Case Study 28Julia Kofler, M.D.

The brain in this case is from a male infant who was delivered prematurely at 30.5 weeks gestation due to intrauterine growth restriction, oligohydramnios and fetal distress. He was found to have significant heart abnormalities including a patent ductus arteriosus resistant to indomethacin-therapy, and a large atrial septal defect leading to high-output cardiac failure with significant shunting. The baby died of multiorgan failure at 6 weeks of age. At autopsy, the brain was significantly below the age-expected weight and showed several gross abnormalities. Describe the findings in the following representative coronal section:

Question 1

Bilateral partially hemorrhagic multicystic lesions in the periventricular white matter.

Answer

Question 2How would you describe the border between gray and white matter? Is this appearance normal or abnormal in an infant of this age? Explain why.

AnswerThere is no or only minimal distinction between gray and white matter. The lack of distinction between gray and white matter is normal in a term infant and is due to incomplete myelination.

By birth, the brainstem and cerebellum contain well-myelinated tracts, whereas the forebrain almost completely lacks myelin. Only a few sites in the forebrain exhibit minimal myelination at birth, including the internal capsule, corona radiata, optic tract and chiasm. Myelination progresses in the forebrain from the central sulcus outward to the poles and is largely completed by the end of the second postnatal year.

Question 3Which stain is commonly used to visualize myelin?

AnswerLuxol Fast Blue (LFB)

Question 4Describe the microscopic findings in a representative H&E section of the occipital lobe.

Click here to view slide.

AnswerCystic lesion with clusters of foamy and pigment-laden macrophages, reactive astrocytes, microglial activation, capillary proliferation, dystrophic calcifications and multifocal hemorrhages in the periventricular white matter.

Question 5What is your diagnosis?

AnswerPeriventricular leukomalacia (PVL)

Question 6Name the three major forms of periventricular leukomalacia (PVL).

Answer Cystic PVL with macroscopic foci of necrosis

which evolve to multiple cysts

Non-cystic PVL with microscopic foci of necrosis resulting in glial scars

Diffuse PVL consisting of diffuse white matter gliosis without focal necrosis

Question 7What is the period of greatest risk for the development of PVL?

AnswerThe period of greatest risk for PVL is in the premature infant during mid- to late gestation (24-32 weeks), but it may also occur in full-term infants, particularly those with congenital cardiac or pulmonary disease.

Question 8Name the major pathophysiologic mechanisms underlying PVL.

AnswerMost important cause of PVL is ischemia, affecting

predominantly watershed areas in the developing white matter and aggravated by immature cerebral autoregulation

Ischemia results in microglial activation, release of free radicals (reactive oxygen and nitrogen species), glutamate release and cytokine release

Maternal/placental/fetal infection can trigger similar cascades

The principal target of released free radicals and glutamate is the immature premyelinating oligodendrocyte resulting in deficient myelination.

Question 9What are common sequelae of PVL in survivors?

AnswerDeficits in survivors may include cerebral palsy in 5-10%, cognitive or behavioral deficits in about 50% and blindness.

Question 10Injury to which parts of the brain underlies cerebral palsy and blindness in PVL?

AnswerCerebral palsy results from damage to axons of the corticospinal tract; blindness from damage to the optic radiation.