Inflammatory Lesions 1 Infections

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The CNS is protected from the direct spread of infectious agents by bony and meningeal coverings and by the blood-brain barrier. There are four routes of infection in the brain: hematogenous spread, direct implantation, local extension, and the neural route. The most common is the hematogenous route. Most viruses, bacteria, fungi, and protozoa use this route, often after local growth in nonneural tissue (mucous membranes of respiratory or enteric systems) or proliferation in the blood stream. There are several ways to penetrate the blood-brain barrier: Transport in infected reticuloendothelial cells, transport in circulating immune complexes, replication in infected endothelial cells, or passive pinocytotic transfer in the plexus chorioideus have been identified as strategies for viruses.

Direct implantation takes place almost invariably in traumatic lesions, but it is also sometimes iatrogenic (ventriculoperitoneal shunt and lumbar puncture). Furthermore, extensions of local adjacent infections of frontal or mastoid air sinuses or an adjacent osteomyelitis are portals of entry for bacterial infections.

The underlying mechanism of the neural route is bidirectional axonal transport that carries products of axolemmal renewal and the constituents of synapses. Pathologic agents may also use either the centropetal pathway (e.g., herpes simplex virus, rabies virus, or tetanus toxin) or the centrofugal pathway (e.g., reactivated herpes simplex or varizella zoster viruses or rabies virus).

Once an infectious pathogen has crossed the barriers into the nervous system, unique anatomical features are encountered. The brain has no intrinsic system for antibody prduction, no lymphatic system in the usual sense, and few phagocytic cells. The blood-brain area that inhibits invasion also deters clearance and impedes the entry of therapeutic agents. However, since few microorganisms overcome the barriers into the CNS, the invasion of the CNS is still a rare event.

The first responses to invading viruses consist of increased levels of lymphocytes (mostly T cells) and monoytes in the CSF. There may also be a modest increase in protein concentration. The reaction to pyrogenic bacteria is a fast and spectacular increase in polynuclear leukocytes and proteins. Less dramatic changes are seen after more slowly developing and less pyrogenic microorganisms (e.g., tuberculosis or lister-ial meningitis) invade. The pathological consequences of CNS infection depend on the type of microorganism. Viruses can induce a perivascular infiltration of monocytes and lymphocytes. Indirect inflammatory or direct cytopathic responses can induce neuronal damage until cell lysis along with damage to the myelin and glial cells and small focal hemorrhages. Various associated immunocomplexes also play a role in the response to viral and CNS components. For example, B cells migrate in, producing antibodies against the invading micororganisms, and as a reaction to the microbial antigens, T cells release cytokines that attract and activate other T cells and macrophages. Viruses show different preferences for inflicted cells:

On the one hand, rabies, polio, and herpes simplex and flavin viruses infect neurons, whereas on the other hand, the Jakob-Creutzfeldt virus attacks oligoden-drocytes. Pathological changes appear more rapidly after bacterial infection. Here, local responses to bacterial antigens and toxins play an important role.

Brain infections such as encephalitis occur much more rarely than infections of the brain membranes such as meningitis. This means that many other factors must interact to allow relatively common bacteria or viruses to cause CNS infection. Bacterial infections are frequently marked by an inflammatory abscess for which the sources are difficult to differentiate. These arise from the immunological response in the form of fibrin deposits and exudates resulting from inflammation. These take the form of capsules and are mostly surrounded by a large edema. Streptococci and staphylococci can be found along with pneumococci, enterococci, and other anaerobic organisms. These abscesses appear as hyperdense areas in a CT scan: The edema presents itself as a ring of enhanced contrast.

Viruses are a more frequent cause of encephalitis than is bacteria. Indeed, the most frequent cause of severe, sporadic encephalitis is the herpes simplex virus. The virus may originate in the nasal mucus and cross the tractus olfactorius, or it may be reactivated from a persistent cache in the trigeminal ganglion. It may then infect the basal regions of the frontal or temporal lobes of either or both hemispheres. The effect is a dimming of consciousness, aphasia (reflecting a preferred infection of the left hemisphere), moderate hemiparalysis, and perhaps focal if not general epileptic discharges.

The pathological characteristics of herpes simplex encephalitis can be clearly visualized, if somewhat delayed, in radiological images. These consist of the spotty but continuous area of necrotic tissue, reflecting the infiltration of granular lymphocytes, and a marked edema in cases of rapid pressure damage (Fig. 3). Persistent tissue damage with severe signs of a neuropsychological deficit is frequent, despite antiviral therapy.

2. Creutzfeld-Jakob Disease

Creutzfeld-Jacob disease (CJD) belongs to the group of transmissible spongiform encephalopathies. This group occurs in animals (scrapie in sheep and bovine spongiform encephalopathy) and in man (Kuru; fatal, familial insomnia; Gerstmann-Straussler-Scheinker disease; and primarily CJD and a new variant nvCJD). They all share the following features: The pathological changes are neuronal degeneration and loss with

Figure 3 MRI scan of a 32-year-old man suffering from encephalitis caused by herpes simplex virus. Note the typical hyperintense lesion of the right temporal and basal frontal lobe.

astroglial proliferation presenting as small cystic (spongiform) areas in gray matter without any inflammatory signs leading to a widespread cortical atrophy. The clinical course includes a prolonged incubation period, possibly a decade or layer, with a subsequent progressive fatal course following the first symptoms. All diseases are transmissible and the responsible agent is the prion (proteinaceous infectious particle). Prions differ from all other microbial agents in that they contain no nucleic acid. This results in no immune response. They are also very resistant to the usual sterilization procedures (heat, radiation, ultraviolet light, and chemical agents). The pathologic prion protein (PrPsc) develops from a physiologic cellular prion protein with the same sequence of amino acids as a result of conformational change with more pronounced beta folding structure. The underlying mechanism of this conformational change is unclear. However, PrPsc is able to induce the same transformation from which it develops.

CJD occurs in sporadic, inherited (several mutations) and iatrogenic forms due to transplants of cornea or dura, insufficiently sterilized neurosurgical instruments, and growth hormone extracted from human hypophyses. The clinical course of all three forms is comparable: progressive dementia often accompanied by myoclonus, visual, cerebellar, or motoric disturbances and finally an akinetic mutism and decerebration. The electroencephalogram shows typical periodic complexes of sharp waves in an underlying decelerated background activity. Since clinical diagnostic tools are not sufficiently, sensitive, a definite diagnosis depends on postmorteum analysis of cerebral tissue, including neuropathologic, immunhis-tochemical, and Western blot analysis with antibodies against PrP.

In 1996, a new variant of Creutzfeld-Jakob disease (nvCJD) was described. In contrast to the classical form, it starts at an ealier age (<30 years) with pronounced psychiatric signs. Also, electrophysiolo-gical and neuropathologic findings differ from those in sporadic cases. The similarity to experimentally induced CJD analog changes in macaque monkeys infected by transfer of BSE led to the hypothesis that nvCJD is caused by food containing BSE. This hypothesis has not been proven.

3. Multiple Sclerosis

Multiple sclerosis is a demyelinating disorder affecting the CNS. The clinical associations reflect white matter damage: upper motor neuron weakness and paralysis, incoordination, visual disturbances, and paraesthesia. The course is often acute onset followed by a progress of many years with alternating remissions and relapses. Less commonly, there are different variants, such as an acute severe disease that incurs a rapid progress to death, chronic progession without remis sion, and minimal signs with very long remissions. The typical pathologic findings are so-called "plaques," areas of demyelination characterized inflammatory infiltrates in early stages, profound myelin loss, an almost total absence of oligodendrocytes, and a scattering of astrocytes in the late stages. Although plaques have a predilection for the angles of the cerebral ventricles and the corpus callosum (Fig. 4), they may occur anywhere in the CNS.

Multiple sclerosis is an autoimmune disease in which the patient's immune system reacts against the neuronal myelin sheath. In addition to demyelination, damage in the CNS occurs to the axons and an inflammatory filtrate can be detected. Although numerous aspects of the genetics, histopathology, and other immunological details have been the subject of recent and wide-ranging investigations, the precise pathophysiological course of the illness remains unclear.

Early microscopic studies revealed that the typical periventricular demyelinated foci oriented radially in the blood vessels. There are three recognized histo-pathological stages of lesion development:

1. Early developing lesions (acute inflammatory reaction of all parts of the myelin system and disrupted blood-brain barrier)

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