Inflammatory Diseases

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Inflammatory Diseases 29

29.1 Bacterial CNS Diseases 582 29.1.1 Purulent Leptomeningitis 582 29.1.1.1 Neuropathology 584 29.1.1.2 Late Complications 585 29.1.1.3 Neonatal Meningitis 585 29.1.1.4 Meningococcal Meningitis 585 29.1.1.5 Haemophilus Influenzae Meningitis 585 29.1.1.6 Pneumococcal Meningitis 585 29.1.2 Epidural Abscess 585

29.1.3 Subdural Abscess and/or Empyema 586 29.1.4 Brain Abscess 586

29.1.5 Tuberculous Brain Infection 587 29.1.6 Septic Encephalopathy 587

29.2 Abacterial CNS Diseases 590 29.2.1 Classification 590

29.2.2 Pathogenesis 591 29.2.3 Clinical Features 591 29.2.4 Neuropathology 591

29.3 AIDS and the Nervous System 593 29.3.1 Primary HIV-Associated

Nervous System Infection 593 29.3.1.1 HIV Encephalopathy

(Subacute Dementia Encephalopathy) 593 29.3.1.2 HIV Myelopathy 593

29.3.1.3 HIV Neuropathy 594

29.3.2 Secondary HIV-Associated NS Infection 594 29.4 Transmissible Spongiform Encephalopathies 595

29.5 Non-Infectious Inflammatory Diseases 596 29.5.1 Acute Hemorrhagic Leukoencephalitis

(Hurst’s Disease) 596

29.5.2 Acute Demyelinating Disease 597 29.5.3 Chronic Demyelinating Disease:

Multiple Sclerosis 598

Bibliography 601

References 601

Because infectious diseases of the nervous system are generally accompanied by a conspicuous clinical picture, they are rarely associated with “sudden”

unexpected deaths. Isolated cases do occur, however, usually due to fulminant processes such as acute generalized bacteremia, septicemia, or viremia. Some- times, too, an infectious disease will follow a slow, latent course that eludes detection by the attending physician. Failure to make a timely diagnosis can also be due to the patient’s poor insight into the nature of their illness, poor compliance, or unwilling- ness to undergo the indicated diagnostic procedures and therapy.

The essential clinical and neuropathological findings of selected bacterial and viral diseases as well as of prionic diseases (transmissible spongiform encephalopathy) will be presented here. For more detailed information the reader is referred to the rel- evant clinical-neuropathological textbooks. More- over, our short remarks should mention the group of non-infectious inflammatory diseases, especially multiple sclerosis and allied diseases.

The CNS is normally well protected against microorganisms by structures of the surrounding covering and by the blood−brain barrier (BBB). Once these defenses are breached, however, the CNS is more vulnerable to infection than most other body organs.

Pathogenic organisms may reach the CNS via four different routes (Chason 1977):

1. The most common route of spread are the blood vessels, mainly the arteries, after the organisms have first infected the lungs or cardiac valves.

Microorganisms also invade the CNS through diploic or emissary veins in the context of a retro- grade thrombophlebitis or an embolus draining neighboring infections, or from distant structures. The paravertebral venous system is rarely implicated.

2. The brain or spinal cord or their coverings may be involved in the spread of infections from the mastoid sinuses, middle ears, paranasal sinuses, skull, and vertebrae.

3. Mechanical violence, gunshot wounds, or medi- cal procedures, including surgery and lumbar puncture, can cause microorganisms, chemical toxins, or even particulate materials to be im-

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planted directly upon the coverings or within the CNS.

4. By centripetal movement within the cellular cytoplasm and perhaps through the neurotubules, certain viruses − including rabies, herpes simplex and herpes zoster, once implanted within the axoplasm of a peripheral nerve − are able to reach the perikaryon within the spinal ganglia, spinal cord, or brain.

After the organism has invaded the CNS, an infection can spread by direct continuity or by following the usual direction of fluid flow (anterograde), ret- rograde, or in both directions within the ventricular, subarachnoid, or Virchow−Robin spaces.

The basic principles of CNS immunology are described elsewhere in this volume (p. 67). Inflamma- tion of the CNS is as difficult as that of other organ systems (Bauer et al. 2001). T-lymphocytes play a key role in immune surveillance and in the regulation of the inflammatory response (as seen especially in multiple sclerosis, see Lassmann 1998). Major contributions are also made by B-lymphocytes and activated macrophages and/or microglia (Gay et al.

1997), by cytokines (Cannella and Raine 1995) and chemokines, especially by adhesion molecules (Sobel et al. 1990), as well as by their receptors (Simpson et al. 1998). The roles of these players are complement- ed by local expression and/or upregulation of class I and class II histocompatibility antigens (Traugott 1987), markers of T-lymphocyte and macrophage activation (Brueck et al. 1995). Finally, apoptosis of T- lymphocytes also occurs (Bauer et al. 1999).

29.1

Bacterial CNS Diseases

The mortality rate of bacterial CNS diseases in adults is about 25%. Survivors often experience sequelae such as memory deficits, seizures, hearing loss or vestibulopathies (Smith 1988; Durand et al. 1993).

These sequelae are caused not only by the inflammatory process, which is mainly confined to the leptomeninges, but by the associated complications such as brain edema, cerebrovascular insult, hydrocephalus, and/or elevated intracranial pressure (Pfister et al. 1992, 1993). As in patients with bacterial CNS infection, nitrotyrosine (a marker of the formation of reactive nitrogen species, such as peroxynitrite) could be demonstrated immunohistochemically in the cerebrospinal fluid (CSF) (Kastenbauer et al.

2002); this finding indicates that oxidative stress due to reactive nitrogen species and altered antioxidant defenses are additional factors that play important roles, and that in humans these factors are involved in the pathophysiology of bacterial meningitis.

Clinically and morphologically the following forms of bacterial inflammation associated with the CNS can be differentiated:

1. Purulent leptomeningitis 2. Abscess

3. Mycotic aneurysm 4. Septic encephalopathy

29.1.1

Purulent Leptomeningitis

Bacterial dissemination usually occurs secondarily, originating in the blood and spreading within the CNS mesenchyma and/or spaces of the CSF, i.e., within the leptomeninges (subarachnoid space), along the Virchow−Robin spaces, and within the ventricles (Fig. 29.1). Since the arachnoid laminae possess no capillaries, the rate of neutrophil invasion may be insufficient to generate an early cytological reaction. The leptomeninges of the brain and spinal cord (Fig. 29.2) are equally affected.

Bacteria may also invade the CNS primarily by virtue of fractures or surgery, of ventricular drainage or ventricular or lumbar puncture. Recurrent meningitis can arise secondary to a head injury due to a defect created in the dura at the base of the skull.

The most common microorganism is Staphylo- coccus epidermidis, which is observed in 50−65% of cases of purulent meningitis. Staphylococcus aureus is demonstrated in 15−25% of cases of CNS infection, Gram-negative bacteria in 5−15% (Editorial, Lancet, 1989; I:647−648). Prognosis depends in large part on the type of microorganism. Although prognosis has improved dramatically in the meantime, the data from 1984 are still able to illustrate how truly dan- gerous the various microorganisms can be: pneumococcal meningitis was fatal in 95−100% of cases, Haemophilus influenzae meningitis in 90%, and me- ningococcal meningitis in 70−90% (Swartz 1984).

The clinical picture is first characterized by non- specific generalized symptoms: fever, somnolence, nausea, and vomiting. The clinical diagnosis is based on the presence of “meningismus” (neck pain and stiffness) and is confirmed by lumbar puncture (purulent CSF, cytological CSF analysis – see Oehmi- chen 1976, and positive bacteriological culturing).

Cranial computed tomography is normal in most cases. Focal neurological deficits are rarely, if ever, seen. Treatment consists of administration of high- dose antibiotics.

In this regard we have to refer to the alleged risk of cerebral herniation complicating lumbar puncture performed to diagnose acute bacterial meningitis (Oliver et al. 2003). All cases of purulent meningitis are associated with increased intracranial pressure, but herniation is a rare complication (5%).

An accurate clinical history combined with recogni-

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Fig. 29.1a−e. Purulent leptomeningitis. a Autopsy findings are characterized by distinct creamy-purulent yellow-to-green de- posits in the leptomeninges, b while the post-fixation expression often is non-characteristic; c leptomeningeal infiltration as well

as infiltration of the Virchow−Robin spaces. The inflammation may involve the ventricular system causing an ependymitis (d) marked by glial nodules at the ventricular surface (e) (c, e H&E;

magnification ×200)

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tion of the early systemic and neurologic findings of bacterial meningitis will indicate a safe setting for performance of a diagnostic lumbar puncture with little likelihood of complicating herniation. However in patients whose disease process has progressed to the neurologic findings associated with impending cerebral herniation, a delay of the diagnostic proce- dure is indicated (Oliver et al. 2003).

29.1.1.1

Neuropathology

The morphological picture is characterized by purulent infiltration of the leptomeninges. In cases with hematogenous dissemination, the hemispheres are especially likely to be symmetrically affected. Tu- berculous or syphilitic infections feature a basal cytological infiltration.

At autopsy, creamy-purulent, yellow or green deposits are macroscopically evident in the leptomeninges (Fig. 29.1a). Formalin fixation reduces this to a grayish cloudiness of the leptomeninges (Fig. 29.1b), rendering macroscopic diagnosis difficult. Acute cases generally exhibit concomitant petechial hemorrhages in the skin and gastrointestinal tract, bilateral adrenal bleeding, plus morphological changes secondary to shock syndrome in the lung, liver, and kidney.

The macroscopic changes are visible at the sur- faces of the hemispheres, the base of the brain, and in the basal cisterns. As already stated, diagnosis is

confirmed by both bacterial culture and cyto-histo- morphology. The histological examination discloses a dense infiltration of the leptomeninges with neutrophils. Bacteria are sometimes visible intracel- lularly and/or extracellularly. Sometimes there is a concomitant infiltration of the perivascular spaces of the cortical vessels, and − rarer still − a leukocytic infiltration of the cortical neuropil. The cortex is spongiform and edematous, with demonstrable ischemic neuronal alterations.

After antibiotic therapy or in subacute cases a decline in the number of neutrophils is seen with a parallel increase in the number of plasma cells and macrophages. Fibrinoid necrosis and thrombosis of blood vessels may produce small foci of cortical necrosis. A few neutrophils are evident within the sub- pial neuropil and perivascular spaces. There is also a slight proliferation of microglia and astrocytes, especially in pneumococcal infections.

Bacteria and pus may be found within the ventricular system. The ependymal surface is sometimes covered by flakes and pus. Neutrophils infiltrate the choroid plexus, which sometimes exhibits hemorrhagic inflammation.

Hydrocephalus is an almost invariable feature (Fig. 29.1c, d), sometimes caused by impaired re- sorption due to extensive inflammatory exudate, sometimes by occlusion of the exit foramina of the fourth ventricle resulting from the presence of thick pus or granulation tissue. If a leptomeningitis is sur- vived, the altered fibrous leptomeninges can remain

Fig. 29.2a−c. Purulent meningitis. a Secondary meningitis after a traumatic event associated with a basal skull fractures, b, c with

inflammatory invasion of the subarachnoid space along the spinal cord

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visible as a cicatrix even decades after the inflammatory process.

29.1.1.2

Late Complications

Late complications due to S. pneumoniae meningi- tis are especially likely in children, who can suffer neurological damage involving auditory neuritis, sensorineural deafness, labyrinthitis, and injury of central auditory pathways. Children are also liable to further neurologic, intellectual, and behavioral deficits. Three further phenomena are of morphological interest:

1. Purulent meningitis, especially of meningococcal meningitis, often causes meningeal fibrosis fea- turing thickening of the leptomeninges around the spinal cord.

2. Subdural effusions or hygromas, clear or blood stained, can develop; their cause, however, is not known.

3. A brain abscess with encapsulation may form, even in adults, but this is not the rule. Usually, abscess and meningitis remain distinct types of infection without crossover.

The following diseases constitute special forms of purulent leptomeningitis:

29.1.1.3

Neonatal Meningitis

The pathogen is usually maternal genital Strepto- coccus agalactiae or Escherichia coli. Infants of low birth weight and/or requiring resuscitation at birth are most at risk of developing neonatal meningitis.

Their host defenses are relatively ineffectual. Neo- natal meningitis has a high mortality of up to 60%

and morbidity as high as 50% (see Kroll and Moxon 1988).

29.1.1.4

Meningococcal Meningitis

The most common cause of meningitis in infants and children is a Gram-negative bacillus, Neisseria men- ingitidis, which tends to epidemic outbreaks since meningococci are spread in airborne droplets that colonize the throat and nasopharynx. Similar pat- terns have been attributed to group A meningococci in many parts of the world. Since meningococci are sensitive to penicillin, prompt treatment can reduce mortality to less than 7% (Wylie et al. 1997; Schild- kamp et al. 1996), 9% (Thorburn et al. 2001) or 20%

(Derkx et al. 1996).

If sepsis complicates a case of meningitis (meningococcal septicemia), however, the mortality increases two- to threefold. Such cases are termed

Waterhouse−Friderichsen syndrome and are com- plicated by all phenomena associated with shock, particularly disseminated intravascular coagulation, which in turn is often associated with dermal petechial and adrenal hemorrhages. The septicemia may precede the meningeal manifestations, thus no signs of a purulent leptomeningitis are found. Such fulminating septic events with high fever generally involve Neisseria meningitidis, which in these cases can only be diagnosed in blood via bacteriological culture or polymerase chain reaction (PCR). Death can occur within a matter of hours.

29.1.1.5

Haemophilus Influenzae Meningitis

Another major cause of purulent meningitis in children aged 3 years and younger is the small Gram- negative aerobic Haemophilus influenzae. It, too, is spread by airborne droplets. Once cellular immunity is acquired, it persists for life.

29.1.1.6

Pneumococcal Meningitis

Although the microorganism Streptococcus pneu- moniae is sensitive to most strains of penicillin, it is responsible for a 15−20% mortality rate in instances of meningeal manifestation. This pathogen is the most common cause of meningitis in adults. The walls of pneumococcal cells are potent stimulators of inflammation. The inflammatory cascade is ac- celerated by lysis of bacteria as a result of antibiotic therapy.

Kastenbauer and Pfister (2003) reviewed 87 of their own cases and summarized the complications.

A good outcome was observed in 48.3% of the cases.

The respective incidences of diffuse brain edema (28.7%), hydrocephalus (16.1%), arterial (21.8%) and venous (9.2%) cerebrovascular complications as well as spontaneous intracranial hemorrhages were very high. The in-hospital mortality was 24.1%.

29.1.2

Epidural Abscess

Within the epidural space, bacterial infections are very rare. They are caused by the spread of microorganisms from the mastoid sinuses, middle ear, and paranasal sinuses due to osteomyelitis − of basal skull fractures − or neurosurgery. In the majority of these cases a focal epidural abscess forms. An associated subdural empyema may arise if microorganisms invade via emissary or diploic veins. Epidural infections affect the spinal cord more often than the cranium because osteomyelitis is more prevalent in the vertebral canal. The dura mater‘s adhesion to the

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inner skull surface usually restricts the infection to a small, flattened space-occupying process. In addi- tion, the dura‘s resistance to infection confines the inflammatory process in most instances to the epidural space.

29.1.3

Subdural Abscess and/or Empyema

Infection of the subdural space seldom leads to en- capsulated purulent inflammation, but rather to

inflammation extending along the entire subdural space in the form of an empyema. The sources of inflammation are the same as those listed above for epidural abscesses. “Sympathetic” purulent infections are common within the subarachnoid space due to the numerous capillaries and their absence from the arachnoid. The result is an accompanying purulent meningitis. Only rarely is a pachymeningitis seen, which may then spread to the subdural space.

29.1.4 Brain Abscess

Abscesses of the brain may be blood-borne or local.

Hematogenous dissemination often occurs secondary to septic emboli (bronchiectasis, lung abscess, bacterial endocarditis, etc. − Strong and Ingham 1983). Immunodeficient patients with sepsis may develop multiple brain abscesses. Hematogenous dissemination is common in drug addicts with endocarditis or infected injection sites (Karch 1993). A local source of abscess may be pericranial infections (sinusitis, mastoiditis). They may be a severe complication of stab wounds and gunshot injury of the brain via local infection of the brain by microorganisms transmitted by knives or bullets into the brain.

The source of infection remains unknown in 10−15%

of cases.

Clinical Features. The clinical pictures depend ini- tially on the nature of the primary insult, e.g., on whether it is endocarditis, sepsis, gunshot injury, etc.

Solitary metastatic abscesses may be slow in developing, by which time the original infection may have healed, for example Staphylococcus aureus from skin sepsis of osteomyelitis. After wounding by gunshot, it may take years before an abscess develops.

The clinical symptoms reflect the presence of infec- tion (fever, etc.) and may include focal neurological deficits depending on the size and localization of the abscess.

Neuropathology. The brain may be characterized by a diffuse leukocytic infiltration of the white matter associated with serodiapedesis and erythrodiape- desis like a phlegmenous inflammation (cerebritis) (Fig. 29.3a); because of the fulminant fatal infectious process no glial reaction occurs. However, abscesses are characterized by a prolonged inflammatory process. Abscesses of local origin are dependent on the location of external infectious lesions (Fig. 29.3b).

Abscesses of hematogenous origin (Fig. 29.3c) are usually distributed by the middle vertebral artery, followed in order of frequency by the anterior cerebral artery and posterior circulation. Cytologically the abscess is characterized by a wall-like aggregation of mononuclear cells (lymphocytes, plasma

Fig. 29.3a−c. Bacterial brain infection. a Early indistinct infil- tration of the neuropil (cerebrítis); b demarcated abscess; c he- matogenous origin of multiple microabscesses associated with intense neutrophilic infiltration of the brain parenchyma (H&E, magnification ×200)

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cells, and macrophages) accompanied by collagenous fibers around a core of neutrophils and neutrophilic debris (Fig. 29.4). Grey and Alonso (2002) describe the stages of abscess development in detail:

▬ The infection begins with microvascular injury, giving rise to an early cerebritis 1−3 days after inoculation. The lesion features congestion, pa- renchymal necrosis, microthromboses, petechial hemorrhages, perivascular fibrinoid exudate, and neutrophil infiltration.

▬ The late cerebritis (4−9 days after inoculation) still exhibits a necrotic purulent center.

▬ In the next stage (10−13 days) a capsule forms composed of granulation tissue (lymphocytes, macrophages, plasma cells, fibroblasts, capillaries, and collagen fibers).

▬ The capsule grows firmer (>14 days) due to the production of collagen fibers; invading macrophages are visible.

In all instances, the abscess is surrounded by an extensive edema that sometimes has a light green tinge.

29.1.5

Tuberculous Brain Infection

Infection of the CNS by Mycobacterium tuberculo- sis manifests mainly in the form of a “tuberculous”

meningitis, rarely as a tuberculous abscess or tuber- culoma.

CNS infection can be fulminant, especially in children: the mycobacterium will spread from a primary tuberculous focus and the fulminant process seems to be a hypersensitivity phenomenon. The cy- tology in these cases typically features neutrophils in the subarachnoid space.

In most cases the tubercular lesion is caused by bacillemia following a primary infection or may result from late reactivation of a latent infection elsewhere in the body. Commonly, the process of pathogen spread will be subacute. Infection can also occur in connection with a miliary tuberculosis.

Clinical Features. A tuberculous meningitis should always be suspected if there has been prior contact with infected patients or a high-risk group. Diagno- sis is made by examining the CSF for cell count, cell picture including lymphocytes, neutrophils, plasma cells, macrophages (Oehmichen 1976), bacterial culture, and PCR (Lin et al. 1995).

Pathology. Macroscopically the basal cisterns con- tain a gelatinous exudate and there is a slight opacity of the meninges over the convexity. Microscopically the infiltrating cells include lymphocytes, neutrophils, macrophages, and plasma cells which may be accompanied by a dense network of collagenous fibers (Fig. 29.5a, b). Some cases exhibit a vasculitis accompanied by fibrinoid necrosis and/or thrombosis. Sometimes tubercle bacilli are demonstrable (Fig. 29.5c, d). Tuberculomas and tubercular abscesses are rare.

29.1.6

Septic Encephalopathy

Septic encephalopathy is a reversible condition of the CNS that is seen in 9−71% of patients with sepsis (Sprung et al. 1990). More effective management of sepsis has led to an increase in the number of reg- istered encephalopathy cases. Twenty-three percent of the 1333 sepsis patients evaluated by Sprung et al.

(1990) had septic encephalopathy. This group had a higher mortality rate (49%) than cases without men- tal involvement (26%).

Fig. 29.4a−c. Abscess membrane. Wall-like aggregation of mononuclear cells (macrophages and plasma cells) accompanied

by a network of collagenous fibers (a, b van Gieson stain; c tri- chrome stain; magnification (a, b ×100; c ×500)

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Clinical Features. The clinical diagnosis requires ei- ther the exclusion of other causes, or the presence of obvious changes in the level of consciousness and EEG findings, which are a sensitive index of brain function (Young et al. 1990; Bogdanski et al.

1999). Characteristic are cranial nerve dysfunctions, symptoms of diffuse brain dysfunction without focal deficits, paralysis, or decerebrate posturing as well as cardiovascular autonomic failure. Sepsis gives rise not only to CNS symptoms but also to periph- eral nervous system involvement known as “critical illness polyneuropathy” (Nauwynck and Huyghens 1998), which is mainly a motor axonal dysfunction and affects about 7% of patients (Witt et al. 1991) in a setting of respiratory insufficiency (Nauwynck and Huyghens 1998). Sepsis is also associated with “criti- cal illness myopathy” (Latronico et al. 1996), which occurs in 50−80% of the critically ill. There is a cor- relation between the severity of septic encephalopathy and mortality, bacteremia, and renal and hepatic dysfunction (Eidelman et al. 1996). Septic encephalopathy entails a mortality rate of 50% (Sprung et al.

1990; Young et al. 1990).

Pathogenesis. Septic (or “early”) encephalopathy cannot be explained by hepatic or renal dysfunction,

hypoxia, or hypotension, whereas “late” encepha- lopathy is attended by multiple organ failure, hypo- tension, and other systemic disorders (Papadopou- los et al. 2000). In early encephalopathy, sepsis leads to a derangement of plasma and brain amino acids:

branched chain amino acids decrease, most neutral amino acids increase (Mizock et al. 1990; Basler et al. 2002). Aromatic amino acid levels correlate with mortality. The mortality rate correlates with levels of ammonia and amino acids containing sulfur (Sprung et al. 1990). The definitive cause of septic encephalopathy remains unknown, although it has been related to respiratory insufficiency during systemic inflammatory response syndrome or multiple organ dysfunction syndrome. The systemic inflammatory response to sepsis has been attributed in part to the adrenergic system, which is thought to participate in controlling blood−brain barrier permeability since perimicrovessel edema formation is inhibited by the β2-adrenoreceptor agonist dopexamine, whereas it is provoked by the α1-adrenoreceptor agonist methox- amine (Davies 2002). Originally defined as “altered brain function related to the presence of microorganisms or their toxins in the blood” (Bolton and Young 1989), septic encephalopathy is today thought to involve a cytotoxic response by brain cells to in-

Fig. 29.5a−d. Tuberculous meningitis. a, b The typical sign is a granulomatous inflammation consisting of a macrophage-lymphocytic-granulocytic cell mixture associated with collagenous fibers; the cytological marker may be the demonstration of giant

cells of the Langhans‘ type (b, d); c, d tubercle bacilli may be visu- alized by specific staining techniques. (a, b van Gieson stain; c, d Ziehl−Neelsen stain; magnification a ×100; b ×500; c, d ×1,000)

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flammatory mediators (cytokines and others) or the action of these mediators on the brain (Papadopou- los et al. 2000). A more recent study gave evidence of an association of septic shock with neuronal and glial apoptosis within the autonomic centers, which is strongly associated with endothelial expression of inducible nitric oxide synthase (iNOS) (Sharshar et al. 2003).

Neuropathology. The brain morphology features marked edema (Fig. 29.6a, b) secondary to a breakdown of the blood−brain barrier (Papadopoulos et al. 2000). Cytologically there is a disruption of astrocyte end feet in association with perivascular edema (Papadopoulos et al. 1999). Astrocyte damage in turn may hinder the regulation of local blood flow. The injury of astrocyte end feet may impair the transport of energy substrates from microvessels to neurons, thus reducing synaptic activity (Tsacopoulos and Magistretti 1996). Hemodynamically controlled pigs were found to have shrunken, dark, apparently de- generating neurons in the frontal cortex after only 8 h of fecal peritonitis (Papadopoulos et al. 1999). It

is not known, however, whether sepsis in humans induces neuronal injury. It is known that septic encephalopathy occurs in sepsis before cerebral hypo- perfusion or cerebral hypoxia/ischemia could have caused neuronal death. Nevertheless, in single cases we see intracerebral hemorrhages caused by disseminated intravascular coagulation (Fig. 29.6a, b) as well as hypoxic changes − possibly secondary to the septic disease (Fig. 29.6c). Moreover, in histological sections we have to refer to edema (Fig. 29.7a) as well as to the phenomenon of pyemia, i.e., the em- bolic transport of bacteria into the brain parenchyma (Fig. 29.7b, c). The latter gives rise to the neuro- pathologic finding of innumerable microscopic glial nodules (Young et al. 1990; Fig. 29.7d). These microabscesses or glial nodules (Fig. 29.7d) could easily be missed if the brain is only examined and cut in the fresh state, without proper fixation and microscopic examination.

A recent investigation in 23 patients who had died in an intensive care unit from septic shock (Sharshar et al. 2003) gave evidence of hemorrhages in 26%, hy- per-coagulability syndrome in 9%, microabscesses

Fig. 29.6a−c. Septic encephalopathy. a The external inspection of the corpse demonstrates multiple hemorrhages which give evidence of disseminated intravascular coagulation; b this pre- sumptive diagnosis was confirmed by gross inspection of brain

sections which also demonstrated multiple hemorrhages; c the obviously secondary (ischemic) encephalopathy may also be expressed by isolated hypoxic brain lesions diagnosed by the dark- brown color of the putamen and hippocampus

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in 9%, multifocal necrotizing leukoencephalopathy in 9%, and ischemia in 100%. Vascular iNOS expression assessed by immunocytochemistry was higher in sepsis and correlated with neuronal apoptosis in the autonomic centers. The authors concluded that septic shock is associated with diffuse cerebral damage and specific autonomic neuronal apoptosis which may be due to circulating factors, particularly iNOS.

29.2

Abacterial CNS Diseases

29.2.1 Classification

There are two types of abacterial meningitides: viral meningitis and non-infectious, abacterial inflammation. The latter has non-viral causes, including non- specific reactions to iatrogenic chemical/mechanical irritation of the leptomeninges and adverse reactions to medications (for review see Love and Wiley 2002;

see also Oehmichen 1976; Oehmichen et al. 1977a, b).

Viral infections of the CNS may manifest as viral meningitis or as encephalitis or encephalomyelitis, or even in combined form as meningoencephalitis.

Viral meningitis is a benign infection that seldom entails sequelae. Encephalitis and encephalomyelitis are accompanied by edema and destruction of neurons and glial cells, as well as proliferation of astrocytes and microglia. The sequelae differ depending on the infecting virus‘ properties of neurotropism, neuroinvasion, and neurovirulence. Neurotropism refers to the attraction of certain viruses, such as po- liomyelitis virus or herpes simplex virus, to neurons in certain CNS locations. Neuroinvasion refers to the non-specific invasive capabilities of the virus in pen- etrating the nervous system via the blood−brain barrier or via peripheral nerve axons. Neurovirulence refers to the consequences once the virus enters the nervous system, and may range from benign dor- mancy to causing hemorrhagic necrotizing disease.

Acute post-infectious encephalitis (post-vaccinal encephalitis) is known to follow chickenpox, measles, rubella or mumps, as well as rabies or smallpox vac- cination. Some viruses, measles viruses in particular, are capable of causing subacute encephalitides with clinical symptoms that persist for months or years, as a cause of subacute sclerosing panencephalitis (SSPE). Progressive multifocal leukoencephalopathy

Fig. 29.7a−d. Histological features of septic encephalopathy.

a Edema; b septicopyemia with neutrophilic infiltration; c mul- tiple microabscesses as a result of metastatic distribution of

bacteria and/or infectious thrombi; d innumerable glial nodules (a, d H&E, b, c NAS-DClAE; magnification a ×200; b, c ×300;

d ×500)

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(PML) is caused by an opportunistic viral infection of an immunocompromised host‘s brain. For more on the immunological background the reader is referred to the reviews by Schneider-Schaulies et al.

(1997) or Love and Wiley (2002).

29.2.2 Pathogenesis

The predominant entry route of CNS infection is via the mucous membranes of the gastrointestinal or respiratory tracts. If the invading virus is not neu- tralized by IgA antibody, it infects the cell of first contact and multiplies, spreading to local lymphatic tissue and often to the blood stream. Viral infection of the CNS begins with local virus growth in non- neural tissue and then disseminates via the neural or hematogenous route to the cord or brain. Viruses taking the neural route (herpes virus, rabies, and po- lio virus) can grow in axon cylinders distant to the perikaryon’s metabolic activity − both centripetally and centrifugally. However, access is gained by most viruses via the blood stream.

29.2.3

Clinical Features

In most cases the first manifestations are meningeal symptoms and psychopathological deficits.

Neurological deficits may also occur, especially if the parenchyma of the brain (encephalitis) or spinal cord (myelitis) is involved. The diagnosis must be confirmed by virological analysis (PCR or antibody). Examination of the CSF in most cases demonstrates infiltration by plasma cells and lymphocytes and may disclose a slight increase in the cell count (Oehmichen 1976).

29.2.4

Neuropathology

Macroscopically there may be vascular congestion, a slight meningeal opacity, and swelling of the brain (Fig. 29.8). These phenomena however are non-specific. In cases with pronounced edema, symptoms of herniation are found, together with the sequelae of ischemia. In some cases spot-like hemorrhages are found (Fig. 29.8c) as an indication of a hemorrhagic meningoencephalitis. The microscopic alterations are diverse and partly specific (Esiri and Kennedy 1997); most cases are characterized by a mononuclear meningitis that is associated with an encephalitis − at least morphologically.

▬ Inflammatory cells: the salient cytological al- teration of viral meningitis and encephalitis is a

Fig. 29.8a−c. Viral meningoencephalitis. a, b A slight opacity of the leptomeninges and − in some cases − c a distinct brain swell- ing may be macroscopic markers of a viral infection; spot-like hemorrhages are partly seen as an indication of a hemorrhagic meningoencephalitis (c arrowheads)

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moderate increase of plasma cells, lymphocytes, macrophages, and neutrophils in the perivascular (perivascular cuffing) and/or subarachnoid spaces (Fig. 29.9a, e). The numerical relationships among the different cell types vary with the stage of inflammation and the nature of the infection.

In the early phases, for example, neutrophils predominate over lymphocytes, whereas later plasma cells and finally macrophages predominate.

▬ Activation of microglia: the numbers of microgli- al cells increase in the encephalitic type and these cells become hypertrophic to form so-called rod cells (Fig. 29.9b−d). A typical feature of viral

encephalitis is microglial nodules (Fig. 3.8e), re- flecting the neuronophagic process.

▬ Astrocytic activation: the activation of astrocytes (Fig. 29.9f) depends on both tissue destruction and edema in cases of encephalitic participation.

Both phenomena are present in encephalitis, together with a proliferation of astrocytes express- ing vimentin and/or GFAP as further indications of astrocytic upregulation.

▬ Neuronal changes: the neuronal alterations in- clude loss of Nissl substances, swelling of perikaryon or shrinkage of the cell body, plus eosino- philia of the cytoplasm, all of which are non-specific. In a few cases it cannot be determined with

Fig. 29.9a−f. Viral meningoencephalitis. a Leptomeningeal and perivascular infiltration by mononuclear cells, mainly by lympho- cytes, b microglial and plasma cells; c−f perivascular cuffing and

lymphocytic infiltration of the brain parenchyma with extensive microglial reaction (a, d, e H&E; b, c CD68 reactivity, f trichrome stain; magnification a−c ×100; d−f ×500)

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certainty whether these changes are secondary results of agony or of the edema.

▬ Endothelial activation: this is triggered by up- regulation of the adhesion molecules VCAM-1 and ICAM (Sobel et al. 1990; Raine and Cannella 1992). The morphological alterations of endothelial cells are non-specific and marked by an adhesion and emigration of leukocytes.

▬- Inclusion bodies: inclusion bodies are highly spe- cific for virus-induced inflammation of the brain parenchyma in general and for the type of virus in particular. They occur in astrocytes, neurons, and oligodendrocytes, usually in the form of in- tranuclear or intracytoplasmic bodies (Negri body of rabies). High-magnification microscopy reveals the majority of inclusion bodies of viral origin to have oval or round eosinophilic bodies, sometimes surrounded by a clear halo.

▬ Cell and tissue necrosis: in viral encephalitis necrosis ranges in extent from selective neuronal necrosis to total eradication of large areas of neural tissue. The pattern of distribution may be non-specific, but can be highly typical as is its oc- currence in the temporal lobe in herpes simplex encephalitis, or widespread distribution in the CNS in St. Louis encephalitis.

▬ Demyelination: white matter lesions in post-in- fectious encephalitis arise after acute exanthema- tous diseases such as chickenpox, measles, rubella or mumps, or following immunization against rabies. Microscopically the lesions exhibit cuffing of small veins by a mixture of inflammatory cells composed of lymphocytes, polymorphs, and macrophages. Neural tissue destruction is marked by a breakdown of myelin.

The specific morphological changes associated with the various viral infections are described in the rel- evant textbooks of clinical neuropathology. Only AIDS-related infections of the CNS will be discussed here.

29.3

AIDS and the Nervous System

Acquired immunodeficiency syndrome (AIDS) is caused by a retrovirus, the human immunodeficiency virus (HIV), HIV-infected CD4+ lymphocytes and macrophages. The dramatic drop in the number of T-helper cells compromises the cell-mediated immunity and leads to other abnormalities in the host immune response. Opportunistic infections and neoplasms figure prominently in the neurological manifestation of AIDS. A distinction must be made between:

1. Primary, HIV-associated nervous system infection, and

2. Secondary infections of the nervous system The following text is based largely on the review by Honig (1997).

29.3.1

Primary HIV-Associated Nervous System Infection

The level at which the nervous system is affected depends on which part of this organ system is infected.

29.3.1.1

HIV Encephalopathy

(Subacute Dementia Encephalopathy)

Clinical Features. The most prominent clinical feature is a progressive cognitive decline over a period of months and years exhibiting the hallmarks of

“subcortical” dementia. Common manifestations are personality change, apathy, decreased drive, di- minished attentiveness, vegetative symptoms, and forgetfulness. Orientation, language, and remote memory functions are comparatively spared. The cumulative prevalence of HIV encephalopathy varies between 30% and 90%.

Neuropathology. The brain exhibits macroscopic pallor of the white matter (Navia et al. 1986; de la Monte et al. 1987). Microscopically, demyelination, gliosis as well as macrophage and multinucleated giant cell infiltration are found. An intense infiltration of the brain parenchyma by activated microglia associated with vasculitis and neuronal loss is demonstrable (Fig. 29.10a, b). Additionally HIV encephalopathy is characterized by intravasal fibrin precipi- tation and/or secondary recanalization as well as by serodiapedesis (Fig. 29.10c) and astrocytic activation (Fig. 29.10d). The frontal cortex matter is also involved, with substantial loss of neurons (20−40% − Ketzler et al. 1990; Everall et al. 1991) and of synaptic and dendritic complexity (Masliah et al. 1992). Mo- lecular techniques reveal intraparenchymal HIV infection of macrophages, microglia, and multinucleated giant cells.

29.3.1.2 HIV Myelopathy

Clinical Features. About 20% of AIDS patients have spinal cord involvement (Budka 1991) that commonly presents as subacute or chronic progressive thoracic myelopathy with loss of the dorsal column sensory modalities (proprioception and vibration)

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and spastic weakness of both legs. Cord atrophy may be disclosed by MRI.

Neuropathology. Pallor marks the white matter tracts, especially in the dorsal and lateral funiculi.

Microscopy reveals a spongy appearance attribut- able to vacuolation of variable size and coalescence between the myelin sheath lamellae; the term vacuolar myelopathy derives from these changes. Axons are intact, and the degeneration of myelinated white matter resembles that associated with vitamin B12 deficiency.

29.3.1.3 HIV Neuropathy

HIV-infected individuals are afflicted by various types of neuropathy: acute and chronic inflammatory demyelinating polyneuropathy, distal sym- metric polyneuropathy, motor polyradiculopathy, mononeuritis multiplex, and autonomic neuropathy.

These disorders derive in part from drug or nutrition toxicity or from opportunistic infections. A number of neuropathies, however, appear to be intrinsic to HIV infection.

29.3.2

Secondary HIV-Associated NS Infection

Because of the profound immunodeficiency state induced by HIV infection, patients are vulnerable to a wide range of historically rare neoplasms and opportunistic infections. T-cell dysfunction is combined with significant B-cell dysfunction and the appearance of leukopenia, which is most often due to bone- marrow suppression induced by medications. Be- cause AIDS usually involves impaired cell-mediated immunity due to CD4+ T-cell depletion, patients are beset by a variety of fungal, parasitic, mycobacte- rial, eubacterial, and viral infections (Bredesen et al.

1988; Johnson et al. 1988). Among the pathogens are herpes virus (Fig. 29.11), Mycobacterium tuberculosis (Fig. 29.5), Treponema pallidum (Fig. 29.12a,b), cyto- megalovirus, and parasitic infections such as Cryp- tococcus neoformans (Fig. 29.12c, d), Toxoplasma gondii (Fig. 29.13a−c), Taenia solium (cysticercosis) (Fig. 29.13d), Candida (Fig. 29.14) or Aspergillus, etc.

Fig. 29.10a−d. a Intense diffuse and b focal microglial infiltra- tion of the brain parenchyma with perivascular clusters of mi- croglia/macrophages; c vasculitis and perivascular microglial

infiltration; d astrocytic activation (a, b H&E, c CD68 reactivity, d GFAP reactivity; magnification a ×100; b−d ×500)

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29.4

Transmissible Spongiform Encephalopathies Included under this heading is a group of diseases with similar contagiosity and morphology. They can be transmitted to both humans and animals and are characterized morphologically by vacuolar degeneration of neurons and neuropil. However, they lack a cellular inflammatory response. They include sporadic and dominantly inherited Creutzfeldt−Jakob diseases (CJD) and familial fatal insomnia, dominantly inherited Gerstmann-Sträussler-Schenker syndrome, as well as kuru, iatrogenic CJD, and the new variant CJD (nvCJD), all of which are acquired by prion infection (DeArmond et al. 2002). Prion diseases have been in the spotlight since the advent of a new variant of CJD caused by transmission of the bovine spongiform encephalopathy (BSE) pathogen to humans (Aguzzi 1996; Will et al. 1996).

The etiology and pathogenesis of sporadic, genetic, and infectious (iatrogenic) forms of these diseases are currently attributed to a conformational change in the prion protein (PrP), a normal cell membrane protein expressed in nerve cells at particularly high levels (Kretzschmar et al. 1996). The pathological protease-resistant, scrapie-like isoform of the prion

protein (PrP^Sc) accumulates in brain gray matter, where it is responsible for converting normal cellular PrP molecules into the pathologic isoform (Aguzzi et al. 1996; Wieland et al. 1996).

Because about 15% of all human prion diseases are dominantly inherited and accompanied by long- lasting neurological deficits, diagnosis is usually made in the living patient; sudden unexpected death is extremely rare. This disease picture is therefore seldom encountered at legal autopsy. One of the present authors has encountered a single case of sporadic CJD, in which death was attributed to chronic heavy metal poisoning (Oehmichen et al. 2001).

Neuropathology. Since prion diseases are highly in- fectious − even after formalin fixation of tissue − all possible measures must be taken to prevent con- tamination. Decontamination must be performed with formic acids. Brain tissue blocks also need to be decontaminated with formic acids prior to embed- ding in paraffin (cf. Schulz-Schaeffer et al. 1998; see also p. 83).

Microscopically the following histomorphologi- cal alterations are revealed:

1. In the cerebral cortex a marked astrocytic gliosis, a moderate to severe neuronal loss, and a severe

Fig. 29.11a−d. Subacute necrotizing herpes encephalitis (van Bogaert). Bilateral hemorrhagic necrosis and − in the last stage − cystic alteration (a) of the temporal lobe is as characteristic as the

intense astrocytic reaction which is demonstrated by van Gieson stain (b) or by Holzer‘s glial stain (c, d) in the white matter (mag- nification b, c ×300; d ×1,000)

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spongiform changes with confluent vacuoles are evident (Fig. 29.15a, b).

2. Thalamic nuclei and basal ganglia exhibit the same vacuolation.

3. The white matter features astrocyte activation (Fig. 29.15d) plus marked diffuse axonal injury.

4. Perivacuolar reactivity can be demonstrated in the gray matter using a specific antibody (Gö 138 − Kretzschmar et al. 1996) against amino acids 138−152 of the human prion protein (Fig. 29.15c), while focal granular and plaque-like PrPSc deposits are found in the cerebellum, primarily in the molecular layer.

5. Diagnosis is confirmed by molecular genetic analysis, which is currently possible in special- ized laboratories (Nicholl et al. 1995).

29.5

Non-Infectious Inflammatory Diseases

There are three particular types of autoimmune diseases of the CNS that are characterized by demyelination, relative sparing of axon cylinders, periventricular and perivascular inflammation, and macrophage infiltration. The mechanism by which

diverse immune stimuli can trigger a similar pattern of tissue injury is unclear (for review see Genain and Hauser 1997).

29.5.1

Acute Hemorrhagic Leukoencephalitis (Hurst’s Disease)

Clinical Features. The beginning of the disease is acute or hyperacute and rapidly progressive. The disease may occur without known antecedent or may follow immunization (post-vaccinal encephalomyelitis) or infection (post-infectious encephalomyelitis). The disease is characterized by a monophasic fulminant inflammatory hemorrhagic demyelination of white matter, usually post-infectious, and associated with death or severe morbidity within a few days (Geerts et al. 1991; Rossman et al. 1997). The symptoms are signs of meningitis and neurologic deficits, most commonly hemiparesis, aphasia, brain stem dysfunction, and seizures followed by coma and brain death.

The pathophysiology remains unknown. The dis- ease obviously is triggered by infectious respiratory antigens (Geerts et al. 1991; Rossman et al. 1997).

The disease seems to be a hyperacute form of the

Fig. 29.12a−d. Lues cerebrospinalis (neurosyphilis) and Crypto- coccus neoformans. a, b Lues cerebrospinalis associated with periv- asal mononuclear infiltration and vasculitis; c, d Cryptococcus neo-

formans characterized by PAS-positive inclusions and giant cells (a van Gieson stain, b H&E; c, d PAS; magnification a ×100; b ×500, c ×300, d ×1,000)

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more common acute disseminated encephalomyelitis. Both seem to result from an autoimmune process directed against the CNS myelin (Vartanian and Monte 1999).

Neuropathology. The brain is markedly swollen with uncal and tonsillar herniations and loss of gray−white demarcation. The deep white matter has a mottled gray appearance with focal hemorrhages.

The microscopy is characterized by edema, leukocytic infiltration, extravasal erythrocytes, and loss of myelin − without evidence of active infection (Ku- peran et al. 2003).

29.5.2

Acute Demyelinating Disease

The acute type of multiple sclerosis is characterized by the acute onset and often is associated with a post- vaccinal or post-infectious beginning. With rabies immunization this disease is most likely to occur from vaccines that are prepared by propagation in brains of adult animals (Hemachudha et al. 1987).

Post-infectious encephalomyelitis may follow any of

the common childhood viral exanthemas, especially a natural infection with measles virus (Johnson et al.

1984).

Clinical Features. The patients complain of acute fever and headache or neck pain accompanied by evolving visual, motor, or sensory symptoms. In severe cases, lethargy may rapidly evolve to somnolence or coma.

The multiplicity of neurologic deficits is the most characteristic feature of this disease.

Pathologically the disease is characterized by multiple foci of perivenous inflammation (lymphocytes, macrophages) and demyelination found scat- tered throughout the cerebral hemispheres, brain stem, and spinal cord (Griffin 1990). All lesions are of the same age. A distinction between the acute and chronic (multiple sclerosis, MS) demyelinating disease may be possible because the acute type has lesions with more irregular edges while the chronic disease (MS) is thought to be created by concentric outward growth, resulting in a smoothly rounded or oval appearance (Genain and Hauser 1997).

Fig. 29.13a−d. Encephalitis caused by Toxoplasma gondii, and cysticercus. a Macroscopically an extreme demyelination as- sociated with an internal hydrocephalus caused by Toxoplasma gondii; b, c a distinct cellular infiltration of Virchow−Robin spaces

and brain parenchyma is seen as well as the intracellular tachyzo- ite form of Toxoplasma gondii. d The cysticercosis is characterized by multiple cysts within the brain parenchyma (b, c van Gieson stain; d PAS; magnification b ×500; c ×1,000; d ×100)

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29.5.3

Chronic Demyelinating Disease:

Multiple Sclerosis

Multiple sclerosis (MS) or encephalomyelitis dissem- inatais a chronic disorder characterized in its initial stages by episodes of neurological dysfunction (relapses). These relapses are considered to reflect injury primarily of the central nervous system, myelin or its cell of origin, the oligodendrocyte, mediated by an inflammatory response initiated by autoreactive lymphocytes recognizing neural (myelin) constitu- ents.

Clinical Features. The neurologic deficits are charac- terized by sensory symptoms, motor weakness, visual blurring due to optic neuritis, diplopia, ataxia, bladder, bowel or sexual dysfunction, and cognitive dysfunction (Goodkin et al. 1991; Matthews 1991).

The onset of the disease may be insidious or dramatic. Neurologic examination will reveal signs of pyramidal tract dysfunction, e.g., spasticity, but fo- cal areflexia indicates an interruption of the lower reflex. There are two types of MS:

1. Relapsing−remitting MS, which is characterized by discrete attacks of neurologic dysfunction.

2. Chronic progressive MS, which results in gradu- ally progressive worsening without periods of stabilization or remission.

The gross pathology is characterized by multiple sclerotic areas, so-called plaques (Fig. 29.16), which vary in size and localization. Mostly the plaques are centered around small veins and concentrated in the periventricular tissue. Acute lesions consist of periventricular cuffing with mononuclear cells (Fig. 29.17b; see Adams et al. 1989). A demyelination (Fig. 29.17a) occurs with aggregation of macrophages which scavenge myelin debris, and − secondarily − astrocytes proliferate (Fig. 29.17c; see Adams et al.

1989; Prineas et al. 2002). The final stage is characterized by complete demyelination and dense gliosis.

Inflammatory cells may be present (chronic active plaque) or absent (chronic inactive plaque).

Epidemiology. MS is the most common disease with neurologic disability arising between early- to mid- adulthood. MS is approximately twice as common in females than in males. Ten percent of cases begin before the age of 18.

Fig. 29.14a−d. Candida encephalitis. a The macroscopic feature is characterized by hydrocephalus while the microscopy (b−d) re- veals PAS-positive fungal filaments and an intense macrophage

reaction combined with multinucleated giant cells (magnifica- tion b ×200; c, d ×1,000)

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The pathogenesis is unknown as is the mecha- nism of tissue damage. This disease is by most inves- tigators believed to involve an autoimmune attack on the brain and spinal cord initiated by CD4+ T-cells specifically attacking some as yet unidentified brain

antigen (Raine 1994; Williams et al. 1995). There is an immense literature and there are a lot of findings and hypotheses, which are excellently summarized by Prineas et al. (2002).

Fig. 29.15a−d. Creutzfeldt−Jakob−Disease (see Oehmichen et al. 2001). a, b The cortical structures are marked by a loss of neu- rons and a vascuolar degeneration of the neuropil; c in the gray matter granular and plaque-like prion-protein (Gö 138) reactive

deposits are demonstrable as well as d a strong astrocytic reac- tion in the white and gray matter (a, b H&E; c Gö 138 reactivity;

d GFAP reactivity; magnification a ×50; b ×1,000; c, d ×300)

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Fig. 29.16a−c. Multiple sclerosis. Disseminated foci of demyelination (plaques) in the white matter of a the cerebrum, b the cerebel- lum, and c the spinal cord