Case Study 28

1. Case Study 28 Julia Kofler, M.D.

2. Question 1 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:

4. Answer Bilateral partially hemorrhagic multicystic lesions in the periventricular white matter.

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

6. Answer There 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.

7. Question 3 Which stain is commonly used to visualize myelin?

8. Answer Luxol Fast Blue (LFB)

9. Question 4 Describe the microscopic findings in a representative H&E section of the occipital lobe. Click hereto view slide.

10. Answer Cystic 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.

11. Question 5 What is your diagnosis?

12. Answer Periventricular leukomalacia (PVL)

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

14. 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

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

16. Answer The 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.

17. Question 8 Name the major pathophysiologic mechanisms underlying PVL.

18. Answer • Most 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.

19. Question 9 What are common sequelae of PVL in survivors?

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

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

22. Answer Cerebral palsy results from damage to axons of the corticospinal tract; blindness from damage to the optic radiation.