Permanent Global Ischemia

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Permanent Global Ischemia 15

15.1 Classification 319 15.2 Pathophysiology 319 15.3 Clinical Features 321 15.4 Neuropathology 321 15.4.1 Gross Examination 321 15.4.2 Microscopic Examination 322 15.5 Forensic Implications 323 15.5.1 Respirator Brain

and/or Postmortem Autolysis 323 15.5.2 Declaration of Death 325 15.5.3 Time of Brain Death 326

15.5.4 Time of Causal Event Leading to Brain Death 327 15.5.5 Morphological Statement

of Intracranial Circulatory Arrest 328

Bibliography 328

References 328

15.1

Classification

In 1968, an Ad Hoc Committee at the Harvard Medi- cal School, Boston, Mass. proposed “a new criterion for death”: total and irreversible loss of functioning of the whole brain. The motivation was clearly stated as follows: (1) to relieve the “burden” imposed by severely brain-damaged patients; and (2) to quell the

“controversy in obtaining organs for transplantation” (see Youngner 1992).

It was not until 13 years had passed (1981) that James Bernat and his colleagues offered the first comprehensive effort to provide a conceptual frame- work for the ad hoc committee‘s criterion (Bernat et al. 1981). “We define death,” they wrote, “as the permanent cessation of functioning of the organism as a whole,” which they further explained as “the spon- taneous and innate activities carried out by the inte- gration of all or most subsystems.”

As each individual human brain constitutes a human individual, a patient without a vital brain must be considered a “non-individual,” i.e., a dead person, irrespective of the condition of the rest of the body including organs other than the brain. This classification caused in different countries long and heated debates (Backlund 1999) but is still accepted by the Western community (Capron 2001) though single problems remain unresolved (Swash and Beresford 2002). The currently accepted standards in clinical criteria and confirmatory tests for diagnosing death with the use of brain-based criteria were recently summarized by Wijdicks (2001). The determination of brain death requires documentation of unrespon- sive coma, absence of brain stem reflexes, and apnea.

Though the process of organ transplantation is now accepted worldwide along with the classification of brain death, there is no global consensus in diagnostic criteria. Wijdicks (2002) pointed to differences in accepting the apnea test and could describe other major differences in the procedure of diagnosing brain death in adults.

15.2

Pathophysiology

The sequelae of non-perfusion of the brain as a “permanent global ischemia” are dependent on the time interval of cerebral blood flow interruption. As we learned by experiments of Hossmann and Kleihues (1973; Kleihues and Hossmann 1973; Bodsch et al.

1986), under certain circumstances of experimental post-ischemia treatment, reperfusion will succeed − and recovery of neuronal function could be established − even after a period of 20−60 min of total ischemia of the brain.

However, under the common circumstances of human resuscitation, these results could not be re- produced. Reperfusion is accompanied by an initial brief period of hyperemia followed by a prolonged phase of cerebral hypoperfusion. The complex prob- lem of no-reflow may be based on vascular swelling and micro-aggregation within vessels during the period of ischemia which result in irregular patchy

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perfusion in certain circumstances (Symon 1993).

The question of vascular occlusion by physical factors such as endothelial swelling remains controver- sial, but both increased vascular smooth muscle tone as a result of vasoactive substances released during ischemia, and permeability changes resulting in pericapillary edema could produce the increased cerebrovascular resistance.

As mentioned in Chapter 14, the sequelae of persistent brain ischemia by suffocation or strangula- tion as well as by cardiac arrest for a time of 5−10 min will, under normothermic circumstances, finally lead to an irreversible interruption of cerebral blood flow in the cerebrum and cerebellum with the consequence of a respiratory arrest, while the circulation of the body may be stable. The same phenomenon will be observed as a result of an increase of intracranial pressure, especially that caused by extreme edema, hemorrhages, inflammation or tumors. Un- der conditions of artificial respiration, general circulatory and cardiac function will still persist with the exception of the brain circulation, i.e., non-perfused brain or respirator brain or brain death. On the other hand, accidental hypothermia may allow successful resuscitation within a period of nearly 4 h of cardiac arrest (Walpoth 2004). Depending on the time between interrupted cerebral blood flow and the final cardiac arrest the morphology of the brain will vary.

Permanent global ischemia constitutes brain death, and is a direct result of a decrease in the cerebral perfusion pressure (CPP=MABP−ICP, where MABP is mean arterial blood pressure and ICP is intracranial pressure). This, in turn, usually arises from either an increase in ICP or a decrease in MABP to bring CPP (the difference between the two) to less than 6 kPa (45 mmHg) for a protracted period. After some time has elapsed, the brain can never be reper- fused due to capillary closure, and “brain death” en-

sues (Fischer 1973). The term “brain death” is used (Black 1978; Korein 1978) as well as respirator brain (Towbin 1973) or dissociated (brain) death (Kramer 1966). Non-perfused brain is the extreme, irreversible form of permanent global ischemia, in which blood flow to the intracranial contents is never re- stored. The primary causes of non-perfused brain are summed up by Walker (1985; Table 15.1).

Complete interruption of the cerebral circulation for a period of 5 min irreparably damages the brain.

A fall in cerebral blood flow of even 50% depletes the store of high-energy phosphates, and the brain begins to cannibalize itself (Walker 1985).

Various attempts have been made to extend the reversible period of normothermic cardiac arrest beyond the 5-min limit (Hirsch and Müller 1962;

Hirsch 1982; Safar et al. 1987). Ames and Nesbett (1983) reported that retinal neurons can tolerate up to 20 min of anoxia. Hossmann and Kleihues (1973) and Hossmann (1988) showed that most cerebral neurons can recover electrical and chemical activity after up to 60 min of normothermic complete global ischemia (see Bodsch et al. 1986). Studies by Siesjö (1981, 1988) indicated that treatable pathogenic factors are involved.

The secondary derangements associated with normothermic cardiac arrest have at least four interacting components (Safar et al. 1982; Safar 1986) (compare with Table 15.2). Safar et al. (1993) have ad- ditionally shown that the outcome is determined by the duration of the no-flow insult and the temperature. However, flow arrest caused by asphyxiation is more injurious (Vaagenes et al. 1984) to the brain than the same period of normovolemic ventricular fibrillation arrest, while that caused by isolated ex- sanguination (Negovsky et al. 1983) may be less injurious (Safar 1988).

In addition to the 5-min limit, a relationship exists between the duration of cerebral anoxia and disturbances of brain function. On the biochemical and cellular level, changes resulting from systemic or local anoxia proceed in the following sequence:

intra- and extracellular acidosis develops increas- ingly (Lindenberg 1972; Jabre et al. 2000), leading to activation of hydrolytic enzymes with swelling of lysosomes, especially in astrocytes (Plesnila et al. 1999: cytotoxic brain edema – see p. 47), whose breakdown causes a disturbance in the osmotic bal- ance. The consequently marked uptake of water pro- duces a brain edema. The endothelial cells swell, re- ducing the lumen of vessels, which become plugged with deformed erythrocytes. The permanent arrest of cerebral circulation begins. Once ischemic total cerebral ischemia occurs, the autolytic process begins; since the relatively high temperature of 37°C is maintained, autolysis proceeds faster than under postmortem conditions.

Table 15.1. The primary causes of a non-perfused brain (N=503) Source: Walker 1985, modified

Cause n %

Cardiac disorders 105 20.9

Cerebral trauma 94 18.7

Cerebral hemorrhage 74 14.7

Exogenous intoxication 36 7.2

Metabolic disorders 36 7.2

Subarachnoid hemorrhage 34 6.8

Other 124 24.6

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15.3

Clinical Features

The Uniform Determination of Death Act has classi- fied brain death according to the following criteria (cf. Ad Hoc Committee in Brain Death 1987):

Brain death has occurred when cerebral and brain stem functions are irreversibly absent.

Absent cerebral function is recognized clini- cally as the lack of receptivity and responsiv- ity, that is, no autonomic or somatic response to any sort of external stimulation, mediated through the brain stem. Absent brain stem function is recognized clinically when pupil- lary light, corneal, oculocephalic, oculovestibular, oropharyngeal, and respiratory reflexes are irreversibly absent.

Thus, apnea (tested for longer than 7 min), dilated pupils, cerebral unresponsivity, absence of brain stem reflexes including the oculovestibular (doll‘s eyes) reflexes, and the vestibulo-caloric reflex are indicative for brain death. An isoelectric (flat) elec- troencephalogram (EEG) for 30 min, at least 6 h after ictus, is needed for final diagnosis (Guidelines for the Determination of Death 1981; Hamburger 1988). There is cessation of blood flow through the carotid arteries at the foramen lacerum. Angiogra- phy and strict electroencephalographic criteria are rarely applied to diagnose this condition any longer;

rather clinical criteria are relied upon. This under- scores once again the importance (see above) of dis- tinguishing brain death or even neocortical death from the various types of hypoxic damage outlined above.

Irreversibility is recognized when the cause of coma is established and is sufficient to ac- count for the loss of brain function, and when

the possibility of recovery is excluded by observation for an appropriate period of time.

The period of observation will vary, depending on the circumstances and possible causes. In most cases in which the cause is established and seems appropriate, such as in severe inoperable head trauma, a period of 6 h seems reasonable and is commonly recommended, whereas with hypoxic−ischemic en- cephalopathy, observation for 24 h may be more appropriate. These short time intervals commonly used nowadays render the development of the neuropatho- logic changes of brain death less well developed and observable than when longer intervals of brain death precede autopsy. Confirmatory laboratory findings may be appropriate in determining primarily the irreversibility of brain death, and possibly acceler- ating the determination of irreversibility. However, if cause and irreversibility are established and the clinical examination yields unequivocal findings, confirmatory tests are unnecessary. When they are appropriate, confirmatory laboratory examinations that may prove helpful include electroencephalogra- phy, radionuclide brain scan, and brain-stem-evoked potentials.

15.4

Neuropathology

The exact morphological sequelae depend in part on the age of the patient, time on the respirator, and the cause of the non-perfusion. The pathological changes of the non-perfused brain take about 12 h to develop (Black 1978), although they become more obvious in 24 h (Walker 1985), an important interval if the neuropathologist is called upon to confirm brain death. As a rule, the typical changes are observed in cases of clinically diagnosed non- perfused brain (Table 15.3, − p. 327). The following parameters merit particular mention (Walker 1985;

Oehmichen 1994).

15.4.1

Gross Examination

The brain mass commonly is increased (1.6−1.8 kg), but the increase is definitely a function of time on the respirator (Schneider 1970; Walker 1985).

Depending on the primary cause of ischemia and time on the respirator, the following macroscopic changes are observed: a distinct swelling of the total brain (Fig. 15.1a); the cerebrum may be well- preserved and gray-colored (Fig. 15.1b) or a nonde- script friable or mushy mass; the swollen and congested cerebral hemispheres have a dusky hue; the

Table 15.2. Interacting secondary derangements as- sociated with normothermic cardiac arrest that have at least four interacting components Source: Safar 1986

Perfusion failure Reoxygenation injury

Self intoxication from post-anoxic viscera Blood dyscrasias after stasis

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leptomeninges often show a quantitatively different extent of congestion and fibrin precipitation as an indication of different regional no-reflow phenomena (Fig. 15.1b); transtentorial herniations are com-

mon (Fig. 15.1c). Gross sections of the brain show a lead-colored, grayish cortex, a partly extreme compressed ventricular system, and sometime focal hemorrhages in white and/or gray matter, which is demonstrated in Fig. 15.2a, b in comparison with a normal-colored edematous brain section after formalin fixation. The brain stem is often torn and is characterized by congestion and hemorrhages; the softened herniated cerebellar tonsils are commonly necrotic (Fig. 15.3b), with necrotic tissue of tonsillar cerebellum lodged along the spinal cord any- where from the cervical segment to the cauda equi- na (Fig. 15.3c−e). This phenomenon is considered characteristic of brain death lasting more than 36 h (Schneider and Matakas 1973) and may be one neu- ropathologic-diagnostic sign of brain death (Sayer et al. 1981). In addition, hemorrhagic softening of the upper few segments of the cervical spinal cord occurs, but is often overlooked if that part of the cord is not dissected. In about 10% of cases, the cut sections appear grossly normal, but in more than half of brains the white matter is edematous and soft (Fig. 15.3f).

15.4.2

Microscopic Examination

As a general rule, ischemic neuronal alterations are only observed after reperfusion lasting at least 2 h (Pendl 1986). The brain stem is almost always changed by edema, secondary hemorrhage, infarction, necrosis, and/or neuronal loss. The mesen- cephalon is distorted by local edema or external compression by herniating tissue of the medial tem- poral structures or the anterior cerebellar lobes. The striking feature of the cerebellum is swelling and congestion; autolysis of the granule cell layer of the cerebellar cortex (Fig. 15.2c) is often observed (Oga- ta et al. 1986). The diencephalon is characterized by edema and often by patchy lytic changes in the neurons. The cortex is most frequently and severely damaged. Primary ischemic infarcts or hemorrhagic infarcts result in primary or secondary occlusion of cerebral arteries. The cortex is diffusely congested and edematous, and the cortical neurons exhibit various degrees of acute ischemic changes, characterized by dark staining nuclei and, in hematoxylin and eosin preparations, a pink-staining cytoplasm.

Neither a glial nor a hematogenous inflammatory reaction is seen.

“Brain death” or “respirator brain” is characterized by the autolysis of the brain. The diagnosis early during the period of non-perfusion may be difficult but in the late phases the diagnosis will be evident.

The brain death syndrome during the early phase will microscopically be characterized by the following two phenomena:

Fig. 15.1a−c. Gross external findings in respirator brain. a Ex- treme brain swelling (autopsy specimen); b the external surface may be well preserved, and is gray colored with indications of different regional no-reflow phenomena (formalin-fixed speci- men); c distinct indications of herniation with uncal and tonsillar necrosis are seen

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1. Border zone reactions (demarcation zone): leukocytic infiltrations accompanied by hemorrhages in the upper segments of the cervical spinal cord (Fig. 15.4), in the optic nerve (Fig. 15.5a), and in the hypophysis (Fig. 15.5b, c).

2. Reactivity and alterations of the leptomeninges of the spinal cord: very early after cessation of brain perfusion a leukocytic infiltration within the subarachnoid space of the spinal cord is seen (see Figs. 15.6b, 15.5a). Some time later, necrotic tissue components, especially cerebellar tissue, will appear within the subarachnoid space (Fig. 15.6b−d), partly mixed with leukocytes.

15.5

Forensic Implications

15.5.1

Respirator Brain and/or Postmortem Autolysis Schneider et al. (1969) maintained that most of the alterations described in respirator brain are not pa- thognomic of brain death. They suggested that only after 36 h of brain death do the more specific changes appear, namely herniation and fragmentation of necrotic cerebellar tissue into the spinal subarachnoid space, hemorrhagic softening of the upper cervical segments, and necrosis of the anterior lobe of the pituitary gland.

The question arises as to whether changes occur within the first 36 h that can be distinguished from

Fig. 15.2a−c. Gross findings on brain sections in formalin-fixed respirator brain. Demonstration of a brain section in respirator brain (a) in comparison with an edematous, but non-respirator

brain (b); c hemorrhagic necrosis and color alterations in brain stem, pons, and cerebellum

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Fig. 15.3a−f. Cerebellar tonsillar herniation and hemorrhagic tonsillar necrosis. The necrotic tonsillar tissue (a, b, arrowheads) is lodged along the subarachnoid and subdural space (c arrow- heads) along the surface of the spinal cord (c, d, e). Hemorrhagic

necrosis of the upper segments of the cervical spinal cord (c, circle, e, f) as an indication of a demarcation zone: necrotic brain tissue versus well preserved spinal cord which is supplied by a brain-independent vasculature

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postmortem changes in the sense of a delayed fixation. The following features are indicative of respirator brain: extreme swelling, and dislocation of the brain. In most cases, however, the neuropathologist will have difficulties in differentiating between brain death and postmortem alterations, if both anoxic and autolytic factors are operating to varying degrees in different regions of the brain.

15.5.2

Declaration of Death

Artificial respiration enables the physician to dis- continue respiration at any time or to continue it ad infinitum. Termination of support, however, can be regarded as unlawful killing (Gerber 1984) or eutha- nasia (Oehmichen 1996), an issue that was exhaus- tively discussed, for example, also in the controversy

Fig. 15.4a−c. Microscopy of the demarcation zone in the cervi- cal spinal cord. As macroscopically demonstrated (Fig. 15.3c) an intraspinal bleeding occurs (a) which is accompanied by a leuko- cytic infiltration of the leptomeninges of the spinal cord (b) and − during the last stage of demarcation − by a leukocytic wall within the neuropil of the spinal cord (c) (a H&E, b, c N-AS-DClAE; mag- nification a ×100; b ×200; c ×300)

Fig. 15.5a−c. Demarcation zones in: a the optic nerve and b, c the hypophysis, with a disseminated leukocytes (red colored);

b necrotic, non-stained hypophysial tissue (in the center) near the stained tissue and c diffuse leukocyte infiltration of parts of necrotic hypophysial tissue (a−c N-AS-DClAE; magnification a ×500; b ×200; c ×300)

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surrounding the Quinlan decision (Beresford 1977).

Prolongation of artificial respiration can conflict, on the other hand, with the individual‘s “right to die with dignity.” This in turn may be opposed by the necessity for removal of vital organs for transplantation and by the prohibitive cost of extended time on a respirator.

In cases with an unfavorable prognosis, therefore, irreversible loss of brain function is a cogent criterion on which to base declaration of death. Of fundamental importance are the clinical and tech- nical criteria on which the diagnosis is based. In Germany, the criteria for brain death are set by the Scientific Advisory Committee of the Bundesärz- tekammer, as last issued in 1998 (Deutsches Ärzteb- latt 95:B1509−B1516). Similar criteria exist in other countries (Walker 1985). These criteria resulted in a new definition of “death” that was readily accepted by physicians and judges (Grassberger 1973; Roxin 1973).

The definition of death is based on the irreversible loss of total brain functions, and − when the stipulated criteria have been met − on the termination of artificial respiration. It also enables the dis- continuation of resuscitative measures if it can be assumed that brain death has already occurred. In theory then, death can be declared after circulatory

arrest lasting for a period of at least 10 min; however, to allow a margin of safety, attempts at resuscitation are generally continued for 15−20 min.

15.5.3

Time of Brain Death

The time of death, i.e. the end of brain perfusion or the beginning of brain death, is defined as the time of the first manifestation of intracranial circulatory arrest. However, declaration of death is only made after the patient has been observed long enough to establish the irreversibility of this state. Hence, the time at which brain death begins is not known (Deutsch 1997).

Even today, retrospective estimation of the time of intracranial circulatory arrest is scarcely possible by means of macroscopic or microscopic criteria (Kramer 1973). Schröder (1983a) lists the criteria of a brain death diagnosis for estimating the time of brain death (Table 15.3) and provides evidence of the time- dependent alterations (Schröder and Richard 1980;

Schröder 1983a, b). The gray color of the brain sur- face as well as the beginning of brain softening will occur 2 days after interruption of the CBF (Schneider 1970). The myelin staining intensity is reduced after

Fig. 15.6a-d. Leptomeningeal reaction of the spinal cord. a Early leukocytic infiltration of the hemorrhagic subarachnoid space (SAS) and b−d late demonstration of hemorrhagic necrotic tissue

within the SAS commonly originating from the cerebellar tonsils.

(a, c N-AS-DClAE; b, d van Gieson stain; magnification a−c ×300)

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16−21 h. Single eosinophilic neurons are seen >48 h after cessation of intracranial blood flow in nearly all cases within the cerebral cortex and, especially, within the medulla oblongata. This late eosinophilic expression allows the supposition that the stagnant blood flow prevents the eosinophilic transformation of neurons. Inflammatory reactions within the sub- arachnoid space do not correlate with the survival time.

Reduction of Luxol fast blue stain in the optic nerve and cervical cord are still observed after 8 h of survival time. Spongious demarcation develops after 12−16 h. Demarcating hemorrhages are observed after 30 h of survival time, especially in the cervical cord, and only in one-third of cases (Schneider et al.

1969). Demarcating emigration of leukocytes is seen as early as 24 h; especially in the leptomeninges. A demarcating macrophage reaction is observed 38 h after cessation of intracranial blood flow in the spinal cord (but not in the optic nerve), while an astro- cytic reaction is absent.

A number of forensic practitioners have dealt with the forensic implications of determining the time of

brain death (Schwerd 1969; Spann 1973; Holczabek 1973) with an overview by Pendl (1986). The time of death is of particular importance in questions of civil law, such as inheritance rights, insurance law, etc.

Example 1. An example of implications in insurance law: a car leaves the highway without any explanation and hits a tree at high speed, killing the driver. The diagnosis at autopsy: myocardial infarction; while the postmortem reveals crushing of the skull and brain. The lawyer contends that myocardial infarction − also cardiac arrest − does not meet the criteria for determining death under the brain death classification, and that the death, in fact, resulted from the crushing of the brain in the accident. A claim on the accident insurance was therefore made.

Berg and Helwig (1990) have shown that the time of brain death can also have a bearing on certain as- pects of criminal law.

Example 2. A doctor refuses to come to the aid of a child severely injured in an accident, who contin- ues to exhibit gasping for breath. The question here is whether brain death had already occurred within 30 min after the accident, that is at a time when the doctor could have come to the aid of the child.

15.5.4

Time of Causal Event Leading to Brain Death If brain death occurs as a result of ischemic (→ edema) or mechanical (→ hemorrhage) violence, the time of the causal event must be determined, especially in cases involving more than one causal event.

Example. A 30-year-old man suffers occult cranio- cerebral trauma in a fight; the injury, however, does not require immediate medical treatment. Twenty- four days later the man collapses under unknown circumstances and is found unconscious. A subdural hematoma is diagnosed and drained. A secondary hemorrhage develops, leading to intracranial circulatory arrest. The question of concern for criminal law is whether death was a result of the fight or of injury sustained from the collapse. In this case, demonstration of reactive cells, i.e., of siderophages, proved that death was a result of the fight.

Particular importance attaches to the difference in the case of crimes of violence creating conditions that predispose to brain death when the significance of a further violent act, e.g., stabbing with resultant hemorrhage, has to be assessed. The simple vital reaction of bleeding does not in itself constitute proof in such a situation, unless it is possible to say with a good degree of certainty that brain death did not occur at the moment when the victim was stabbed.

It may, however, be possible to state that brain death

Table 15.3. Neuropathological findings in brain death which support the postmortem diagnosis of non-perfusion brain

Gross examination

Increased brain mass (>12%) Extensive brain swelling

Herniation (hippocampal, tonsillar) Brown discoloration

Pink centrum semiovale due to poor fixation Poorly defined demarcation of gray and white matter

Microscopic examination

Structural effacement/washed out tissue picture due to poor staining

Eosinophilia without tissue reaction Regressive neuronal changes Congestion

Borderzone alterations (hemorrhages, cell reactions)

Anterior pituitary lobe

C1/C3 cervical segments of the cord Displacement of cerebellar tissue of the subarachnoid space of the spinal column Infarction of the optic tract

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that could have been caused by violence has not yet occurred if complex vital reactions, such as inflammation of a wound, are seen (Adebahr 1986).

Adebahr (1986) discussed another point of view in forensic pathology: the diagnosis of poisoning as the cause of brain death can be checked by toxico- logical examination of brain tissue and of blood in the sinus of the dura mater, since the metabolism in the brain and sinus blood is markedly reduced while drugs and toxic substances continue to be broken down in other organs.

15.5.5

Morphological Statement of Intracranial Circulatory Arrest

Brain death is characterized by morphological changes without accompanying glial or hematogenous cell reactions, with one exception: the demarcation reaction (see above). In contrast, if reperfusion occurs, reactive cells will be present, as pointed out by Pear- son et al. (1977, 1978). Thus, the near-complete lack of reactive changes must be regarded as a definitive indicator of total intracranial circulatory arrest.

Schröder (1978, 1983a), by contrast, observed inflammatory alterations beginning in the posterior cranial fossa as a consequence of a partial recirculation 2 days after intracranial circulatory arrest.

Hemorrhagic inflammatory phenomena can even be the consequence of reperfusion due to a diminution of the high intracranial pressure, first in the posterior cranial fossa and then also in the supratentorial region. These findings were confirmed, although to a much lesser extent, by Ito and Kimura (1992).

Usually there are no difficulties in declaring morphological proof of brain death on the basis of necrosis of the whole brain. In case reactive cells appear, this should not be proof of a (at least partly) successful reperfusion. Otherwise, the reactive changes at the border zones of the optic nerve, hypophysis, and the cervical cord may provide some evidence of the survival time of the intracranial circulatory arrest.

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Intoxication IV

Chapter 16

Introductory Remarks 333 Chapter 17

Specific Types of Neurotoxins 339 Chapter 18

Alcohol, Organic Solvents, and Aerosols 371 Chapter 19

Illegal Drugs and Drug Dependence 391