Pathology of Periventricular Leukomalacia

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Periventricular leukomalacia (PVL) is a term used to describe cerebral white matter injury, both focal and diffuse. ^[1] The focal component consists of localized necrosis deep in the periventricular white matter, usually around the upper-outer angles of the lateral ventricles (see the images below), and it may be cystic. The diffuse component of periventricular leukomalacia more widely affects the cerebral white matter and is characterized by marked astrogliosis and microgliosis, and initially by a decrease in premyelinating oligodendrocytes and subplate neurons. ^{[1, 2, 3]}

Periventricular leukomalacia is the most common type of brain injury affecting survivors of premature birth (< 32 weeks’ gestation, very low birth weight [VLBW] [< 1500 g] infants) ^[4] ; imaging studies report 50% or more of VLBW infants show findings consistent with this condition. ^[1] Clinical sequelae—including cognitive, behavioral, attentional, or socialization deficits—are found in 25-50% of VLBW infants, whereas major motor deficits/cerebral palsy are seen in 5-10%. ^[1]

See Periventricular Leukomalacia for more details.

Epidemiologic studies demonstrate that periventricular leukomalacia is highly associated with prematurity and less so with chorioamnionitis. ^[5] However, a study by Herzog et al found that maternal obesity and chorioamnionitis increase the risk of periventricular leukomalacia beyond that expected solely from prematurity. ^[6]

The pathogenesis of periventricular leukomalacia is thus thought to relate to a confluence of factors that make the premature white matter vulnerable to injury related to 2 broad upstream mechanisms: ischemia and inflammation. ^{[7, 8]}

The propensity of premature infants to cerebral ischemia is thought to be due to: (1) intrinsic vascular anatomic factors—susceptible areas within the white matter lie within arterial end zones and are thus highly vulnerable to even minor decreases in cerebral perfusion; and (2) impaired regulation of cerebral blood flow due to immaturity of intrinsic vasoregulatory mechanisms. Inflammation (including ischemia or infection-related inflammation) contributes through upregulation of cytokines and diffuse microglial activation with generation of free-radicals. Furthermore, oligodendroglial precursors, which are abundant in the white matter during this period of development, are particularly vulnerable to free-radical damage as well as to excitotoxicity.

Investigation of possible genetic factors underlying susceptibility to perinatal brain injury suggests polymorphisms in cytokine and coagulation pathway genes may be risk modifiers for periventricular leukomalacia. ^[9]

Periventricular leukomalacia most commonly arises in the setting of a sick premature infant. Clinical signs secondary to this condition itself are often undetected in the newborn period, with the injury instead documented using imaging techniques. However, with improved survival of very low birth weight infants, by school age, clinical sequelae including cognitive, behavioral, attentional, or socialization deficits are found in 25-50%, whereas major motor deficits/cerebral palsy are seen in 5-10% of these children. ^[1]

Cranial ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) can all be used to detect injury to the premature brain—each has its relative strengths as well as weaknesses. (See Periventricular Leukomalacia Imaging.)

This imaging modality is commonly used for detection of cystic periventricular leukomalacia, and a characteristic progression of imaging features has been well documented. ^[10] During the first week following injury, there are echogenic foci in the periventricular white matter due to local necrosis with congestion and/or hemorrhage. This is followed, during weeks 1-3, by the appearance of echolucent cysts, which correlates with cyst formation due to tissue dissolution. By 2-3 months, ventriculomegaly appears, often with disappearance of the cysts.

Ultrasonography is, however, relatively insensitive for the detection of diffuse periventricular leukomalacia and, thus, for predicting cognitive disabilities. For this MRI is much more sensitive.

MRI is much more sensitive than ultrasonography in detecting diffuse periventricular leukomalacia and predicting cognitive disabilities; however, studies correlating these findings with long-term clinical sequelae are lacking. Instead, most studies with long-term clinical follow-up have focused on the use of MRI for investigation of patients diagnosed with periventricular leukomalacia by ultrasonography during the perinatal period. Studies of former premature infants when they reach adolescence show reductions in overall brain volume, including white and gray matter volume, with an increase in lateral ventricular volume. ^[11] These alterations in cerebral volumes are associated with cognitive and motor deficits. ^{[12, 13]}

The following are part of the differential diagnosis of periventricular leukomalacia:

Diffuse white matter gliosis

Periventricular venous infarction

Only a small minority of periventricular leukomalacia lesions is readily apparent macroscopically during the perinatal period, namely those lesions that fall into the category of cystic periventricular leukomalacia. The most acute lesions are not seen grossly but become apparent as white spots, approximately 2-6 mm in size, several days after the insult (see the image below).

These lesions are usually found at the upper, outer angles of the lateral ventricles at the level of the foramen of Monroe, the lateral regions of the trigone and occipital horns, and anterior to the frontal horns. After several weeks these lesions cavitate, leaving cysts, which may eventually collapse to form glial scars in the same regions, as shown in the following image.

With severe damage, ventriculomegaly will be apparent, and there may be an overall reduction in cerebral volume and thinning of the corpus callosum.

Focal lesions of periventricular leukomalacia represent areas of coagulative necrosis that are apparent within 24 hours of the insult (see the image below).

Axonal spheroids can usually be found around the lesion. Within 3-5 days, macrophages infiltrate, and by approximately 1 week, reactive astrogliosis can be seen at the margins. See the following images.

After several weeks, there is cavitation with cyst formation and, in some cases, glial scar formation with associated mineralized axons. Foamy macrophages may be found in the region for months after the insult. The diffuse component may be more subtle and consists of widespread astrogliosis and microgliosis and, initially, by a decrease in premyelinating oligodendrocytes. ^[1]

Human beta-amyloid precursor protein immunostaining can be used as a marker of damaged axons and may be helpful in highlighting more subtle focal lesions of periventricular leukomalacia. Activated microglia can be identified with antibodies to CD68 and O4, and O1 immunohistochemistry (IHC) may aid in recognizing loss of oligodendroglial precursors; more acute injury to these cells may be identified with TUNEL staining (terminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling). More experimentally, markers for various cytokines and reactive oxygen species have been used to investigate the underlying pathogenesis.

The clinical sequelae of periventricular leukomalacia include major motor deficits/cerebral palsy, which are most highly correlated with cystic periventricular leukomalacia. More diffuse periventricular leukomalacia is thought to correlate with subsequent cognitive, behavioral, attentional, and socialization deficits. ^{[1, 14]}

Most studies have looked at the ability of imaging modalities including ultrasonography and magnetic resonance imaging (MRI) to predict clinical outcome. Head ultrasonograms before 32 weeks’ gestation are able to predict subsequent cerebral palsy with a positive predictive value of, at best, about 50%. ^[10] This modality is very poor at predicting subsequent cognitive disabilities. However, the presence of parenchymal lesions by conventional MRI studies obtained at term equivalent, near the time of discharge of the premature infant from the hospital, gave a sensitivity of 100% and specificity of 79% for motor abnormality. ^[15] Early studies suggest that MRI may be a more sensitive predictor of cognitive outcome as well. ^[16]

Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009 Jan. 8(1):110-24. [Medline]. [Full Text].

Haynes RL, van Leyen K. 12/15-lipoxygenase expression is increased in oligodendrocytes and microglia of periventricular leukomalacia. Dev Neurosci. 2013. 35(2-3):140-54. [Medline].

Pavlova MA, Krägeloh-Mann I. Limitations on the developing preterm brain: impact of periventricular white matter lesions on brain connectivity and cognition. Brain. 2013 Apr. 136:998-1011. [Medline].

Volpe JJ. Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol. 1998 Sep. 5(3):135-51. [Medline].

Deng W, Pleasure J, Pleasure D. Progress in periventricular leukomalacia. Arch Neurol. 2008 Oct. 65(10):1291-5. [Medline]. [Full Text].

Herzog M, Cerar LK, Sršen TP, Verdenik I, Lučovnik M. Impact of risk factors other than prematurity on periventricular leukomalacia. A population-based matched case control study. Eur J Obstet Gynecol Reprod Biol. 2015 Apr. 187:57-9. [Medline].

Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed. 2008 Mar. 93(2):F153-61. [Medline]. [Full Text].

Falahati S, Breu M, Waickman AT, Phillips AW, Arauz EJ, Snyder S, et al. Ischemia-induced neuroinflammation is associated with disrupted development of oligodendrocyte progenitors in a model of periventricular leukomalacia. Dev Neurosci. 2013. 35(2-3):182-96. [Medline]. [Full Text].

Baier RJ. Genetics of perinatal brain injury in the preterm infant. Front Biosci. 2006 May 1. 11:1371-87. [Medline].

Neil JJ, Inder TE. Imaging perinatal brain injury in premature infants. Semin Perinatol. 2004 Dec. 28(6):433-43. [Medline].

Nosarti C, Al-Asady MH, Frangou S, Stewart AL, Rifkin L, Murray RM. Adolescents who were born very preterm have decreased brain volumes. Brain. 2002 Jul. 125:1616-23. [Medline].

Melhem ER, Hoon AH Jr, Ferrucci JT Jr, Quinn CB, Reinhardt EM, Demetrides SW, et al. Periventricular leukomalacia: relationship between lateral ventricular volume on brain MR images and severity of cognitive and motor impairment. Radiology. 2000 Jan. 214(1):199-204. [Medline].

Wang S, Fan G, Xu K, Wang C. Potential of diffusion tensor MR imaging in the assessment of cognitive impairments in children with periventricular leukomalacia born preterm. Eur J Radiol. 2013 Jan. 82(1):158-64. [Medline].

Ferriero DM. Neonatal brain injury. N Engl J Med. 2004 Nov 4. 351(19):1985-95. [Medline].

Valkama AM, Pääkkö EL, Vainionpää LK, Lanning FP, Ilkko EA, Koivisto ME. Magnetic resonance imaging at term and neuromotor outcome in preterm infants. Acta Paediatr. 2000 Mar. 89(3):348-55. [Medline].

Logitharajah P, Rutherford MA, Cowan FM. Hypoxic-ischemic encephalopathy in preterm infants: antecedent factors, brain imaging, and outcome. Pediatr Res. 2009 Aug. 66(2):222-9. [Medline].

Cynthia E Hawkins, MD, PhD, FRCPC Associate Professor, University of Toronto Faculty of Medicine; Neuropathologist, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children; Scientist, The Labatt Brain Tumour Research Centre

Cynthia E Hawkins, MD, PhD, FRCPC is a member of the following medical societies: American Association for Cancer Research, American Association of Neuropathologists, Ontario Medical Association, Society for Neuro-Oncology

Disclosure: Nothing to disclose.

Abeyat Zaman-Haque, MD Resident Physician, Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, Canada

Disclosure: Nothing to disclose.

Adekunle M Adesina, MD, PhD Professor, Medical Director, Section of Neuropathology, Director, Molecular Neuropathology Laboratory, Texas Children’s Hospital, Department of Pathology and Immunology, Baylor College of Medicine

Adekunle M Adesina, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Neuropathologists, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Pathology of Periventricular Leukomalacia

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