Autopsy Manual: Brain



            Subarachnoid Hemorrhage:

            Mild trauma: Delivery is likely responsible for small incidental hemorrhages over the subarachnoid surface of the brain in preterm infants.

            Intraventricular hemorrhage (IVH): 

Intraventricular hemorrhage is usually the result of germinal matrix hemorrhage or hemorrhage from periventricular leukomalacia. The germinal matrix exists from early gestation to term as a reserve of immature cells that will become neurons and glia. The amount decreases after 33 weeks of gestation. The risk of IVH synchronously decreases with the maturation of the germinal matrix. Hemorrhage in this soft embryonic appearing tissue with prominent thin-walled vessels may occur in response to various risks including hypoxia, cytokines, or suddenly changing vascular pressures. Most hemorrhages are identified after birth. However, intraventricular hemorrhage can be found in previable fetuses at autopsy (Fig 1).

Fig 1: These 2 slices of brain demonstrate blood grade 3 intraventricular hemorrhage. The arrow points to hemorrhage in the area of the germinal matrix. This 19.5 weeks of gestation infant was an intrapartum death. Three days before delivery, the fetal membranes ruptured prematurely. The placenta demonstrated funisitis and purulent chorioamnionitis.

Grossly, in the intact brain, blood in the ventricles often seeps and pools around the base of the brain (Fig 2).

Fig 2: Subarachnoid blood is surrounding the base of the brain around the pituitary and optic chiasms and over and in the fourth ventricle. This 20 weeks of gestation infant was an intrapartum death with a lethal skeletal dysplasia who demonstrated an IVH from a germinal matrix hemorrhage.

A simple grading system for IVH is: Grade 1: hemorrhage confined to the germinal matrix; Grade 2 hemorrhage into but not expanding the ventricle; Grade3 hemorrhage expanding the ventricle; Grade 4 hemorrhage into the white matter. Since the blood is likely to follow the path of least resistance, these Grade 4 hemorrhages likely flow into areas of periventricular leukomalacia which are also more frequent in more premature infants (Fig 3). 

Fig 3: The arrow points to hemorrhage into the white matter. Microscopically, there was extensive telencephalic white matter necrosis. This 25 weeks of gestation infant was delivered as an emergency with a 50% premature placental separation, and survived one day. 


            During birth, the compression around the scalp can produce a caput succendaneum. This is a harmless, usually bloody appearing subcutaneous, edema from compression of cranial veins during delivery. A cephalohematoma can occur with bleeding into the scalp sometimes associated with the use of a vacuum extractor. A subgaleal hematoma beneath the scalp aponeurosis can occur with vacuum extraction, but also with trauma to the underlying bone (Fig 4)

Fig 4: The subgaleal hematoma overlying the right parietal bone is evident. 

. The amount of blood from such hematomas may be sufficient to cause hypotension in the infant. With a subgaleal hematoma, there is a possibility of parenchymal hemorrhage as well. 

            Subdural Hematoma: 

            As in adults, this is the result of trauma tearing small veins traversing the subdural space (Fig 5).

Fig 5: There is a liquid subdural hematoma over the right hemisphere in this 32 weeks of gestation infant who died 6 hours before delivery with evidence of acute asphyxia. The subdural may have occurred during delivery.

There is evidence that lethal subdural hemorrhages can occur prior to birth1. In New Zealand, there is evidence that traditional practices of abdominal massage can lead to such hemorrhages2.

            Parenchymal hemorrhage: 

Deep hemorrhages may be evident in the intact brain if the hemorrhage extends to the subarachnoid surface (Fig 6a, b).

Fig 6a: The brain demonstrates subarachnoid hemorrhage over the posterior temporal occipital area in thus 33 weeks of gestation infant with a camptomelic osteochondrodystrophy who suffered an intrapartum death.
Fig 6b: The cut sections of the same brain as in Fig 6a demonstrate numerous hemorrhages in the temporal-occipital lobes with rupture dissecting thorough the brain into the subarachnoid. Microscopically, the hemorrhagic areas show early necrosis but no gliosis. 

The causes of such hemorrhage may be from vascular malformation such as Vein of Galen aneurysm or from thrombocytopenia especially with anti- platelet antibody A1 in the mother3,4. As with Rh disease, the fetus must be A1 positive in an A1 negative mother. Infarctions of the brain may appear hemorrhagic. Because of the large proportion of spinal fluid and the flexible skull with unfused sutures, hemorrhage into the brain can cause fetal anemia and hemorrhage shock (Fig 7a, b, c). 

Fig 7a: This image shows residual blood in the cranial cavity of a 21 weeks of gestation fetus with parenchymal and large subarachnoid hemorrhage as well, but photos of the brain are not available There was approximately 48 hours of postmortem retention. Testing for platelet antigens was suggested.
Fig 7b: This is the same infant as in Fig 7a demonstrating marked pallor of the internal organs.
Fig 7c: This image is from a 37 weeks of gestation infant with intracranial hemorrhage from arterio-venous malformation that demonstrates how widely the sutures can be separated to expand the cranial cavity volume (arrows). The infant survived for 12 hours. 


            Following prolonged experimental hypoxia in monkeys, Dr. Myers discovered that the mechanism of brain injury involved edema from vascular leaking5,6. In the older gestation fetal brain, edema when marked can be recognized as compression of the lateral ventricles (Fig 8). This edema may also increase the expected weight of the brain for a given gestation. 

Fig 8: The cut sections of this brain show obliteration of the lateral ventricles by edema. This 34 weeks of gestation infant survived for 3 hours but died with severe enterococcus pneumonia.


            Whether from edema, hemorrhage or mass lesion, uncal and tonsillar herniation of the brain is rare in the fetus because of the increased proportion of spinal fluid and the expansible skull. Herniation may be present in older gestation infants (Fig 9a b). 

Fig 9a: This brain is from the same infant as in Fig 8, The groove from tentorial herniation is much further anterior and larger than the usual uncal herniation in adults. The gyri are also flattened consistent with the massive edema.
Fig 9b: This infant had a prolonged bradycardia 2.5 hours prior to delivery at 40 weeks of gestation with survival for 6 hours. The arrow points to the tonsillar herniation The gyri are severely flattened. 


            In my residency training, I saw a stillborn brain with multiple scattered small cortical infarctions and in my fellowship, a typical middle cerebral artery distribution infarction. They were attributed to differential blood flow with hypoxia. However, there is adequate clinical evidence now that infarctions in the fetal brain can occur from severe genetic, or immune acquired, thrombophilia or from emboli from thrombi on the venous side of the placental circulation (Fig 10a, b)7. A cortical brain infarction may not be diagnosed in the nursery in an uncomplicated pregnancy.

Fig 10a: The one cerebral hemisphere is replaced by hemorrhagic infarction in this 38 weeks of gestation infant who survived 7 hours with severe pulmonary hypoplasia associated with a large diaphragmatic hernia. There were infarctions in multiple visceral organs including liver, spleen and kidney as well as infarctions in the cerebellum and pons.
Fig 10b: This microscopic image of a hemorrhagic infarction of the pons in the same infant at Fig 10a shows that on the right many hemosiderin laden macrophages and on the left reactive capillaries. These changes did not occur in the 7 hours of survival. The placenta was not available for examination, but an underlying thrombophilia was suggested. (40x, H&E)

Periventricular leukomalacia and leukotelencephalic necrosis: 

            In premature infants, brain injury tends to occur in the white matter of the cerebral cortex, often in a periventricular pattern, but it may be more extensive. Early on there may be a chalky coloration, but over time the necrotic areas may develop into cystic cavities (Fig 11)8.

Fig 11: The arrows point to white matter cysts in the brain of this 31 weeks of gestation infant who survived 3 hours and who was born with severe fetal hydrops with evidence of hemolysis.

This white matter vulnerability in preterm infants has been attributed to low blood flow, increased glutamate receptors on immature oligodendroglia, etc9,10. In Dr. Myers experiments in monkeys white matter lesions could be produced even in mature monkeys with partial asphyxia and oligoacidotic hypoxia that is a  pO2 at 8-10 mmHg while the pCO2 and pH remain minimally affected11.


            It is not the purpose of this manual to include malformations, but common malformations include holoprosencephaly, various forms of hydrocephalus (e.g. Dandy Walker (Fig 12), Arnold Chiari, aqueductal stenosis), and midline cyst with absent corpus callosum (Fig 13).

Fig 12a: This view of the brainstem is looking caudally from the cerebral peduncles, the cerebellar lobes are split with an intervening membrane that shows the ruptured cyst beyond it. This infant had an intrapartum death at 19 weeks of gestation.
Fig 12b: The brain slices from the same brain as in Fig 12a shows the ventriculomegaly.
Fig 13: This dorsal posterior view of the brain shows the falx between the cerebral hemisphere without a corpus callosum. Between the hemisphere there is a central cyst (arrows).  This 32 weeks of gestation infant with oro-facial-digital syndrome survived for 2 days. 


            There are congenital tumors of the brain, although uncommon and unlikely to be encountered in stillbirth. The most common malignant tumor is glioblastoma multiforme12

Gestational age: 

Comparing the gyral pattern of the brain to several available charts of gestational age development provides a relatively simple and accurate way to estimate gestation of the infant13(See manual post on gestational age). There are also microscopic changes in the brain that can be used to estimate gestation such as the loss of the external granular layer in different cortical locations (Fig 14a, b)14.

Fig 14a: This section from the prefrontal cortex still shows a line of small blue cells of the superficial granular layer (arrow) beneath the molecular layer over the surface of the brain, and a primitive corticopetal fiber arrangement of the gray matter. This is a 28 weeks of gestation infant with absent kidneys who survived one hour. (10x, H&E)
Fig 14b: This section from the prefrontal cortex of a 39 week gestation infant who could not be resuscitated after birth shows that the molecular layer is no longer present. (10x, H&E) 


White matter injury: 

            Early white matter injury can be difficult to discern, but will show on H&E slides a difference in texture from surrounding areas. As the lesion progresses there will be vascular growth and endothelial swelling, astrocytic gliosis with distinct eosinophilic cytoplasm and macrophage (microglia) ingestion of debris. The final stage may be a gliotic scar or a lacuna of spinal fluid surrounded by glial scarring (Fig 15).

Fig 15: This low magnification image shows cystic structures with dense eosinophilic glial scars in the brain of a one month old neonate. (2x, H&E)

In a stillborn infant, the progression of changes can provide a window of timing of a previous insult (Fig 16a, b).

Fig 16a: The vascular proliferation and enlarged endothelial cells are easily seen in the white matter of this 31 weeks of gestation infant with 24-48 hours of postmortem retention who had a complex heart malformation. (40x, PAS)
Fig 16b: From the same brain as Fig 15a, the accumulation of cell debris in the macrophages is evident, and the arrows point to reactive astrocytes. (40x, PAS)

Grey matter necrosis: 

            Gray matter necrosis shows neuronal necrosis, and progresses with astrocytic gliosis, vascular proliferation, gitter cells and eventually a glial scar or cavitation (Fig 17a, b).

Fig 17a: This low magnification image shows the loss of normal architecture and the beginning of cystic change in the gray and white cortex. This brain is from a near term infant with a severe intrapartum asphyxia who died nine days later. (2x, H&E)
Fig 17b: This higher magnification demonstrates gliotic outer later beneath the meninges with many activated astrocytes with prominent eosinophilic cytoplasm. The area beneath that is primarily macrophages and vascular proliferation. This degree of injury would not be expected in a stillborn infant because this degree of asphyxial injury would usually lead to death without external resuscitation. (20x, H&E)


Neuronal necrosis:

            Neuronal necrosis is an apoptotic cell death of individual neurons. In Myers experiments in monkeys, there was a stereotyped progression of brain nuclei showing neuronal necrosis as the period of complete asphyxia increased (Fig 18a, b).

Fig 18a: This section of the basal ganglia nucleus shows neuronal necrosis of isolated neurons with pyknotic nuclei and eosinophilic cytoplasm (arrows). This 40 weeks of gestation infant hadmore than 96 hours of postmortem resuscitation. The autopsy showed only acute pericardial and pleural effusions, and increased nucleated red cells in the blood. (40x, H&E)
Fig 18b: This section from a brainstem nucleus shows many pyknotic neuronal nuclei. This 40 weeks of gestation infant died 6 hours after a traumatic delivery. The scenario is similar to the experimental production of neuronal necrosis by acute asphyxia in a previously well oxygenated infant who after a period of complete asphyxia is resuscitated. (10x, H&E)

This pattern only occurred if the experimental monkey was initially not acidotic, and the progression showed a relationship to metabolic activity in those nuclei. In the perinatal autopsy, a frequent pattern of neuronal necrosis with karyorrhexis is found in the pons and subiculum (for more detail, see blog on Sept 30,2020 on “Cesarean section association with autism and attention deficit?”).


            Intraventricular hemorrhage originating in the germinal matrix can often be identified microscopically (19a, b).

Fig 19a: The germinal matrix (GM) shows dilated thin walled vessels and a large hemorrhage that has broken into the ventricle in this 23 weeks of gestation infant with intrapartum death. (2x, H&E)
Fig 19b: There are multiple basal ganglionic, and in the top hemorrhage perhaps in the periventricular white matter in this 23 weeks of gestation, approximately 24 hours of postmortem retention who had fetal hydrops secondary to 1 cm, small cell tumor originating in a paraganglia. The hydrops and the hemorrhages may have been caused by adrenergic hypertension. (4x, H&E)

Where the hemorrhage extends into surrounding white matter that portion appears necrotic. From the histology, it may not be clear whether the hemorrhage caused the necrosis or the hemorrhage bled into a necrotic area. If the surrounding non-hemorrhagic white matter is necrotic, a reasonable inference is that the hemorrhage passively entered the necrotic area. Not all intraventricular hemorrhages are from the germinal matrix but may occur with other deep brain hemorrhage (Fig 20).

Fig 20: The hemorrhage here in the ventricle but also in the necrotic white matter beneath the ependyma which at least in this section appears intact. This brain is from a 40 weeks of gestation infant who lived 6 days and had a basal ganglionic hemorrhage. (H&E)

Parenchymal  hemorrhages may have underlying vascular lesions that are not perceptible grossly (Fig 21a, b).

Fig 21a: This image is of a cerebral angioma approximately 3 x4 x2 cm in the occipital lobe with delicate vessels that hemorrhaged in the brain of a 30 weeks of gestation infant with 24-48 hours of postmortem retention who demonstrated fetal hydrops, erythroblastosis and shock lesions. (10x, H&E)
Fig 21b: This 37 weeks of gestation infant lived 6 hours after an emergency Cesarean section because of onset of tachycardia. The sutures were distended and there was parenchymal and intraventricular hemorrhage. The Virchow Robin spaces were filled with anomalous appearing small vessels as seen in this image. (10x, H&E)

Hemorrhage can also occur into infarctions in the brain (Fig 22)

Fig 22: There is acute hemorrhage in an area where the neuropil showed eosinophilia and cell nuclei were fading as evidence of coagulation necrosis from infarction. This image showed thrombus in a thin-walled vessel. No large arterial thrombus was found in the brain nor venous thrombi in the placenta in this 32 weeks of gestation intrapartum death. (40x H&E)

Infection: The most common fetal infections that directly affect the brain are CMV and HSV. CMV typically produces periventricular calcification. HSV may produce a necrotizing, geographic patterned encephalitis (Fig 23).

Fig 23: This image shows the surface of the brain over a large cystic area. The brown staining cells are positive for an HSV 1 & 2 antigen. This sample is from a 33 weeks of gestation infant who survived 2 days with stigmata of herpes simplex infection and with hydranencephaly due to the destructive herpetic encephalitis. (10x, H&E)

The role of fetal septic responses in white matter necrosis has been proposed.

See short case presentation below  on an infant with hypoxic/ischemic brain injury.


1.         Demir RH, Gleicher N, Myers SA. Atraumatic antepartum subdural hematoma causing fetal death. Am J Obstet Gynecol 1989;160:619-20.

2.         Becroft DM, Gunn TR. Prenatal cranial haemorrhages in 47 Pacific Islander infants: is traditional massage the cause? N Z Med J 1989;102:207-10.

3.         Bussel J, Kaplan C. The fetal and neonatal consequences of maternal alloimmune thrombocytopenia. Baillieres Clin Haematol 1998;11:391-408.

4.         Spencer JA, Burrows RF. Feto-maternal alloimmune thrombocytopenia: a literature review and statistical analysis. Aust N Z J Obstet Gynaecol 2001;41:45-55.

5.         Myers RE, Beard R, Adamsons K. Brain swelling in the newborn rhesus monkey following prolonged partial asphyxia. Neurology 1969;19:1012-8.

6.         Bondareff W, Myers RE, Brann AW. Brain extracellular space in monkey fetuses subjected to prolonged partial asphyxia. Exp Neurol 1970;28:167-78.

7.         Rayne S, Kraus F. Placental thrombi and other vascular lesions classification; morphology and clinical correlations. Path Res Pract 1993;189:2-17.

8.         Banker BQ, Larroche J-C. Periventricular leukomalacia of infancy. Arch Neurol 1962;7:386-410.

9.         Folkerth RD. Neuropathologic substrate of cerebral palsy. J Child Neurol 2005;20:940-9.

10.       Jensen FE. Role of glutamate receptors in periventricular leukomalacia. J Child Neurol 2005;20:950-9.

11.       Myers RE. Four patterns of perinatal brain damage and their conditions of occurrence in primates. Adv Neurol 1975;10:223-34.

12.       Winters JL, Wilson D, Davis DG. Congenital glioblastoma multiforme: a report of three cases and a review of the literature. J Neurol Sci 2001;188:13-9.

13.       Larroche JC. Developmental Pathology of the Neonate: Excerpta Medica; 1977.

14.       Friede RL. Developmental Neuropathology, Second Edition. Heidelberg: Springer-Verlag; 1989.p.5

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