Basic Principles 20
20.1 Epidemiology 407
20.1.1 Injuries During the Perinatal Period 407 20.1.2 Acquired Postnatal Injury 408 20.2 Developmental Neuroanatomy 408 20.2.1 The Coverings 408
20.2.2 The Brain 411 20.3 Autopsy Findings 412 20.3.1 Head and Cranial Contents 413 20.3.2 Cervical Spine 413
20.3.3 Ears and Mastoids 414 20.3.4 Eyes 414
20.4 Microscopic Examination:
Cell Reaction 414
20.5 Postmortem Biochemistry 415 20.6 Diffuse Cerebral Swelling 415 20.6.1 Hyperemia 416
20.6.2 Edema 416 20.6.3 Hydrocephalus 416
20.7 Forensic Aspects (Expert Witness) 417 20.7.1 Medical Malpractice 417
20.7.2 Physical Abuse 419 20.7.3 Ethical Aspects 419
Bibliography 420
References 420
The developing brain’s liability to insult from impact, asphyxia, and exposure to chemicals and drugs is well known. This vulnerability is based on (and character- ized by) phenomena associated with the proliferation of neurons and glial cells, the migration of neurons, the differentiation of neurons and glial cells, includ- ing synaptogenesis, gliogenesis and myelination, as well as with apoptosis as a form of programmed cell death (Barone et al. 2000). The brain of the fetus, the infant, and the toddler differs chemically, structur- ally, and thus also functionally and biomechanically
from the adult brain. Its size and mass depend on its developmental age. The infant brain consists of
>90% water, the adult brain only 76% (Davison and Dobbing 1966; Blinkov and Glezer 1968). Unlike the adult brain, the infant brain is not held together by an extensive network of myelinated nerves; its essence is its fluidity. Beginning in the womb, normal devel- opment of the nervous system requires that the con- comitant and coordinated ontogeny of proliferation, migration, differentiation, etc. as well as a specific reactivity to different impacts occur in a temporally and regionally dependent manner. For these and re- lated reasons a separate section is presented dealing with the unique problems associated with forensic pediatric neuropathology. The developmental phases depicted in Fig. 20.1 (Vorhees 1986) apply to the clas- sification of the gestational age used here.
20.1
Epidemiology
The forensic pediatric neuropathologist must distin- guish deaths occurring in the perinatal phase from postnatal deaths.
20.1.1
Injuries During the Perinatal Period
The perinatal period shortly before and after birth is delimited as a phase beginning with the completion of the 28th week of gestation and is variously defined as ending 1−4 weeks after birth. The literature offers numerous surveys on perinatal mortality rates. The comparison of their findings, however, is often diffi- cult due to differences in the definitions applied and in the objective of the authors (Golding 1993). More- over, the perinatal mortality rate in a given country reflects the quality of medical care available to its citizens. Industrially developed nations have a peri- natal mortality rate of about 4−7 per 1000 live births (Guyer et al. 1999). The principal causes of stillbirth deaths in these countries are as follows (Hovatta et al. 1983 − necropsy classification):
▬ Asphyxia, as demonstrated by meconium aspira- tion, petechiae on serous membranes and intra- cerebral hemorrhages: 38.3%
▬ Major malformation: 16.9%
▬ Severe erythroblastosis fetalis: 0.8%
▬ No cause found: 1.2%
▬ Maceration only, without a demonstrable cause of death: 42.8%
The morphologic picture of inflammatory infiltra- tions (inflammatory and reparative tissue reaction) in developing human CNS was investigated by Dam- ska et al. (2004). Morphological feature of inflam- matory reaction in the immature CNS develop in the second half of pregnancy. The final localization in fully mature inflammatory reactions is prolonged in time. It was found that numerous granulocytes ap- pear in bacterial infections, but not in aseptic lesions of the brain. The changes depend on the character of the injurious factor and the level of maturation of the CNS. The topography of maturing brain lesions due to infectious and anoxic/ischemic damage was similar and the lesions were localized most often in the periventricular white matter.
20.1.2
Acquired Postnatal Injury
Among the causes of brain injury occurring after birth, i.e., during the early postnatal period, are traumatic events, bleeding, anoxia, infections, brain tumors, and other malignant disorders. A review of morbidity and mortality to the age of 14 years re- vealed a cumulative incidence of serious mechani- cally induced brain injury (MBI) of 235 per 100,000 in a Finnish population (Rantakallio and Wendt 1985). This is comparable with a total incidence of acquired brain injuries of 175−200 per 100,000 in the population of the USA reported by Kraus and McAr-
thur (1996). Epidemiological data from the USA, Germany, and other western countries (e.g., Swe- den − Emanuelson and Wendt 1997) reveal similar statistics: in Germany, about 100,000 cases of MBI are documented each year, half of the victims being under 25 years old, 15% are children 5 years of age or younger (Mayer 1998 − Dtsch Ärztebl 94:C2516). In the USA, the estimated annual incidence of MBI per 100,000 population ranges from 193 to 367 (Kraus et al. 1986; Tullous et al. 1992).
20.2
Developmental Neuroanatomy
It would exceed the limits of the present volume to offer a detailed description of CNS development in the infant. The reader is referred to the relevant monographs, in particular that of Feess-Higgins and Larroche (1987). Instead, only a short review is in- tended. Though we cannot describe the functional development of the nervous system in early infancy, it will be important to know the relation of neuro- logic findings in preterm infants reaching term age in comparison to infants of gestational age at birth.
Preterm infants examined at term were more hyper- excitable and tended to have less flexor tone in the limbs and less extensor tone in the neck in the sitting posture (Mercuri et al. 2003).
20.2.1 The Coverings
The scalp of the newborn and child is thinner than that of the adult, contains less fat tissue, and is more elastic, but is more susceptible to blunt impacts and to tearing forces. Erythema and pressure marks are relatively uncommon, making it easy to overlook the
Fig. 20.1. Developmental periods (upper panel) and developmental processes of or- ganogenesis and histogenesis of the central nervous system (source: Vorhees 1986)
effects of blunt force impact by external macroscopic inspection alone (i.e., without autopsy). A special type of injury seen in the newborn infant is massive subgaleal hematoma, sometimes associated with skull fractures. The time-dependent morphological alterations of subcutaneous or subgaleal hematomas may differ from that of comparable injuries in adults (Gonzales et al. 1954; Wilson 1977).
The neonatal skull is characterized by open su- tures between the cartilaginous bone plates. Because the cartilaginous skull, especially the cranial vault, ossifies only gradually over the first 2 years of life, the infant skull retains an enormous elasticity. The circumference of the head/skull increases with that of the brain (Fig. 20.2, Table 20.1) and thus is depen- dent upon age. The fontanels close at different ages (Peacock 1986):
▬ The posterior fontanel: 2nd postnatal month
▬ The anterior fontanel: between the 7th and 19th postnatal months (90% of the cases − Aisenson 1950)
The neonatal dura has a structure (Friede 1989) dis- tinct from that of the adult meningeal membrane.
The arachnoid granulations do not attain their fi- nal form until adulthood, nor do the bridging veins, which display an age-related difference in elasticity (Yamashima and Friede 1984; Friede 1989). A com- parative prospective study has shown that so-called subdural neomembranes unassociated with MBI or different types of delivery are common in infants (Rogers et al. 1998).
The outer surface of the arachnoid membrane is fused with the inner surface of the dura mater in a manner which confers scant cohesion at the interface
layer, the dura separating easily from the arachnoid.
Upon disruption of the interface layers, some cells remain on the surface of the arachnoid and some on the dura mater. Proliferation of these residual cells produces neomembranes. Stretching and tearing of the bridging veins are partly responsible for subdu- ral hemorrhages, the walls of bridging veins in in- fants being particularly thin (Friede 1989). Moreover, in children the dura tends to develop hygroma or is involved in the process of growing skull fractures as well as leptomeningeal cysts (see below).
Table 20.1. Head circumferences of children. Sources: Altman and Dittmer 1962; Prader and Budliger 1977; Dekaban 1977
Age Head circumference (cm)
Males Females
Birth 35.3 (33.5−37.0) 34.7 (33.4−36.0)
0.25 years 40.9 (39.2−42.1) 40.0 (38.5−41.7)
0.5 years 43.9 (42.7−45.4) 42.8 (41.4−44.5)
0.75 years 46.0 (44.5−47.1) 44.6 (43.2−46.3)
1 year 47.3 (45.5−48.4) 45.8 (44.3−47.7)
1.25 years 48.0 (46.3−49.2) 46.5 (44.9−48.4)
1.5 years 48.7 (47.0−49.9) 47.1 (45.5−49.0)
2 years 49.7 (48.0−51.0) 48.1 (46.4−50.1)
2.5 years 50.2 (48.5−51.6) 48.8 (47.0−50.8)
3 years 50.4 (48.9−51.9) 49.3 (47.5−51.1)
Fig. 20.2. Head circumference of boys. Source: Nellhaus 1968
Table 20.2. Brain mass before birth in relation to gestational age. Sources: Gruenwald and Minh 1960; Schulz et al. 1962;
Guihard-Costa and Larroche 1990
Gestational age (weeks)
Gruenwald and Minh (1960)
Schulz et al (1962)
Guihard-Costa and Larroche (1990)
N Brain mass (g) N Brain mass (g) N Brain mass (g)
14−15 2 15±1
16−17 3 21±1
18−19 10 37±8
20 5 45
20−21 15 52±7
22−23 9 75±17
23±2 317 70±18
24 24 112 ±36
24−25 15 101±18
26±0 311 107±27
26−27 21 130±17
27±5 295 143±34
28 47 169±46
28−29 18 169±19
29±0 217 174±38
30 − 31 21 203±25
31±3 167 219±52
32 70 283±52
32±4 148 247±51
32−33 13 234±28
34±6 140 281±56
34−35 14 280±28
36 62 354±70
36±4 124 308±49
36−37 6 325±40
38±0 120 339±50
38−39 10 391±41
39±2 138 362±48
40 64 409±60
40±0 144 380±55
40±4 133 395±53
40±4 106 411±55
40±6 57 413±55
40−41 17 409±37
41±4 31 420±62
41±2 15 415±38
20.2.2 The Brain
Due in part to differences in anatomical proportions and relative brain masses, the pathological and clini- cal features of brain injury in infants and children differ from those in adults. The infant brain com- prises 15% of total body mass at birth, compared to 2% in the adult. The immature brain grows rapidly, reaching 75% of adult brain mass within 2 years and over 90% of adult brain mass by age 6 (Friede 1989).
The mass of the childhood brain depends on the stage of development, both before (Table 20.2) and after (Table 20.3) birth. The brain‘s rapid expansion in the time just preceding and after birth reflects the ongoing maturational process, including a prolifera- tion of connections among neurons that facilitates neuronal function and contributes to structural complexity. This growth in size is accompanied by a decline in the water content of the cortex and white matter from 87% and 89%, respectively, at birth, to 85% and 77% during the first decade of life. The adult norms of 83% and 69% are gradually attained late in the second decade (Katzman and Pappius 1973).
Development of the cerebral cortical surface pro- ceeds gradually from the flat lissencephalic brain of the fetus to the adult pattern of sulci and gyri. The gyral formation does not develop until the 18th week of gestation (Fig. 21.4). Primary fissures appear be- tween weeks 18 and 28. Opercularization of the Syl- vian fossa and the Rolandic sulcus begins at week 20, the superior temporal sulci are set between weeks 24 and 28. The schedule of these changes is invariable.
The cortical surface area of the newborn brain mea- sures approximately 700 cm2, 61% of which is intra- sulcal (Hesdorffer and Scammon 1935; Scammon and Hesdorffer 1935) compared to the adult figure of about 43%, which is reached by the second year of life. The surface area more than doubles postnatally, to reach the adult value of approximately 1,600 cm2.
During early embryogenesis (5th−6th weeks) the hemispheric wall consists of an inner and a super- ficial germinal layer plus a cellular zone (the “Rand- schleier”). The maturation of cortical layering is ac- companied by a decrease in the packing density of nerve cells. This is a universal feature of maturation of gray matter attributable to an increase in the vol- ume of neuropil, mainly due to dendritic growth and the ramification of afferent processes.
The criteria of cortical maturation include the development of dendrites and the degree of their spe- cialization (Purpura 1975). The shape and length of the dendritic spines in particular reflect the extent of cortical maturation: long, thin spines indicate im- maturity; stubby, mushroom-like spines indicate ad- vanced maturity.
Another clear marker of neuronal maturation, synaptophysin as demonstrated by immunohisto- chemistry, obviously depends on the increase in the number of synaptic connections of the neurons. It may therefore be an indicator of presynaptic readi- ness in specific regions of the brain and spinal cord.
CNS tissue of 8- and 10-week-old fetuses shows no immunoreactivity for synaptophysin in any part.
At 12 to 14 weeks of gestation, the ventral horns of the spinal cord and the molecular layer (lamina I) of the cerebral neocortex express synaptophysin, while other areas exhibit a different time dependency (Sar- nat and Born 1999). It is assumed that mental retar- dation will be the result of defects in synaptic struc- ture and function (Chechlacz and Gleeson 2003).
Table 20.3. Brain mass after birth and its age-related variability. Source: Boyd 1952
Age Brain mass (g)
Male Female
Newborn 353 347
0−0.25 years 435 411
0.25−0.5 years 600 534
0.5−0.75 years 877 726
0.75−1.0 years
1−2 years 971 894
2−3 years 1076 1012
3−4 years 1179 1076
4−5 years 1290 1156
5−6 years 1275 1206
6−7 years 1313 1225
7−8 years 1338 1265
8−9 years 1294 1208
9−10 years 1360 1226
10−11 years 1378 1247
11−12 years 1348 1259
12−13 years 1383 1256
13−14 years 1382 1243
14−15 years 1356 1318
15−16 years 1407 1271
16−17 years 1419 1300
17−18 years 1409 1254
18−19 years 1426 1312
19−20 years 1430 1294
The expression of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in the developing brain is important for understanding early neuronal development. As demonstrated by Takikawa et al.
(2001), neuronal NOS can be detected only at 28 and 33 weeks of gestation in the cerebrum and at 15, 18, and 23 weeks of gestation in the brain stem. Nitric oxide (NO) probably contributes to neuronal differ- entiation and is cytotoxic in large quantities due to its reaction with superoxide anions. These data sug- gest that SOD serves as a scavenger of superoxide an- ions at an early developmental stage in preparation for stage-specific expression of neuronal NOS for a potential differentiation role and to avoid NO cyto- toxicity. The results of Folkerth et al. (2004) indicate that a developmental „mismatch“ in the sequential antioxidant enzyme cascade likely contributes to the vulnerability of free radical toxicity of the immature cerebral white matter due to ischemia/reperfusion, particularly between 24 and 32 gestational weeks.
Up to the 30th week of gestation, the germinal layer (matrix cells) of the lateral ventricles forms a subependymal sheet of tightly packed immature cells lining the entire ventricular wall. After that the layer begins to thin out. The cerebral white matter grows at a slower rate than the cortex during fetal develop- ment, but postnatally it continues to grow long after the gray matter has attained its definitive volume.
The onset of function in a neuron probably corre- lates well with its acquisition of a myelin sheath. The spinal anterior root is one of the nerve structures that begins to be myelinated at the earliest stage − at around 16 weeks − of fetal life, whereas myelination of the pyramidal tract begins just before birth and is completed at around 2 years of age (for a timetable of myelogenetic cycles, see Yakovlev and Lecours 1967;
Peacock 1986).
Cortical growth subsides by the second year of life. Although most of the brain has been myelinated by the second year of life (Norton 1972), the hemi- spheric white matter continues to grow until after the first decade from continued accumulation of myelin- ated fibers and an increase in their caliber (Scammon 1932). Between the 6th and 18th postnatal months the white matter is smaller in volume than the almost fully developed, deeply gyrated cortex. Myelination of the structures involved in the highest intellectual functions; i.e., the short intracortical connections of the association areas in the frontal, parietal, and tem- poral lobes, begins in the third postnatal month and may continue even into the sixth decade.
Differentiating astrocytes exhibit changes in their expression of intermediate filament proteins.
The radial glia and immature astrocytes are positive for vimentin and negative for glial fibrillary acidic protein (GFAP) (Bignami and Dahl 1976; Voigt 1989).
During the first two postnatal weeks, a transition from vimentin to GFAP takes place (Schnitzer et al.
1981; Voigt 1989). Astrocytes in adult brains (of ani- mals) are usually positive for GFAP and negative for vimentin. During the transitional period, both vi- mentin and GFAP can be co-expressed.
Just before myelin formation begins, there is a massive proliferation of glial cells known as myelin- ation gliosis (Roback and Scherer 1935). Before onset of myelination gliosis, glial density of white matter is low. The processes of the radial glia, which extend from the ventricular walls to the pia mater, can be demonstrated by the 12th week of fetal life (Choi 1986); the radial glia also stain for vimentin (Pixley and de Vellis 1984). Sheath formation is associated with metabolic activation of the sheath cells.
Hippocampus. The hippocampal area is selectively vulnerable during development. Development in the CA1 subfield of the rat hippocampus after birth is accompanied by a rapid increase in the number of N-methyl-D-aspartate (NMDA) receptor sites. The number of sites is greatest during the second postna- tal week, and subsequently declines to the adult level of about 50% by the end of the third postnatal week.
These changes are attributed to a proliferation of NMDA sites, rather than to a change in ligand affin- ity (Tremblay et al. 1988). Though the significance of these changes is unclear, they must have an influ- ence on function and on the morphological sequelae of cerebral ischemia−hypoxia (Taskar 1999).
Cerebellum. The rate of cerebellar growth lags be- hind that of the cerebral hemispheres until the fifth month of gestation. Early in embryonic life, Purkinje cells form in the alar plate and migrate directly to their definitive cortical sites. The superficial granu- lar layer forms from germinal cells of the rhombic lip, which migrate during early fetal life to the cor- tical surface and continue to proliferate there long after the periventricular germinal tissue has dis- appeared (Uzman 1960). The definitive cerebellar granular layer forms from proliferating cells in the superficial granular layer; their descent is guided by the processes of glial cells (Rakic 1971).
Cervical Spine. Due to the scant musculature of the neck and throat, the cervical spinal column pos- sesses a relative biomechanical instability. This, in combination with the comparatively heavy head, makes the child liable to certain forms of injury and especially at risk when subjected to certain types of external violence (pp. 493 ff).
20.3
Autopsy Findings
Macroscopic examination of the head and brain should always be preceded by an external examina-
tion of the whole body of the fetus or baby. The fol- lowing examinations and/or measurements should be carried out (Emery 1989 − modified):
1. A radiograph of the whole body and limbs in standard position, particularly of the head.
2. Measurement of the head − its circumference and its diameters as well as the diameters of the open fontanels − to document the extent of growth or growth retardation.
3. Inspection of the posterior margin of the fora- men magnum and preservation of cerebrospinal fluid (Wigglesworth and Husemeyer 1977; Em- ery 1989; Keeling 1993a): the child is placed face down with the body mass supported on a block.
The skin at the back of neck is opened by inci- sion, at the atlanto−occipital junction. A cerebro- spinal fluid sample can be conveniently taken at this point with needle and syringe. After dural incision the cervical cord and foramen magnum are exposed. Observation of the cerebellar ton- sils can provide information on their downward displacement (herniation syndrome) and/or the presence of Arnold−Chiari malformation, which usually accompanies meningomyelocele.
4. Extraction of vitreous fluid from the eye.
20.3.1
Head and Cranial Contents
In infants up to about 3 months of age the “flower”
method of dissection of the head is preferred; in old- er children the usual method is the same as that for removing the adult brain.
Flower Method. After external inspection of the scalp, face, and neck as well as photographic docu- mentation of the pathology, a coronal incision is made in the scalp starting behind one ear, cutting posterior to the vertex toward the other ear. The inci- sion permits satisfactory reconstruction of the head should further viewing of the body be required; it also imparts a degree of stability should skull bones be retained for examination. The size of the anterior fontanel and width of suture lines are noted. Where there is increased intracranial pressure, particularly of recent origin, the fontanel is tense and bulging and the suture lines may be wider than normal. If there has been long-standing increased intracranial pres- sure, the anterior fontanel often extends forwards, widely separating the frontal bones along their en- tire length.
The anterior fontanel is incised parasagittally with a scalpel, taking care not to damage the sagittal si- nus. Incisions are extended forward and backward on each side in turn. On each side, the frontopari- etal and parieto-occipital suture lines are incised.
The frontal and parietal bone flaps can be deflected
laterally (like the opening of flowers, see Fig. 25.5) and the surface of the brain inspected on each side in turn (Prahlow et al. 1998). Observe the cerebral gyral pattern: the normal gyral pattern appears uni- form. Its increasing complexity with fetal maturity has been well documented by Dorovini-Zis and Dol- man (1977).
Next, the head is tipped forwards and laterally and the occipital pole gently lifted with a finger or scalpel handle to inspect the falx and tentorium for hemorrhage and tears. Congestion and focal hemor- rhage within the dural folds are common and usually insignificant. The whole of the falx and tentorium can be examined in this way.
The removal of the brain will usually follow tech- niques used in adults. Under special circumstances as well as for special documentation, removal under water or separate removal of each of the hemispheres may be recommended. Moreover, special attention is paid to the subdural space. In the presence of sub- dural hematoma (SDH), the disrupted bridging vein must be located − if possible. The bridging veins are attached to the sagittal sinus. Acceleration of the head may lead to stress on these veins which can dis- rupt and bleed into the subdural space.
After removal, the brain is placed in fixative. Af- ter about 14 days, the brain should be examined in detail and described meticulously after external in- spection. The mass (and volume) is to be measured, then − depending on the context − the brain is cut in the frontal, transverse or sagittal plane and the find- ings recorded photographically and by full descrip- tion. Due to the high water content of the fetal, new- born, and infant brain, the subsequent dehydration process of tissue blocks before routine embedding in paraffin should proceed very slowly, allowing about twice as much time as the dehydration of histological blocks of adult brain tissue.
20.3.2 Cervical Spine
In nearly all cases of MBI in infants and children as well as in cases of suspected physical abuse and − es- pecially − in cases of shaken baby syndrome the re- moval and examination of the cervical spine includ- ing the occipito−cervical junction will be obligatory or at the very least recommended. The removal tech- nique is described elsewhere (p. 89). The demonstra- tion of spinal dural hemorrhages as well as of axonal injury of the spinal cord is of significant importance in providing additional evidence of a traumatic event which may be the cause of death, though there may be no other macroscopic indications.
20.3.3
Ears and Mastoids
The middle ears and mastoids should be inspected macroscopically and microscopically at all necrop- sies, as quite surprising results are frequently found.
The middle ears and mastoid cavities in the baby can easily be removed using a pair of bone forceps to make the incisions. It is helpful to stabilize the poste- rior tip of the bone forceps in one of the cranial nerve apertures when making these cuts.
20.3.4 Eyes
It is important to examine the eyes both macroscopi- cally and microscopically as intra-ocular damage consisting of vitreous and retinal hemorrhage, lens opacity, optic nerve damage, retinal detachment, and displaced lens is known to be very common in non-fatal (Friendly 1971; Tomasi and Rosman 1975) and fatal child abuse. Up to 70% of children with subdural hemorrhage also have retinal hemorrhage (Tomasi and Rosman 1975 − see pp. 497 ff). To re- move the eyes, the frontal base of the skull should
be opened and the eyeballs, or in most cases only the posterior half of the eyeballs, are extracted from the interior of the skull.
20.4
Microscopic Examination:
Cell Reaction
The classification and assessment of cellular appear- ance and cell reactivity depend on knowledge of the normal, i.e., age-dependent, phase of cellular devel- opment (prenatal development of cellular reagibility
− see p. 408). We have to record the stage-like den- sity of cortical neurons and astrocytes (Fig. 20.3) in the white matter and of neurons in the gray matter.
Myelination occurs during the first 2−10 years (see above), etc.
Early fetal anoxic/ischemic brain injury may mimic malformation, e.g., polymicrogyria. Peri- or postnatal hypoxia/ischemia injury results in typical morphological changes also found in adults known as hypoxic/ischemic neuronal cell changes and scar- ring processes. The various types of cell reaction during development of the infant brain are discussed briefly in the following (cf. Friede 1989).
The manifestations of ischemic neuronal necrosis during early infancy differ in terms of cell changes and in regional distribution. The neuronal changes include cytoplasmic swelling, chromatolysis, nuclear pyknosis, and occasional karyorrhexis. Pontosubic- ular neuronal necrosis in particular is characterized by karyorrhexis.
Moreover, immunohistochemical staining for β-amyloid precursor protein (β-APP) is a well es- tablished marker for mechanically induced axonal injury in adults (pp. 205 ff). A recent investigation (Reichard et al. 2003) found β-APP-reactive axons in 27 of 28 pediatric autopsies (infants and young chil- dren − up to 7 years), which were mainly caused by brain swelling and secondary vascular compromise but also by mechanically induced injury in 19 out of 28 cases.
During the first half of gestation almost no re- sidual gliosis is seen, even with massive tissue de- struction. Astrocytes develop the capacity to react with proliferation and hypertrophy during the last trimester of gestation, as is evident in the mature newborn‘s response to asphyxia, for example, in the manner of ulegyria or periventricular infarcts. As- trocytic hypertrophy is often less pronounced when compared to the adult brain. Reactive astrocytes have a moderate density of nuclear chromatin and less cytoplasmic hypertrophy, sometimes up to twice that of the nuclear diameter. Using GFAP immuno- histochemistry, reactive astrocytosis − in contrast to non-reactive astrocytes − can first be detected at
Fig. 20.3a, b. Increased astrocytes in the white matter during the process of myelination (a H&E, b GFAP reactivity; magnifica- tion a, b ×300)
20 weeks of gestation; plump gemistocytic astrocytes are first seen at 23 weeks of gestation (Roessmann and Gambetti 1986a, b). Metabolic astrocytosis as a consequence of metabolic diseases is readily detected in infants older than 1 or 2 years (Friede 1989).
Removal of necrotic tissue by macrophages oc- curs in the fetal brain at a time when the astrocytic response is still minimal. The rate of removal ap- pears to be even greater than in the adult. Monocytes found in the circulating fetal blood as early as the fourth week of gestation may emigrate and become extravasated macrophages (or activated microglia).
The scavenger function of brain marcophages after hemorrhages are described on p. 429.
The early experimental studies of Spatz (1920) give evidence of the cell reaction pattern during the developmental stages and are summarized as fol- lows:
▬ Liquefaction and dissolution of necrotic tissue is exceptionally rapid in newborns. Organization may be essentially complete after 8 days and the last phagocytes disappear by the 12th day, with a certain dependency on the extent of necrosis.
▬ Little or no proliferation of „fixed“ glial elements occurs during the early fetal stage. No gliomeso- dermal scars form, organization being carried out mainly by macrophages which disappear rapidly from lesions. The residual cavity forms a smooth-walled porus. The walls of the porus are formed by a thin layer of glial tissue deficient of neurons, but without glial scarring. Glial tissue may persist subpially, forming a thin gliomeso- dermal membrane.
Moreover, recent data have suggested that recovery from injury in the preterm brain may involve the reactivation of radial glia in the germinal layers (Ganat et al. 2002). In the days after acute or chronic hypoxic/ischemic insult, there is increased cell proliferation in both the subventricular zone and the dentate gyrus, and the “reactive” cells that divide after perinatal hypoxia appear phenotypically to be a type of radial glia (see Vaccarino and Ment 2004).
20.5
Postmortem Biochemistry
Chemical investigations can help establish the cause of death (hypoglycemia, dehydration); they can aid in assessment of the physiological effects underlying anatomic findings at autopsy, and may help to estab- lish the time of death.
It is not the task of forensic neuropathology to delve deeper into the significance of those investi- gations. The reader is referred to the review of Coe (1989), which among other things provides the range
of values for sodium and chloride in vitreous humor for diagnosis of dehydration in newborns, infants, and children.
20.6
Diffuse Cerebral Swelling
The clinical features of elevated intracranial pressure in infants are seizures, split sutures, a bulging fonta- nel, a high-pitched cry, and coma. Brain mass and size are of little use in neuropathological evaluation of cerebral swelling due to their wide variability in children (Emery 1989). It is the volume of the brain within its own cavity that matters and the pouting of the brain tissue through the cervical incision is much more important than the mass of the brain.
The macroscopic manifestations of increased intra- cranial pressure are flattening of the gyri, narrowing of the ventricular systems and − rarely − herniation of cerebellar tonsils.
Pathophysiology. The immature brain is thought to respond to severe mechanical load, infection or in- toxication differently than the adult brain. Because the cranial vault of the infant is more pliable and elastic, the manifestation of increased intracranial pressure in the newborn differs from that in adults.
In infants, the fontanels and the open sutures permit distension of the cranium, thus weakening the force of caudal pressure; secondary midbrain hemorrhag- es are therefore unknown in the newborn. Moreover, cerebellar herniation and acute tonsillar necrosis are hardly ever seen during the first year of life.
Children appear to be more likely than adults to develop diffuse cerebral swelling. A number of studies have reported its incidence to be two to five times higher in children than in adults (Aldrich et al. 1992; Lang et al. 1994); for example, up to 44%
of children exhibit diffuse cerebral swelling after the incidence of severe MBI (Berger et al. 1985). Clinical studies have reported a 50% mortality rate in chil- dren with diffuse cerebral swelling (Aldrich et al.
1992); the mortality is even higher in younger chil- dren (<4 years), who more frequently develop dif- fuse swelling (Luerssen et al. 1988). These findings contrast with observations made in animal experi- ments on cats on early postnatal development show- ing that the immature brain is less prone to develop edema (Go et al. 1973), which appears to occur inde- pendently of a breakdown of the blood−brain barrier (Okuma and Yamada 1978).
Pathology. The morphological features are sum- marized by Kirkham (2001), and are characteristic of the presence of intracranial pressure (see also Chap. 4, pp. 42 ff):
1. Intracranial hypertension induces a decline in cerebral perfusion pressure, since the latter is the difference between the mean blood pressure and the intracranial pressure. This causes cerebral ischemia, particularly in the marginal zones of the main arterial territories.
2. If supratentorial hypertension is present, i.e., if there are pressure differences between the fore- brain compartment and the posterior fossa, a single (uncal herniation) or both temporal lobes may herniate through the tentorium (dience- phalic and midbrain/upper pontine herniation syndrome).
3. Sub- or infratentorial pressure may cause the brain to herniate upward through the tentorium of the cerebellum.
Among the possible causes of diffuse brain swelling are hyperemia and edema of the brain.
20.6.1 Hyperemia
Hyperemia (vascular enlargement, congestion) is thought to be a major cause of diffuse cerebral swell- ing (p. 42) especially in infants and children (Bruce et al. 1979, 1981; Obrist et al. 1979). It is thought that changes in cerebral metabolism can induce impair- ment of the autoregulatory mechanisms of the cere- bral vasculature. Recent findings from experimental studies support the role of hyperemia following the incidence of severe head injury in children: Biagas et al. (1996) were able to demonstrate a delayed in- crease in cerebral blood flow (CBF) in immature and young rats, but not in adult rats.
Suzuki (1990) studied CBF in 80 normal unanes- thetized children. It was shown that CBF in normal children may range from 40 ml/100 g per minute dur- ing the first 6 months of life to a peak of 108 ml/100 g per minute at 3−4 years of age, and down to 71 ml/
100 g per minute in children aged 9 years. Consid- ering this large range, comparisons of CBF data in children are valid only when small, well-defined age ranges are selected. As Zwienenberg and Muizelaar (1999) could demonstrate, a substantial increase of CBF did not seem to exist. Therefore, hyperemia may not be as common in severe pediatric MBI as previ- ously thought (see also Sharples et al. 1995; Adelson et al. 1997).
20.6.2 Edema
The available recent data do not allow the inference that diffuse cerebral swelling is due in large part to hyperemia. In addition to the aforementioned vas-
cular reactivity and impairment of autoregulatory mechanisms, disruption of the blood−brain barrier seems to be the principle mechanism underlying the increased intracerebral volume, i.e., the develop- ment of vasogenic edema (see Chap. 4, pp. 44 ff). The blood−brain barrier function is not present at birth but only develops as the child grows. Hyperbilirubi- nemia at birth is known to cause acute bilirubin en- cephalopathy (kernicterus), a phenomenon not seen in adults (pp. 452 f, 611). Damage to the blood−brain barrier in conjunction with hyperemia can lead to vasogenic edema, increased osmotic and oncotic gradients contributing to the fluid flux into the ex- tracellular space. The blood−brain barrier can re- constitute within 24 h, although a secondary episode of increased permeability is possible. The edema generally peaks within 24−72 h after the traumatic event.
As already mentioned elsewhere (Chap. 4, pp. 42 ff), especially ischemia and various types of intoxication result in a cytotoxic/cellular edema in the adult and child brain. The injury-induced break- down of the normal metabolic processes of cells and the inability to correct imbalances in the ionic spe- cies (Na+, K+, Ca2+) initiate further cellular damage and fluid influxes. Ischemia contributes to energy failure leading to depolarization, spreading depres- sion, calcium accumulation, lactate accumulation, and acidosis (Stein and Vannucci 1988). This can lead to further cellular breakdown and damage.
Moreover, inflammation, free radicals, excitotoxic- ity, and calcium influx contribute to the cytotoxic edema (Adelson and Kochanek 1998).
20.6.3
Hydrocephalus
As summarized on pp. 54 ff (see also pp. 482 f) hy- drocephalus will be a specific type of reaction in in- fants and children caused by malformation, inflam- mation, tumors or MBI. Hydrocephalus will be asso- ciated with a growing head circumference in infancy
Table 20.4. Syndromes of fatal child abuse. Source: Pearn 1989
Neonaticide Infanticide Euthanasia
Syndrome of repetitive physical child abuse Child neglect
Murder – homicide
and early childhood because of the intraventricular increase of fluid pressure.
20.7
Forensic Aspects (Expert Witness)
In cases of birth-related lethal or non-lethal cerebral injury, obstetricians are being increasingly subjected to medical malpractice lawsuits (Oehmichen 2000a;
Shevell 2001). Public awareness of the phenomenon of physical abuse resulting in injury or death of the child is also growing. In both instances the pediatric neurologist and/or forensic neuropathologist may be called to serve as an expert witness. In cases of acute, unexpected, non-accidental death of a child the fo- rensic neuropathologist is also asked to confirm or establish the cause of death by forensic autopsy and additional investigations (cf. Table 20.4).
20.7.1
Medical Malpractice
Medical malpractice is not rare during the perinatal period. A survey of published selected cases in Ger- many is given in Table 20.5. Because the placental barrier between mother and fetus is permeable to many types of substances, medications taken by the mother during pregnancy can injure especially the brain of the unborn child. It follows that pregnant women should restrict their ingestion of medications to a necessary minimum and be discouraged from self-medication (for review see Ashton 1981; Simar 1999). Some other types of medical intervention dur- ing pregnancy, such as amniocentesis, entail a risk of brain injury as well as death to the fetus (Keeling 1993b).
Intrapartum monitoring may be accompanied by complications, i.e., injury of the brain (Ashkenazi et al. 1985). The complications arising from breech delivery have long been associated with increased mortality and morbidity among babies delivered vaginally. The consequences of breech delivery in-
Table 20.5. Examples of published cases of medical malpractice. Source: Oehmichen and Schmidt 1995
Author Age Disease Consequential
damages
Medical malpractice
Accused physician
a Newborn Scratch infected by staphylococci
Sepis, bilirubin encephalopathy
Fault of organization Obstetrician
a Newborn M. haemolyt.
neonat.
Bilirubin encephalopathy
Diagnostic mismanagement
Pediatrician
d Newborn M. haemolyt.
neonat.
Bilirubin encephalopathy
Diagnostic mismanagement
Pediatrician
a Newborn Lues connata Injection induced
necrosis: amputation of the leg
Therapeutic mismanagement
Pediatrician
a Baby Enteritis Mechanical brain
injury
Fault of organization Pediatrician
b Baby Congenital hip
dislocation
Motor disturbances Diagnostic mismanagement
Pediatrician
c 3.5 weeks Pyloric stenosis, electrolyte dissociation
Mechanical brain injury
Therapeutic mismanagement (10% NaCl-solution)
Nurse
b 4 weeks Enteritis Intracerebral
hemorrhage
Diagnostic misman- agement
General practitioner b 5 months Angina tonsillaris,
purulent meningitis
Mechanical brain injury
Therapeutic mismanagement
General practitioner
a Bappert (1980); b Cyran (1992); c Mallach et al (1993); d BGH, Urt v 14.07.1992
clude ischemic encephalopathy, osteodiastasis, dis- placement tears underlying venous sinuses, and cat- astrophic hemorrhage. Injury of the craniocervical junction and of the cervical region of the spinal cord may also occur if the neck is hyperextended dur- ing delivery. Extracranial lesions of the scalp of soft tissue of the face as well as skull fractures and pa- ralysis of motor and/or sensory facial nerves may be the consequence of forceps delivery or − partly − of vacuum extraction. If a child is delivered by cesarean section and suffers ischemic brain injury, the ques- tion arises as to whether the injury could have been avoided if the procedure had been performed sooner or more rapidly.
The forensic expert must distinguish between death of a child that occurs before delivery (fetal death) and death occurring during or shortly after delivery (infant’s death). Such a distinction usu- ally cannot be based on neuropathological findings alone, but requires various types of information, in- cluding the course of labor and delivery, the external aspect of the newborn corpse, especially the degree of antolysis and/or maceration, and the stage of fetal development et cet. (Wecht and Larkin 1989). Mi- croscopy can sometimes help to establish vitality it- self and provides further evidence in determination of the cause of death. As an expert witness, the fo- rensic neuropathologist may be asked to determine whether the death was “avoidable,” a question some- times impossible to answer with certainty.
Laws exist to protect the newborn and/or unborn child in virtually every country. They protect the child in a different manner at the different stages before, during, and after birth. Laws also regulate the use of fertility techniques, which can give rise to hitherto unknown problems and are the subject of ongoing debate (Wertz 1995). However, it is not pos- sible to collate the different laws and legal decisions of all the countries. Therefore, this paragraph may refer to the local as well as national laws.
Legal questions often arise in regard to perinatal brain injury/asphyxia and/or cerebral disability of unknown origin. Both the USA and Germany have seen an increase in the number of civil and criminal proceedings against physicians and nursing person- nel involving claims of medical malpractice. Parents who desire a child want only a healthy child. If the child is born with a mental or physical (somatic, mo- tor) disability, the physician is often held responsi- ble. There is an increasing tendency to employ expert witnesses. This applies equally whether the child is injured and survives or dies during or after birth.
The most common clinical situation about which ex- pert witnesses are called upon to testify concerns the sequelae of perinatal asphyxia secondary to obstet- rical malpractice (Nelson 1999). Here the pediatric neurologist/forensic neuropathologist must answer four central questions (Shevell 2001):
1. What are the child‘s/plaintiff‘s disabilities and handicaps?
2. What is the etiology of the disabilities? − Was as- phyxia or a mechanical injury the root cause of the observed disabilities?
3. When did the asphyxia or mechanical injury oc- cur? − Was it antenatal, perinatal (i.e., intrapar- tum) or postnatal?
4. What is the estimated life expectancy of the child/
plaintiff?
No single definitive biomarker or gold standard has yet been agreed upon for the diagnosis of perinatal asphyxia (Nelson and Emery 1993). If the child has died, the expert witness must − additionally − estab- lish the following (Golding 1993, modified):
5.1 Was the antepartum brain normally formed?
or
5.2 Was there any congenital malformation?
6. Were there any conditions associated with imma- turity?
7. Did an asphyxial situation or traumatic event de- velop during labor (cf. also point 3)?
8. What was the extent/severity and nature of the iatrogenic injury?
8.1 Was the injury foreseeable?
or
8.2 Could it have been avoided, possibly by cesarean section?
In 1998 the Ethics and Practice Committee of the Child Neurology Society in the USA published a sur- vey of the Society‘s membership. The survey featured a 25% response rate and documented that 42% of the responding members had been the subject of a medi- cal liability lawsuit. Ninety percent had reviewed cases for legal counsel as the expert witness, with 13% reviewing more than 10 cases annually. Seventy percent of those surveyed felt the system was unfair and felt there was a need for peer review of expert witness conduct.
Postnatal MBI can also be caused by a mistaken diagnosis or failure to act, sometimes with fatal con- sequences. Here are a few examples:
1. When should roentgenography or computer to- mography (CT) be performed in blunt head im- pact (Leonidas et al. 1982; Frush et al. 1998)?
2. Should CT be routine for all closed head injuries (Stein et al. 1991)?
3. Should CT be carried out to prevent the fatal clin- ical consequences of an epidural hematoma that can be averted by early diagnosis and neurosur- gery (Paterniti et al. 1994)?
4. Is hospitalization required for minimal impact to the head (Roddy et al. 1998)?
5. Does an isolated head injury warrant cervical spine evaluation (Laham et al. 1994)?
Perinatal exposure to CNS-active medications and errors in dosage or type of medication are especially problematic in pediatric therapy (Folli et al. 1987; Si- mar 1999; Kaushal et al. 2001; Committee on Drugs and Committee on Hospital Care 2003). Kaushal et al. (2001) detected 616 medication errors among 10,778 prescriptions by physicians (=5.7%), 26 re- sulting in adverse drug reactions. Because the dosing of most drugs is solely based on body mass, there is the potential for a 300-fold dosing error in children as calculated by Poole and Benitz (2001). In adults a twofold dosing error is usually the maximum en- countered (for review, see Committee on Drugs and Committee on Hospital Care 2003).
20.7.2
Physical Abuse
The expert witness may also be asked to give an opin- ion on whether a child is the victim of physical abuse, especially if the abuse is thought to have resulted in the death of the child. Here the forensic pathologist is responsible for determination of the following:
1. The cause of death (Accident? Disease? Abuse?
Homicide?)
2. The manner of external violence (Iatrogenic? Ac- cidental? Non-accidental? Intentional?)
3. What were the circumstances and/or surround- ings (the scene) of the death?
The forensic pathologist‘s findings can have serious consequences at legal, ethical, and economic levels for both the child and its carers (further information see Chap. 25 − pp. 489 ff).
20.7.3
Ethical Aspects
Pregnancy and childbirth are bound up with nu- merous ethical problems that may be only peripher- ally connected with neuropathological findings (cf.
Wertz 1995). In addition to the question of whether an artificial abortion can be justified for social rea- sons (see Marshall 2000), questions arise regarding preimplantation diagnosis to avoid the birth of a genetically defective child (molecular genetic di- agnosis of Huntington’s chorea, for example). One question discussed relates to the principle authority to allow such diagnostic intervention (Oehmichen 2000b; Grote and Schwinger 2003) while the other question regards the risk (and frequency) of neuro- logic defects in cases of in vitro fertilization (IVF), which was recently calculated (European Journal of Pediatrics 2003, 162:64) to be1.7 (SD: 1.3−2.2) for all IVF children and 1.4 (SD: 1.0−2.1) for singletons.
A topic of perennial debate is research employing embryonic stem cells or fetal tissue that is pluripotent and which may be of use for example in the treat- ment of organ failure. Here the differences in bio- ethical principles and legal status differ from coun- try to country and are still subject to change in light of ongoing medical advances and changing social and political climates (Franz and David 2003; Maio 2003). In the USA, the use of fetal tissue is still al- lowed under special conditions.
A series of medical, legal, and ethical questions are bound up with the topic of euthanasia and end- of-life decisions regarding the most severe malfor- mations (Chiswick 2001; McHaffie et al. 2001a, b;
Oehmichen and Meissner 2003). The obstetrician or pediatrician is required to make decisions regarding
„passive“ killing, non-performance of resuscitation, or termination of artificial respiration, especially if a baby has obviously entered the process of dying (Chiswick 1990). In the past, physicians in USA and Germany could allow some newborns with little or no chance of normal life to die after discussion of the infant‘s prospects with the parents. In a public dis- cussion in the USA, many people agreed that in some cases it was right:
1. Not to resuscitate infants at birth
2. To withdraw life support for infants with poor prognosis
3. To shift resources from care for an infant with a poor prognosis to an infant with a better progno- sis
4. To intervene directly to kill a dying infant in order to prevent further suffering (Jonsen et al.
1975)
Since that time, Baby Doe laws have established that handicap alone is not a sufficient reason for refusing treatment, just as a hospital may not refuse to treat a burns patient simply because the patient is deaf.
Today, overtreatment rather than undertreatment is usually the villain. Pragmatic strategies are the subject of ongoing discussion and recommendations have been published for helping parents (and staff) with end-of-life decisions (Chiswick 2000, 2001;
McHaffie et al. 2001a, b). The laws of most countries concur that artificial respiration should be stopped in the case of brain death. Active euthanasia, by con- trast, is banned in most countries (exception: the Netherlands). In April of 2002, the European Court of Human Rights ruled against the right to assisted suicide in the case of a terminally ill English woman whose disease was “so advanced that she cannot kill herself without assistance” (Times Online, April 30, 2002, “Diane Pretty loses battle for right to assisted suicide” Frances Gibb).
Wertz (1995) mentions anencephaly as a special case. Although born with only a brain stem, anen- cephalics do not fit current US and German legal
