 74.1% (RR 0.98, 95% CI 0.93-1.03)
    • death or necrotizing enterocolitis in 30.1% vs. 25.9% (RR 1.16, 95% CI 1-1.35)
    • ≥ 1 serious adverse event in 85.1% vs. 86.5% (RR 0.98, 95% CI 0.94-1.01)
  • 4 severe skin injuries in cerebral oximetry monitoring group reported
  • Reference – SafeBoosC-III trial (N Engl J Med 2023 Apr 20;388(16):1501)

Guidelines and Resources

Review Articles

• review of pathology and mechanisms of white matter injury in preterm infant can be found in Acta Neuropathol 2017 Sep;134(3):331
• review of cerebral white matter injury in premature infant can be found in Neuroscience 2014 Sep 12;276:216full-text
•  review of periventricular leukomalacia, inflammation, and white matter lesions in developing nervous system can be found in Neuropathology 2002 Sep;22(3):106PDF
•  review of neurobiology of periventricular leukomalacia in premature infant can be found in Pediatr Res 2001 Nov;50(5):553full-text
•  review of pathogenesis of cerebral white matter injury of prematurity can be found in Arch Dis Child Fetal Neonatal Ed 2008 Mar;93(2):F153full-text
•  review of neonatal brain injury can be found in N Engl J Med 2004 Nov 4;351(19):1985, commentary can be found in N Engl J Med 2005 Feb 24;352(8):839

MEDLINE Search

•  to search MEDLINE for (Periventricular leukomalacia) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

1. Pleasure D, Soulika A, Singh SK, Gallo V, Bannerman P. Inflammation in white matter: clinical and pathophysiological aspects. Ment Retard Dev Disabil Res Rev. 2006;12(2):141-6.
2. Deng W, Pleasure J, Pleasure D. Progress in periventricular leukomalacia. Arch Neurol. 2008 Oct;65(10):1291-5full-text.
3. Blumenthal I. Periventricular leucomalacia: a review. Eur J Pediatr. 2004 Aug;163(8):435-42.