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NEUROPATHOLOGY MINI-COURSEPATHOLOGY OF THE NEURON AND ITS PROCESSES

PRETEST: Answers can be found in the text of this chapter

1. The basophilic, Nissl positive material in neuronsis____________________________.

2. Axonal injury may result in what change in the distribution of thismaterial ?

3. What is the location of the inclusion body of Parkinson's disease? ofrabies infection?

4. Neuronophagia results in______________________ and is carriedout by_______________.

5. What is Wallerian degeneration?6. The two principal histological hallmarks of Alzheimer disease

are________________________.

The cellular elements of the central nervous system are neurons and glia. All ofthese cells have processes in addition to their cell bodies. The neuronalprocesses are called axons and dendrites.

In the peripheral nervous system, there are no glia. There are Schwann cellswhich surround the axons and produce myelin in the same manner as theoligodendroglia of the CNS. Interestingly, the Schwann cells also become

phagocytes, devouring the debris from injured peripheral nerves, and thisproperty is not shared by the oligodendroglia.

NEURONAL CELL BODY

The image above is an example of a normal anterior horn nerve cell. The normalanterior horn cell serves as a good illustration of a normal neuron. The nucleusis centrally placed and contains a large, prominent nucleolus. In the cytoplasm,large clumps of blue-black material are seen which represent the prominentaggregates of ribonucleoprotein (RNA). This material is often called Nisslsubstance, after the man who devised special stains for staining it. One suchstain, cresyl violet, has been used in this image.

The image above, with the more routine hematoxylin and eosin stain, alsodiscloses Nissl substance, which is a shade of purple. Although the neuronsillustrated in this image are typical of large neurons, please remember thatneurons of all sizes exist in the central nervous system.

The image above illustrates central chromatolysis. In response to transection odestruction of the axons, whether by mechanical trauma or by other means, acharacteristic change known as central chromatolysis occurs in the neuronal celbody. The nucleus moves to an eccentric position, the Nissl material is visibleonly peripherally, and the central area of the neuron is free of stainable materialThis is a reversible change and electron microscopy shows that theribonucleoprotein is dispersed rather than aggregated as in the normal neuronThe normal appearance of many neurons, especially in the brain stemresembles that of central chromatolysis.

The reversible movement of RNA within the cell body in response to axonainjury is apparently related to the call on the cell for increased protein synthesis a demand arising as the cell attempts to regenerate a new axon. Regeneration

can be completed in the peripheral nervous system, but is only abortive in thecentral nervous system. When the demand for increased protein synthesis isended, the Nissl substance returns to its normal position.

When the axon is injured very close to the cell body, or in instances of direcinjury to the cell body, whatever the cause, the cell body may be irreversiblydamaged and simply disappear. Disappearance is a frequent end result oischemic and/or anoxic damage. Prior to disappearance, the cell body mayshow vascular degeneration or become surrounded by or covered by microgliacells (neuronophagia).

The image above is an example of neuronophagia. Neuronophagia is verycommon after viral infection of the CNS, but its occurrence is not restricted toviral diseases. The stain is H&E so the microglia are represented only byelongate , nuclei stained with hematoxylin.


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Viral infection is often accompanied by the presence of inclusion bodies, eitherwithin the nucleus or the cytoplasm of the neuron. In this case the patient hadrabies and the inclusions are called Negribodies.Thesel cytoplasmic inclusionsare illustrated by the red ovoids as seen in the image above (arrows).

Cytoplasmic inclusions are also characteristic of Parkinson's disease. They arecalled Lewy bodies. The large pink bodies seen here (image above) areillustrative of this condition. The pink centers of the inclusion bodies containseveral substances including synuclein. The latter is a normally found atsynapses and its function is unknown.

=

An even larger body, also surrounded by a clear halo, is characteristic ofmyoclonic epilepsy and is illustrated in the image above. They are calledLafora's bodies.

In storage disease, the neuronal cell body may become tremendouslydistended by the storage product. Some of the distended cell bodies on the

image above are demarcated by arrows.

When treated with special silver stains, elongate black neurofibrils can bedemonstrated within the normal neurons as illustrated on this image. Theyextend down the entire length of the axon. The function of the fibrils is notknown, but they may represent artifactually clumped tubules which, in turn,(hypothesis), may serve as conduits for the movement of intracellular materialsfrom the cell body, or factory, down the axon to the synapse.

As we age, most of us will develop alterations of neurofibrils in at least some oour neurons. They will become clumped and twisted into odd shapes like tennisrackets or skeins of wool. In Alzheimer-type dementia, tremendous numbers ofthese neurofibrillary tangles are seen. In this image, arrows point to a neuronfilled with such a tangle. Perhaps this leads to interruption of transport down theaxon and this in turn is related to deteriorating intellectual function.

At the same time, the dendrites may degenerate to produce oval, haystack-likemasses of silver-stained (argyrophilic) fibers. These masses are known assenile plaques or neuritic plaques, the adjective signifying the fact that theplaque is composed of degenerated "neurites".

Another change accompanying aging is an increase in the amount of yellowbrown lipofuscin pigment in the neuronal cytoplasm.

In addition to lipofuscin, some neurons contain neuromelanin. This material i

an end product of catecholamine metabolism and is found in the neurons of thesubstantianigra (images below), imparting a black appearance to this structurewhen seen in a sliced midbrain and presenting as dark brown granules in theneurons observed under the microscope.


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IThe neurons of the substantianigra degenerate and disappear in Parkinson'sdisease. Their pigment is phagocytosed by macrophages which carry it away.The substantianigra then becomes pale, a morphologic tombstone representinga disease with disrupted catecholamine synthesis.

AXON

We will now progress to a discussion of injuries involving the extension of thecell body known as the axon. When the axon is severed or irreversibly injured,all of the axon degenerates distal to the site of injury. The entire axon

degenerates at once, as does its myelin sheath. This form of degeneration iscalled Wallerian degeneration, after Waller, the man who first described it.

Axonal injury is readily manifest by special silver stains and is indicated byaxonal swelling, disintegration, and finally, disappearance. Myelin stains revealdegeneration and then loss of myelin all along the affected axon. Walleriandegeneration can occur in either the central nervous system or in the peripheralnerves. During the process of myelin degeneration in peripheral nerves,phagocytes engulf the myelin debris. Most of these phagocytes come frommonocytes; some come from Schwann cells.

You will remember that the Schwann cell is also the cell which has wrappedaround the axon of the peripheral nerve to form the myelin. The analagous cellof the central nervous system is the oligodendroglia. Unlike the Schwann cell,

the oligo does not become a phagocyte when myelin breaks down. Instead, inthe central nervous system, phagocytosis of myelin debris is performed bymesodermal elements, like monocytes entering from the blood.

In the peripheral nervous system, axons can successfully regenerate afterWallerian degeneration. In the CNS, regenerative sprouts may appear but willfail to continue growth and/or to make renewed functional connections with theiroriginal targets.

When Wallerian degeneration occurs in a large number of axons, runningtogether in a compact "tract," tract degeneration is readily demonstrated onmyelin stains. The image above displays a spinal cord stained with Luxol fastblue. Pallor of the lateral columns (pyramidal tracts) indicates lack of myelin inthese columns or tracts. Wallerian degeneration has occurred.

CYTOPATHOLOGY OF THE NEUROGLIA

PRETEST: Answers can be found in the text of this chapter

1. Name the macroglia and tell what they do.2. Why is "scar" really a misnomer for reactive astrocytosis?3. What are three hallmarks of reactive astrocytosis?4. What is the ultrastructural correlate of the eosinophilia of astroctyic

cell bodies in reactive astrocytosis?5. Such astrocytes also have increased expression and translation of

what protein--stainable by immuno techniques?6. What are microglia and where do they come from?7. What do microglia do?

INTRODUCTION

There are three types of glia: astrocytes, oligodendroglia and microgliaAstrocytes and oligodendroglia are neuroectodermal derivatives. The astrocyteis the principle cell responding in a non-specific way to injuries of the nervoussystem. A major function of the oligodendroglia is to produce myelin. Microgliaare members of the mononuclear phagocyte system (formerly called ReticuloEndothelial System). There is a fixed population which comes from bonemarrow and seed the brain during fetal life. Additional monocytes enter the brainfrom the blood especially after various destructive insults. Generally the tissue

macrophages come from these monocytes. The latter may present antigensSome people think that the fixed population of microglia can becomemacrophages. Other functions of microglia are being actively investigated, e.g.cytokine release, antigen presentation.

In the peripheral nervous system there are no glia. There are Schwann cellswhose nature was discussed in the chapter on the neuron and its processes(chapter 14). They are mentioned only to remind you that they share oneproperty in common with oligodendroglia, namely the production of myelin.

The reactions of glial cells, described in this chapter, occur over and over againin different disease settings. Thus, after reviewing this chapter, the studenshould be prepared to approach other chapters dealing with specific diseaseentities.

ASTROCYTES

This image illustrates several normal astrocytes stained with a special gold stainnamed after Cajal. This and other special stains disclose the starfish likeprocesses of the normal astrocyte. Often, as is the case of several astrocytes inthis image, the processes attach to capillaries and are called foot processes o"sucker feet." The latter term implied that the foot processes serve as conduitsfor substances from the capillary lumen to the brain. In fact, this does NOToccur. Transport is through the capillary was into the extracellular space.

If astrocytes do not act as conduits, what do they do? Their known andhypothesized functions are continually being expanded. They include: removaof potassium ion from vicinity of firing neurons; removal of glutamate, theprincipal excitatory transmitter, from vicinity of firing neurons; metabolism oglutamate to lactate which is then liberated from the astrocyte and may serve aspartial energy source for neurons; production of diverse cytokines with diversepurposes; release of molecules that signal nearby capillaries to express andtranslate structural and functional proteins required to produce and maintainbarriers to proteins and other solutes [i.e. these make up a variety of so-called"blood brain barriers"].

Not all astrocytes have long slender processes. Some, predominantly in greymatter, have shorter processes with more frequent thorn-like side branchesConsiderable confusion has arisen because the latter type of astrocyte has beencalled "protoplasmic" while the former has been called "fibrous." These terms donot refer to the shape of the cell body or its processes. They refer instead to thepresence, or relative absence of delicate fibrils within the cell body andprocesses. These are best seen with a different stain, phosphotungstic acidhematoxylin (PTAH). Normal fibrous astrocytes have large numbers o


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intracytoplasmic fibrils; normal protoplasmic astrocytes do not. Theintracytoplasmic fibrils may represent bundles of intermediate filaments. In anycase, such filaments, seen with the electron microscope, are characteristic ofnormal astrocytes, are more prevalent in fibrous astrocytes, increase in numberwhen astrocytes react to injury, and contain an epitope that is stained by anantibody to glial fibrillary acid protein (GFAP). This antibody labels astrocyticcytoplasm for light microscopy.

Now you may wonder why we have emphasized special stains for astrocytes.That is because when astrocytes are normal, their cytoplasm does not stain with

ordinary stains like hematoxylin and eosin. Only the nucleus stains, and, in fact,the same is true for the other two types of glia. Thus, the normal astrocyte isrecognized on routine stains by its oval, vesicular nucleus, while theoligodendroglia is distinguished by its smaller, more perfectly round, and verydarkly staining nucleus. Some of the latter are indicated by arrows on the imageshown later in this chapter.. The microglia has a small elongated or cigar-shaped nucleus. Now let us review the features and nomenclature of normalastrocytes:

Now you may wonder why we emphasize normal astrocytic features. We do sobecause several of these change dramatically when astrocytes respond to injuryof the nervous tissue. Astrocytic reaction is the most important evidence that"something is wrong" with the brain or cord.

Astrocytes respond to injury by (1) multiplying, (2) increasing the length of theirprocesses, and (3) changing their staining characteristics so that theircytoplasm, normally unstained by H&E, now becomes eosinophilic. Not all ofthese changes need occur. When the cytoplasm does become stainable witheosin, the nucleus is often displaced to the periphery and the cell looks plump orfat. Such a cell is often called gemistocytic or a gemistocyte. Do not apply theterm protoplasmic to these plump, reactive astrocytes. Remember that the term"protoplasmic" is reserved for normal astrocytes with few intracytoplasmic fibrils.In fact, both protoplasmic astrocytes and fibrous astrocytes can react to tissueinjury. When they do so, they both may show an increase in intracytoplasmicfibrils. The eosinophilia

THE FIGURE SHOWS REACTIVE ASTROCYTES STAINED WITH H&E. NOTEVESICULAR NUCLEI AND PINK CYTOPLASM. THE PINK MESH BETWEENCELL BODIES IS REALLY PART OF THE CELL AND REPRESENTS CELL

PROCESSES.

THE FIGURE SHOWS GOLD STAINED REACTIV

E ASTROCYTES WHICHARE INCREASED IN NUMBER COMPARED TO NORMAL.

THE FIGURE SHOWS REACTIVE ASTROCYTOSIS WITH THE PTAH STAINTHE PROCESSES ARE BLUE.

This image shows the edge of a so called glial "scar." It is a dense tangle ofdelicate astrocytic processes stained, in this case, by PTAH. Please remembethis so called "scar" does not consist of collagen, and unlike collagen, which isan extracellular material produced by fibroblasts, the glial processes or fibersare cytoplasmic extensions of the cells themselves. Also note that when CNStissue dies, dense glial scars like that shown here, rarely fill in the resultingdefect. Instead, the defect may remain a cyst, or contain only a loose mesh o

glial fibers.

In hepatic failure, astrocytes proliferate without developing eosinophilia. Known

as Alzheimer Type II astrocytes, they are characterized by irregularly shapednuclei with exaggerated vesicular appearance. They may reflect the importanceof astrocytes in ammonia metabolism. Ammonia is elevated in liver failure andcan elicit formation of these astrocytes.

OLIGODENDROGLIA

Oligodendroglia are glial cells with few processes, hence the prefix "oligo.These processes may wrap around axons to form myelin like the Schwann ceof the peripheral nervous system. Thus, in diseases characterized by myelinloss, there may be a great diminution in the numbers of oligoglia. This will beespecially noticeable in white matter as opposed to grey, since in the latteaxons and their myelin sheath are normally separated by cell bodies oneighboring neurons and glia, while in the white matter there are no neurona

cell bodies, so that the myelinated axons form compact bundles which normallystain quite intensely.

THE ARROWS POINT TO OLIGODENDROGLIAL NUCLEI. CYTOPLASMREMAINS UNSTAINED WITH H&E

In addition to being located along axons where they function as formers ofmyelin, oligoglia are often located next to neuronal cell bodies as "satellites" oadjacent to capillaries. Their function in these locations is uncertain, howevesome evidence exists to suggest that oligoglial satellites may play a metabolicrole connected with the needs of the neighboring neuron.

MACROPHAGES AND MICROGLIAThe macrophage in the CNS looks like the round, foamy, or vacuolatedmacrophage found in any organ. In the CNS, the macrophage is sometimescalled a "Gitter" cell. In many conditions these macrophages come from


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circulating monocytes. This is particularly true in destructive lesions of the brainsuch as traumatic lesions or in infarction. However some workers report that inother sorts of brain injury macrophages may develop from resident microglia.These microglia are "cousins" of the macrophage/monocyte and share some CDsites with them. They can be stained with a special silver stain and withantibodies directed against some lectins. . They arrive in the brain from bonemarrow progenitors either during fetal/neonatal life or later. Thus, they representa resident population of reticulo endothelial (mesenchymal) cells within the CNS.They may present antigen, release cytokines and have other functions identicalto that of related RES cells in other organs. Sometimes, rather than becomingmacrophages , the microglia simply proliferate and their cell bodies elongate.

They are then called "rod cells". One form of tertiary syphillis--so called "generalparesis" or "paralysis of the insane" is characterized by huge numbers of theserod cells throughout the brain. A few of these rod cells are illustrated in the silverstained image shown below.

THE FIGURE SHOWS MICROGLIA STAINED WITH THE HORTEGA STAIN[SILVER CARBONATE]. THESE MICROGLIA HAVE THE ROD-LIKE FORM

AND ARE SOMETIMES CALLED ROD CELLS. THEY CAN ALSO BESTAINED WITH A STAIN DIRECTED AGAINST ONE OF THE LECTINS.

THE FIGURE BELOW IS A LOW POWER VIEW OF A BRAIN AFFLICTEDWITH TERTIARY SYPHILIS AND SHOWS THE HUGE NUMBER OFPROLIFERATING ROD CELLS THAT MAY BE SEEN.

CEREBROVASCULAR DISEASE

Cerebral Infarction | Cerebral Hemorrhage | Cerebral Edema

PRETEST: The answers are found in the text of the chapter

1. What are the gross and microscopic differences between ahemorrhage and an infarct?

2. What is the difference between hemorrhagic infarct andhemorrhage? What underlying conditions can predispose tohemorrhagic infarcts? Are hemorrhagic infarcts frequently multipleand sometimes not only multiple but also of the same age? Why?

3. Describe the progression of gross and microscopic changes as aninfarct ages.

4. What is the significance of atherosclerosis in neck vessels?5. What is a cause of TIA?6. What is a cause of subarachnoid hemorrhage other than trauma?7. What complication of subarachnoid hemorrhage can lead to

infarction?

8. What disease predisposes to both infarction and hemorrhage?9. In that predisposing disease what are the microvascular changes in

the brain that can lead to hemorrhage?10. Distinguish between berry aneurysm and miliary aneurysm.11. What produces lobar hemorrhages?12. What kills patients with hemorrhages or infarcts?13. Name 3 herniations.14. Name 2 types of edema. Which type leads to massive increases in

intracranial pressure and death?15. What is relationship between treatments for edema and what is

known about the causes [i.e. pathogenesis] of edema?

Atherosclerosis and hypertension are the underlying conditions responsible fomost cerebrovascular diseases. The major categories of cerebrovasculadisease are caused either by rupture of a blood vessel, or by anoxia in itsbroadest sense. We will begin with the latter.

ANOXIA

Anoxia of cerebral tissue can be produced by lung disease with generalizedanoxia; by poisons like carbon monoxide, which binds to hemoglobin; bypoisons like cyanide, which prevents oxygen in the blood stream from beingutilized by the brain cell; by hypotension or cardiac arrest, which diminishes theamount of blood reaching the brain; by anemia, and by narrowing or blockade oa cerebral blood vessel or of the major vessels in the neck supplying the brainThe blockade of arteries is produced by emboli or thrombi. Thrombi form oveatherosclerotic plaques. Emboli and thrombi produce infarcts, the prototype othe anoxic lesion.

CEREBRAL INFARCTION

If death occurs within a few hours, no gross or morphologic changes may beobserved at the site of infarction. After about l2 hours, neuronal cytoplasm maybegin to turn eosinophilic and nuclei are pyknotic (image below)by 24 hoursdefinite softening and some discoloration may be noted in the gross tissue

Accompanying breakdown of the blood-brain barrier permits edema flu(plasma) to enter the tissue.

In a jaundiced individual, bilirubin may brightly discolor the edema around recencerebral infarction (image below).


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During the first 48 hours, neutrophils may enter the infarcted tissue, to be rapidlyreplaced by macrophages, which greatly increase in numbers until the infarctedtissue is about two weeks of age.

In the image above, virtually every cell is a macrophage, though only two arelabeled with arrows. They then remain in large numbers for a variable periodafter which they decrease greatly (cyst formation). During the second week orso (and all of these dates are approximate and overlapping), astrocytes begin torespond to the infarction in all of the ways described in the chapter concerningthe cytopathology of the glia. Reactive astrocytosis reaches a peak somewhatlater than does the increase in macrophages, and large numbers of reactiveastrocytes may remain "forever" at the site of infarcts (rarified zone or cyst).

The image above displays reactive astrocytosis in a zone of rarefaction (H & Estain).

The image below show reactive astrocytosis in the form of dense PTAH stainedastrocytic processes at the margin of a cyst.

The image below shows cysts representing old infarcts.

The cyst is the end stage of infarction. The larger the infarct the larger the cystObviously the purpose of astrocyosis is something other than filling in the cysand the term glial scar is a misnomer for astrocytosis.

A cyst is the endstage of any mass destruction of the brain irrespective ocause. The reactive astrocytes serve as suppliers of diverse cytokines whoserole in the injured brain is yet to be understood. In addition astrocytes produce asubstance[s] that induces formation of proteins in capillary walls. These proteinsdetermine various aspects of the blood brain barrier[s]. Newly formed vessels asites of damage do not have these new properties and one role of astrocytosis

is apparently to transform these leaky new vessels into more normal braincapillaries with their blood brain barriers. This occurs as the astrocytic end feeappose themselves to the capillary. But it is not the physical barrier of theendfoot which makes the barrier but rather the diverse structural and chemicachanges in the capillary endothelium whose expression is triggered bysubstances released from the endfeet.

PLEASE REMEMBER THE GENERAL RULES FOR DATING INFARCTS.

y PINK NEURONS 12-18 HOURSy NEUTROPHILS 24-96 HOURSy MACROPHAGES PEAK AT 7-14 DAYSy ASTROCYTOSIS BEGINS AFTER A PERIOD OF DAYS AN

PEAKS AFTER SEV

ERAL WEEKSy PHAGES BEGIN CLEARING OUT AFTER SEVERAL WEEKS

LEAVING REACTIVE ASTROCYTES BEHIND, INITIALLY INGREAT NUMBERS

o THUS LOTS OF ASTROCYTES AND RELATIVELY FEWPHAGES MEANS A LESION THAT IS MANY WEEKS OREVEN MONTHS OLD

y A LESION WITH SHEETS OF PHAGES AND RELATIVELY FEWREACTIVE ASTROCYTES IS 1-2 WEEKS OLD

THESE RULES ABOUT MACROPHAGES AND ASTROCYTES ALSO APPLYTO OTHER DESTRUCTIVE LESIONS OF THE BRAIN OR CORD (E.G.TRAUMATIC LESIONS).

HEMORRHAGIC INFARCTS

A few red cells pass into most infarcts and can be seen under the microscopeBut a hemorrhagic appearance may not be present on gross inspection unlesslarge amounts of red cells have passed through the damaged vessels. Onlyinfarcts with grossly demonstrable hemorrhage are called "hemorrhagic." This ismore likely to occur in infarcts produced by emboli rather than those producedby thrombi. However, red blood cells may be seen even in infarction producedby thrombi. It should be stressed that no matter how large the "hemorrhagic"component of a "hemorrhagic" infarct, the red cells do not form large aggregatesor clots within the tissue, but instead remain dispersed and finely mixed with theintervening necrotic tissue. This is most important because it is so different fromthe character of a true intracerebral hemorrhage with which the infarct must nobe confused. The picture below shows a large empty space which is artifac


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produced when a true hemorrhage--a big blood clot which displacedsurrounding brain--fell out of the brain slice. the other lesions are hemorrhagicinfarcts--intact but necrotic brain into which large amounts of blood has leaked.

Emboli are often multiple. Thus, when an infarct is caused by an embolus, it isoften one of several infarcts having a similar age. The multiplicity of the infarctsplus their hemorrhagic character helps one arrive at the conclusion that theinfarcts were embolic.

Sources of the emboli may vary from the heart or aorta, to the carotid orvertebral arteries in the neck or just entering the skull. Atrial fibrillation is acommon cause of hemorrhagic infarcts since embolic atrial breaks off fromthrombi that often form in the atrium or atrial appendages. This is a major

reason for anticoagulating persons with persistent fibrillation.

TRANSIENT ISCHEMIC ATTACKS (TIA)

Emboli may fragment or lyse within occluded vessels before they have producedpermanent damage to brain or brain blood vessels. Such episodes can produceperiods of symptoms lasting only a few hours. Symptoms are often similar fromone attack to the next because emboli may lodge repeatedly at the same site.Recent serial imaging studies indicate that a permanent lesion is often--but notalways-present in an area producing a transient symptom[s]. It is unclearwhether this lesion was present but silent before the TIA . If so it may have beensimply functionally enlarged but not structurally enlarged by another embolis tothe same vessel[s] or by a transient episode of hypotension or hypoxia whichaffected an already compromised site. It is also possible that no lesion was

present until the embolic episode and that the functional lesion was briefly largerthan the structural change which by itself was too small to produce symptoms.

IMPORTANCE OF PATHOLOGY IN NECK ARTERIES: Pathology in neckvessels will play a role in the development of embolic phenomena affecting thebrain. Atherosclerotic plaques in these vessels may provoke local thrombosisespecially if the plaque has eroded. Aggregated platelets are an importantcomponent of the local thrombus and these as well as other portions of theplaque may embolize from the thrombus to lodge downstream and produceocclusions that are transient [TIA's] or permanent [infarction] or both. In addition,pathology in these large vessels or in arteries of the Circle of Willis by thrombiand thus produce cerebral infarction. Complete occlusion does not always leadto infarction, especially when the occlusion is of a vessel in the neck. That isbecause the other vessels take over the flow of the occluded vessel, and thelarge anastomoses of the Circle of Willis permits all regions of the brain to beadequately perfused. Large numbers of older persons may be walking aroundwith one vertebral or carotid artery occluded. In such cases, the occluded vessel(or vessels) become an "Achilles heel" or point of weakness in so far as theeffects of future occlusions, severe narrowings, or drops in blood pressure areconcerned. Under such circumstances, the presence of one or more alreadyoccluded vessels may have exhausted the capacity of the collaterals, and thenext occlusion, pressure drop, or little bit of additional narrowing in a still openvessel may be sufficient to reduce blood flow below the limits demanded by anormally functioning brain. In such cases, an infarct may occur in the distributionof the vessel with the old occlusion, since this is the vascular territory with theleast collateral reserve.

The importance of atherosclerosis and its complications in neck arteries has ledto carotid endarterectomy as a treatment for persons with TIA. The TIA are awarning sign of impending permanent infarction which occurs in adisproportionate fraction of such patients as compared with persons without TIAIf an artery is at least 70% occluded and the artery is on the side of the lesionproducing the TIA, then the patient is an acceptable candidate foendarterectomy provided the surgical team has a track record with less than 6%combined morbidity and mortality from the procedure. In such cases thereduction of future infarcts makes the procedure statistically worth whileMedical treatment of persons with TIA or persons who have had an infarcfollowing TIA is also worthwhile. This prevents future infarction in a significan

proportion of treated patients. Anti-platelet drugs are the drugs of choice withaspirin being the first drug found useful for this purpose.

HYPOXIC ANOXIA OR GLOBAL ISCHEMIAUnlike thromboemboli plugging individual arteries, hypoxic anoxia produced byrespiratory arrest, poisons or transient total ischemia as seen during cardiacarrest, may produce infarcts in many areas of the brain at once. Since bothcerebral hemispheres will be simultaneously deprived of oxygen by theseinsults, the infarcts will be bilateral, and of similar age. Sometimes the basalganglia and/or thalamus are selectively infarcted. To these hallmarks of globalanoxia are added the peculiar pattern of cortical involvement. Rather than thewedge-shaped infarct involving both cortex and white matter, which ischaracteristic of emboli or thrombi, the infarct which follows global anoxia spares(at least relatively) the outermost and innermost cortical layers. Thus, a linear

portion of the mid-zone of the cortex is involved, and this pattern of necrosis hasbeen called pseudolaminar.You have now completed the portion of this chapter which concerns cerebralinfarction. Before proceeding to the section concerned with hemorrhage, reviewthe appropriate questions in the pretest and see if you know the answers.

CEREBRAL HEMORRHAGEUnlike cerebral infarcts which are caused by blockade of a vessel or by anoxiaor ischemia, cerebral hemorrhages are caused by rupture of a vessel or vessels

Among the causes of vessel rupture, trauma and hypertension are probably firston the list. Hypertension may produce hemorrhage by increasing the pressurewithin a pre-existing anatomic defect or by causing damage to the walls of smallarteries that make them susceptible to rupture.The most common defects are "berry" aneurysms and vascular malformations.The latter may consist of masses of abnormal arteries and veins, or masses of

smaller vessels resembling dilated capillaries.

SUBARACHNOID HEMORRHAGE FROM BERRY ANEURYSMS

The "berry" aneurysms are saccular dilations of the vessel, which appear atpoints of branching in the arterial tree, usually in the Circle of Willis or at itsmajor branch points. These out-pouchings are thought to occur at places wherethe media and elastica of the vessel display a congenital defect. The aneurysmsmay vary in size from less than a millimeter to many centimeters in diameterThe larger the aneurysm the more likely to rupture. They increase in incidenceduring the first three decades of life, and are often multiple. Althoughhypertension may increase the incidence of rupture, these aneurysms oftenrupture in the absence of high blood pressure. The picture below shows thearteries at the base of the brain. The patient had three berry aneurysms [red

arrows].


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The picture below shows a microscopic section of a berry aneurysm at the neckof the aneurysm. The slide was stained with a trichrome stain which stainsconnective tissue blue and smooth muscle red. The normal was is in the left halfof the figure. The aneurysm wall , devoid of smooth muscle, is in the right half ofthe figure. The intima of the aneurysm is greatly thickened by anatherosclerosis-like process. This often happens.

The figure below shows the same aneurysm neck in a section stained with theVerhoef van Giessen stain for elastic tissue. The wavy, black, internal elasticlamella is seen close to the lumen of the vessel wall on the left. It ends abruptlywhere the aneurysm begins. This change in structure is the key to proving thatan aneurysm is truly a berry aneurysm and not simply saccular dilation at a siteof atherosclerosis.

The site of aneurysm formation may be determined in part by hemodynamicfactors in the circle of Willis--for example a rudimentary communicating arterywhich forces more blood to go elsewhere through the Circle.

Since the aneurysms form on middle-sized or small arteries within thesubarachnoid space, the hemorrhage always begins as a subarachnoidhemorrhage. The hemorrhage often dissects into the brain, however, so thatsymptoms of an intracerebral lesion are common. The hemorrhage may evendissect through the brain and re-enter the cerebrospinal fluid via the ventricleinto which it has ruptured.

Subarachnoid hemorrhage often leads to an accompanying infarct. The reasonwhy subarachnoid hemorrhage causes cerebral infarction is not altogether clear,

but may involve interruption of blood supply due to rupture of vessels, kinking ofvessels by the hemorrhage, and spasm of the vessels because of the presencein the blood of some vasospastic material. Indeed progressive spasm,demonstrable on angiograms, can occur following subarachnoid hemorrhageand/or its surgical treatment. The presence of severe generalized spasm is abad prognostic sign.

Ischemia is present at the margin of hemorrhages and is a result of vasospasm.This can produce infarction and/or edema. The edema, together with theincreased intracranial mass produced by the hemorrhage itself, causes anincreased intracranial pressure which may be lethal.

INTRACEREBRAL HEMORRHAGE

We have mentioned that hypertension may increase the incidence with whichberry aneurysms rupture, and may contribute to rupture of vasculamalformations. Hypertension appears to be more directly involved, however, inthe major cause of intracerebral hemorrhage, rupture of a small arteriole withinthe brain.

Hypertension causes fibrinoid necrosis of these penetrating arterioles. Themassive intracerebral hemorrhage which is a complication of hypertensionarises from rupture of a necrotic arteriole or from rupture of a minute "miliaryaneurysm formed at the site of necrosis. These aneurysms were first described

by CHARCOT and BOUCHARD. The frequency of fibrinoid necrosis and miliaryaneurysm formation in vessels within basal ganglia and thalamus accounts forthe frequency of intracerebral hemorrhage in those locations.Fibrinoid isidentified by its structureless or sometimes granular red appearance on H&Estain and by the fact that , unlike hyalinized smooth muscle which is alsoeosinophilic, the fibrinoid areas stain with stains for fibrin such as PTAH or Putzstain or with certain trichrome stains. The fibrinoid change in these vessels wascalled lipohyalinosis by Miller-Fisher in a very influential series of articlesHowever that term is confusing because hyalinized arteries are arteries whosemedia has undergone a pathologic change which is not fibrinoid necrosis andwhich by itself does not lead to rupture. Indeed hyalinized arterioles arecommon in hypertension. The term lipohyalinosis stresses the presence of fat inthe degenerate arteriolar wall but again this change is not the hallmark of thearterioles that are in danger of rupturing or forming miliary aneurysms. Thefibrinoid change is the critical change in these diseased arteriolar segments

looks and stains just like the fibrinoid seen in renal and other arterioles inmalignant hypertension. The important point to remember is that, for unknownreasons, the brain arterioles can undergo fibrinoid necrosis even in so-calledbenign hypertension--that is in patents with only modest blood pressureelevation. For that reason it is important to treat even benign hypertension. Theseries of pictures below illustrates the pathologic processes that can lead torupture.

The picture below shows the wall of an arteriole stained with H&E. Theamorphous pink [eosinophilic] material in the wall could be either fibrinoid oamyloid [see section on amyloid angiopathy later in this chapter]. To prove that itis firbrinpoid the section or its close neighbor should be stained with any one oseveral techniques that stain fibrin [e.g. Putz stain-blue; or the PTAH stain-blueor a trichrome stain such as the azo carmine stain; the azo carmine isparticularly good because it distinguishes fibrinoid from garden varietyhyalinization by staining fibrin/fibrinoid red while staining collagen or hyalinizedcollagen blue.].

The section below was stained with azocarmine. An arteriole in thesubarachnoid space has an amorphous red material occupying a good portionof its wall. This is fibrinoid. Fibrinoid is frequently segmental in distribution sothat the entire circumference may not be involved and other areas along thelength of the vessel may also be spared.


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The slide below was also stained with azocarmine. The arteriole wall is replacedby red fibrinoid and displays aneurysmal dilation.

Sometimes a miliary aneurysm thrombosis rather than ruptures. It then appearsas a fibrous ball which may be separated from the parent vessel due to theplane at which the section has been cut. If the section is close to the parentarteriole there will be elastic tissue at the margin of the ball. This elastic tissuestains black with the VVG stain in the pictures below.;

The pathologist got lucky when the section below was taken. Here a miliaryaneurysm that has neen converted to a fibrous ball or globe is shown inlongitudinal section still connected to the parent arteriole by a thin neck.

The intracerebral hemorrhage produced by rupture of a miliary aneurysm or of anecrotic vessel first appears as a large space-occupying mass (image below).

Thus, if the clot were to be dislodged as i t sometimes is at the autopsy table, alarge cavity is left behind (image below). In this picture there are othehemorrhagic lesions. These are hemorrhagic infarcts. Note that the brain, albeiinfarcted, is still present in these areas into which there has been leakage olarge amounts of red blood cells.

Necrotic tissue is present at the periphery of the clot, but not within it. Thenecrosis at the periphery is histologically identical to that seen in infarcts, and isproduced by interruption of the blood supply due to broken blood vessels, andcompression of tissue. When the hemorrhage itself resolves, it does so via themacrophage, which carries away the blood pigment as hemosiderin.

As resolution occurs, the mass or clot becomes smaller and smaller, and theedges of the displaced tissue around the clot begin to come closer togetherFinally, a linear slit will remain as the only sign of what was a large ovahemorrhage (imagebelow).


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Residual, hemosiderin-laden macrophages may impart an orange color to thewall of the slit or cyst. In other words, if the original hemorrhage is compatiblewith survival of the patient, the actual tissue damage and residual symptomsmay be considerably less than those produced by an infarct of comparable size,since the infarcted mass is all dead brain, while the original hemorrhagedestroys brain only along the path cleaved by the hemorrhage and at theperiphery of the mass of blood.

LOBAR HEMORRHAGE

In hypertensive hemorrhages the hemorrhage is generally in the basal gangliaor pons. The arteries to these areas are short branches from more majorvessels and so the pressure within them is relatively high. Thus the location ofthe microvascular changes in these portions of the vascular tree suggests thatblood pressure level has something to do with the fibrinoid degeneration. Incontrast, there are hemorrhages in the peripheral portions of the various "lobes"of the cerebrum--e.g. frontal lobe or occipital lobe. These hemorrhages arecalled lobar to distinguish them from more centrally located hypertensivehemorrhages. Their cause is usually deposition of beta A4 amyloid--the sameamyloid as is deposited in Alzheimers disease. They tend to occur in individualsover 60 years old. Fibrinoid has also been reported in adjacent vessels in suchcases. Such reports deny the presence of hypertension in these people. If true,then this would represent the only entitiy other than hypertension in whicharterioles of the brain have undergone fibrinoid necrosis.

TEST YOUR KNOWLEDGE ABOUT HEMORRHAGE BY REVIEWING THEPERTINENT QUESTIONS IN THE PRETEST AT BEGINNING OF CHAPTER.

Unfortunately, death often results from intracerebral hemorrhage during its acuteor subacute stages. This death is caused by the increased intracranial pressureproduced either by the hemorrhagic mass itself or by the associated cerebraledema. The final common pathway to death (increased intracranial pressure) isthen identical to that often seen in infarction, brain trauma and tumor. Sinceincreased intracranial pressure produced by edema is often the ultimate causeof death in cerebral vascular disease, and since edema is, in itself, a basicallyvascular phenomenon, it seems appropriate to discuss it here in greater detail.

CEREBRAL EDEMA

TYPES OF EDEMA--There are 2 major types of edema--cytotoxic orintracellular on the one hand and vasogenic on the other. Since edematoustissue must show a net increase in water to meet the definition of edema, cellswelling alone cannot cause edema unless the volume of the swollen cellsoccurs without equalizing diminution of the extracellular space, as might occur ifthe swollen cells encroached upon and squeezed that space. Animal studiessuggest that cellular swelling of that magnitude can occur and this would be truecytotoxic edema. Cell swelling, presumably of both astrocytes and neuronsbegins within 30 seconds of hypoxia due to disabling of ionic pumps by theenergy shortage produced by hypoxia. It is unclear whether cytoxic edema byitself can produce significant increases of intracranial pressure during infarction.In any case within hours the venules and capillaries become leaky and bothprotein and water leak into the extracellular space. This is vasogenic edema. Itis responsible for the morbidity and mortality of infarction, hemorrhage,

infections, etc. because the increased intracranial pressure compromises thebrains function as explained in the section below concerning herniations.

Present therapy of edema consists primarily of infusion of hypertonic solutionsinto the blood stream. These solutions contain large molecules which cannoteasily leave the blood stream. The rationale for this therapy is the idea that suchfluids will retard the leakage of vasogenic edema fluid from the vessels andcause edema fluid to move from the tissues back into the vascularcompartment. However, oncotically active substances like mannitol will leavethe leaking vessels, therefore the actual removal of brain water in patientstreated with these solutions, is from the areas with intact vessels. Because theskull is relatively sealed this removal of water will reduce overall intracranialpressure. In addition.it has been found in experimental studies, that such fluidsmay reduce intracranial pressure by another means: hemodilution, which

decreases hematocrit, blood viscosity and shear. Decreased shear reduces therelease of dilating local hormones [e.g nitric oxide] from the endothelium Thisreduction in local dilators causes vasoconstriction and thus decreasesintravascular volume within the skull. The decreased intravascular volumedecreases intracranial pressure.

Steroids have also been used to treat edema. Their mechanism of action isunknown.

CONSEQUENCES OF EDEMA:

As suggested above, the most common cause of edema that produces braiswelling with a clinically important elevation of intracranial pressure is eitherendothelial injury in capillaries and venules or more massive damage to bloodvessels. This edema is VASOGENIC edema. For reasons that are not definitelyestablished, the edema fluid, which is initially comparable to blood plasmapasses predominantly into white matter, rather than grey. This is true even whenthe lesion is in the grey, so that the edema fluid enters the brain at that pointThe fluid may travel considerable distances in the white matter.

The image above illustrates some inportant points about vasogenic edemaFortuitously the edema in the picture has been stained green by bilrubin in theplasma which leaked out of the vessels. Formalin changed it to biliverdin whichis green. Note the color appears to spare [almost] the arcuate zones [arrows] owhite matter which underlies the cortex. We are not sure why the arcuate zoneis relatively spared by vasogenic edema. In any case, edema can not onlycause brain swelling but, by interfering with white matter nutrition, it can

causedegeneration of the affected white matter. If the patient survives, theaffected areas of white matter become rarified or cystic and the borders of theoriginal lesion, for example an infarct or a contusion, are extended by theadjacent zone of damage produced by the edema. These areas of extension arecharacterized by the fact that they occupy the deeper white matter coniguouswith the original lesion and spare the arcute zone--also known as the "Ufibers.Vasogenic edema is the only basic pathophysiologic process known todistribute itself in the deep white matter with relative sparing of "U" fibers.Sowhen we see a cystic or semicystic lesion whose boundaries are demarcated as

just described we know that edema added to the effects of the original insult.

The image below shows an abscess near the grey-white junction. The lesion issurrounded by greatly expanded white matter, the expansion of which wascaused by edema fluid entering where blood brain barrier broke down near theabscess, and spreading great distances between myelinated white matteaxons.


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The image above shows a great increase in white matter mass especially on theright. There is a brain tumor in this hemisphere but most of the tumor is inadjacent slices. The edema fluid is spreading through white matter remote fromthe source which is at leaky vessels within the tumor. The increased mass withinthe edematous hemisphere causes a bulging and flattening of the cerebralsurface, unless a defect is present in the skull. In the latter case, the surfacebeneath the defect simply protrudes through the defect, while the remainderflattens against the inner aspect of the intact skull.

HERNIATIONS

Not only can an edematous brain herniate through a hole in the skull, but shiftsof cerebral tissue can also occur within the skull. When one hemisphere is

swollen, it may be displaced toward the opposite side of the skull and a portionof the cingulate gyrus may be forced under the falx. Similarly, the temporal lobemay be forced downward and a portion of its medial aspect may be forced underthe tentorium. This portion of the temporal lobe is called the uncus, and the term"uncal herniation" is applied to this lesion. Prior to the stage of herniation, theuncus may be pushed against the sharp edge of the tentorium causing thetentorium to make an "uncal groove" along the medial surface of the temporallobe. A swollen hemisphere may also force the brainstem toward the oppositeside of the skull producing a notch in the contralateral peduncle where it iscompressed against the edge of the tentorium. This is known as Kernohan'snotch. These compressions are not merely morphologic alterations, but areaccompanied by malfunction of the compressed tissue. In addition, cranialnerves or vessels may be compressed by the swelling or displaced brain. Forexample, compression of posterior cerebral arteries may produce infarcts in thedistribution of these vessels. Thus, one cerebral infarct can, through the

consequences of an accompanying edema, produce a second infarct in adistant part of the brain. Thus, one cerebral infarct can, through theconsequences of an accompanying edema, produce a second infarct in adistant part of the brain. Increased intracranial pressure can also cause thebrain stem to herniate downward in an attempt to relieve pressure through theforamen magnum. When this occurs the vessels to the stem are stretched andtear. This produces secondary brain stem hemorrhage. The hemorrhage and/orrelated damage to vital cardiorespiratory centers in the brain stem results indeath and this is frequently the ultimate cause of death in patients with infarct,hemorrhages, traumatic injuries, etc. which originally affected only thecerebrum.

THE FIGURE ILLUSTRATES A SECONDARY BRAIN STEM HEMORRHAGE.

TEST YOUR KNOWLEDGE ABOUT CEREBRAL EDEMA BY REVIEWING

PERTINENT QUESTIONS IN THE PRETEST.

DEMYELINATING DISEASES; LEUKODYSTROPHIES; STORAGE DISEASESINVOLVING MYELIN OR NEURONS

This chapter contains four interrelated sections. They are related becausesome diseases of myelin are storage diseases and some storage diseasesinvolve not myelin primarily but the neuron instead. In many cases the storagediseases are related in the sense that they depend upon a lack of an enzymenormally found in lysosomes, or sometimes in peroxisiomes. Each enzymedeficiency disease is characterized by its own enzyme deficiency, but the facthat lysosomal enzymes are involved has led many writers to lump these

diseases together as lysosomal disorders. The problem with this method oclassification is that it loses the distinction between diseases primarily affectinggrey matter [neuronal cell bodies] and diseases primarily affecting white matte[myelin]. Since this anatomic difference helps make a diagnosis when the brainis examined by imaging or at autopsy and also has some effect on earlysymptoms, we prefer to emphasize the older classification of white mattediseases [ADE, MS and leukodystrophies] on the one hand and the othestorage diseases which have been called neuronal lipidoses on the otherIndeed a traditional term for the neuronal storage diseases has been the term"lipidoses". Because of the pathogenetic similarity between some of theleukodystrophies [white matter lipid storage or lysosomal disorders of whitematter] and the neruonallipidoses [lysosomal disorders] we have included asection concerning the latter in this chapter.The other three sections are:

Section 2 - Multiple Sclerosis

Section 3 - LeukodystrophiesSection 4 - Neuronal Lipidoses

Section 1: Acute Disseminated Encephalomyelitis (ADE)

PRETEST: Answers in text of this section1. Describe the microscopic hallmark of ADE.2. What type of cells are present in the infiltrate?

3.What are some causes of the disease?PATHOLOGY

Acute disseminated encephalomyelitis and postvaccinal encephalomyelitis areapparently identical entities, sometimes also known as postinfectiousencephalomyelitis. As these names indicate, the disease sometimes occursfollowing vaccinations (e.g., for small pox) or after viral infections. Although it is

not entirely clear, the lesions in both cases are probably produced by someimmunologic mechanism involving a neural antigen and an antibody. In the caseof the postvaccinal variant, the body's exposure to the antigen will occur if thevaccine was prepared in neural tissue. The lesions are demyelinating, hence, ifthe immunologic theory is correct, the antigen is probably a component ofmyelin.

The demyelination in acute disseminated encephalomyelitis occurs in aperivenular distribution. Thus, in cross or longitudinal section, lesions have avenule in their center. This is seen in the image below which is stained blueblack for myelin, and which displays the lesions as unstained zones of pallo(x's). The lesions may be confluent, and as indicated in the image, amononuclear infiltrate is found around the vessels. This infiltrate of monocytesand lymphocytes participates in the immunologic events that produce the

disease.


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EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

An experimental model of the disease may be provided by experimental allergic

encephalomyelitis (EAE), a demyelinating disease produced in animals by

immunizing them with neural tissue. In addition to EAE, a disease of the CNS,

produced in response to CNS antibodies, a demyelinating disease of peripheral

nerve can be produced in animals by immunizing them with antigens derived

from peripheral myelin. This experimental disease is called experimental allergic

neuropathy (EAN). In EAE and EAN it has been shown that the demyelination

can be prevented or arrested by agents that kill macrophages (monocytes) orinhibit some of the proteases released from activated macrophages. Others

have shown that EAN is enhanced by increasing the permeability of blood

vessels to cells which can then pass more readily from blood to tissue.

Section 2: Multiple Sclerosis

PRETEST: Answers can be found in the text of this section

1. The gross lesion of MS is called a ______________________ .2. The classical view of MS says that myelin is more affected than

axons [true or false?].3. What role does axon degeneration play in the disease?4. What cell is depleted in the affected white matter?5. Two different but possibly cooperating pathways of pathogenesis

have been implicated--what are they?6. What is Devic's disease?

PATHOLOGY

1. Demyelinating, but axonal injury is also important

2. CNS only - not peripheral nervous system - reason unknown but probablyreflects different antigenic makeup of the peripheral vs central myelin.

3. Preservation of axons is relative, but important in progressive disease. Thelesion of myelin loss with relative axon preservation is well circumscribed and iscalled a plaque.

4. On gross inspection, plaques are circumscribed, grey or translucent, often juxta ventricular.

Myelin stains display these areas, called plaques, as circumscribed unstainedzones of pallor (image below). Oligodendroglia are markedly diminished withinthe mature plaque [arrows demarcate loss of myelin below].

The plaque is also recognizable in the gross brain as a well circumscribed zoneof altered color and density (arrow, image below).

In "young" plaques with active demyelination, the myelin debris is present inmacrophages, which then stain for fats. The fat-laden macrophages carry awaythe fat by passing into the perivascular spaces (Virchow-Robin), which areextensions of the subarachnoid space. As plaques grow, their centers may befree of macrophages which then appear only at the actively expanding perimeteof the lesion. Quiescent plaques contain no lipid-laden macrophages. During ofollowing myelin breakdown, astrocytes proliferate within the plaque andastrocytic processes increase in length and number. The ultimate degree ofastrocytosis is quite variable. Marked astrocytosis imparts a firmness to theplaque in the unfixed brain. This firmness or hardness is responsible for the

term "sclerosis" in the name of the disease.

Although plaques are easier to recognize in white matter because of thcontrast between the plaque and the densely myelinated normal backgroundplaques also occur in grey matter since all CNS axons are myelinated alongtheir entire course.

Perivascular infiltrate of lymphocytes and monocytes is found in fresh or activelygrowing plaques.

Axon degeneration also occurs in plaques and may begin early. Progression odisease is related to increasing amounts of axonal damage.

PATHOGENESIS

Some workers believe the lymphocytes and monocytes participate in thedestruction of the myelin, which is mediated by an antibody bound to themononuclear cell and directed against a myelin antigen. Indeed the presence oa venule with a monocytic\lymphocytic perivascular infiltrate near the center ofresh plaques bears a resemblance to the lesion of acute disseminatedencephalomyelitis, a known immunomodulated demyelinating disease of CNSThis similarity has been used to support the hypothesis that MS is an immunodisease.

Moreover certain immuno-modulating drugs have been affective in slowing oarresting disease progression. On the other hand, much circumstantial evidencesuggests a ling to some infectious agent, possibly a virus. This evidence

includes a geographic distribution favoring a vector--such as an insect--whichlikes temperate as opposed to tropical climates. In addition, MS patients andtheir close relatives have been found to have excessive antibody titers toseveral different viruses including measles. Similar populations have also beenreported to have characteristic patterns of histocompatibility markers whichmight explain persistent antibody in such people. These facts--sometimesdisputed as facts-have led to several hypotheses such as:

[1] increased susceptibility to a virus which attacks the CNS myelin or[2] molecular mimicry with a marker on oligo or oligo produced myelin whichshares epitopes with the virus and so is attacked by the persistent antibody tothe virus;[3] or the attack is on some other cell which releases [or the attacking celreleases] cytokines that attack meylin--an innocent "bystander" theory.


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Some support for molecular mimicry concept comes from a peripheral nervoussystem disease. That disease is one form of GuillainBarre disease in which thepatients have had a preceding infection with campylobacter jejuni. The organismhas a ganglioside that mimics one in the peripheral nerve leading to an immunoattack on the latter as the body fights the infection.

Some support for the innocent bystander concept comes from a demyelinatingdisease or peripheral nervous system that devastates flocks of chickens. This isMarick's disease where cells attacking one site in the nerve release cytokinesthat attack innocent adjacent Schwann cells.

Finally, the two immuno theories of MS and the viral theory may combine toaccount first for the initial injury at a given site [related to a viral attack or attackby an anti viral antibody?] and then for the continuation or progression of thelesion via some immuno mechanism.

REMISSIONS

MS is usually characterized by remissions and exacerbations. The reason forremissions is not well understood but again may have something to do with theinterweaving of the pathogenic pathways discussed above. The ability to remitmay depend upon preservation of axons and possibly on minimal remyelinationsufficient to restore the capacity to conduct. However, inflammation in earlyplaques is accompanied by local leaks from vessels and edema. The waxing

and waning of edema in and around the plaque had been thought by someworkers to account for the ups and downs of the clinical picture but MRI studieshave failed to find the correlation between edema or leaking vessels and clinicalstatus.

It is also possible that inflammatory cells release substances that impairtransmission and wax and wane. In addition, an increased number of sodiumchannels develops after axons lose their myelin. These axons then resembleunmyelinated axons and can conduct electrical impulses. However, if anadaptive increase in sodium channels accounts for remissions in MS, we haveno explanation for recurrence of identical symptoms unless (A) they are reallydue to new plaques, or (B) there is an intermittent factor which inhibitstransmission.

Sometimes MS is progressive at onset rather than remittent. Sometimesremittent MS becomes progressive. Recently it has been found that progressiveMS of either type is characterized by axon damage and loss as well as myelinloss. The axon damage explains the failure to remit.

Two other diseases are thought to be related to MS or to be variants of thatdisease.

DEVIC'S DISEASE

The first of these, Devic's disease or syndrome, is also known asneuromyelitisoptica, a name which emphasizes the preferential distribution ofthe lesions in the spinal cord and optic nerve. Pathologically, in many cases, thelesions are indistinguishable from those of MS. However, in a subgroup of

cases, the lesions differ from the usual MS lesions in the following respects:axons are destroyed as well as myelin, and a marked acute inflammatory cellinfiltrate (polymorphonuclear cells) is present. Some workers believe that theselesions are simply a hyperacute form of MS, rapidly progressing, and indeed,typical MS plaques can be seen in the same case.

The second has been called Schilder's disease after the doctor who supposedlydescribed it. The same disease name has also been applied to a form ofleukodystrophy [adrenoleukodystrophy] which leads to confusion. In the contextof MS, the term Schilder's disease should be dropped and one should simplyspeak of hyperacute MS.

The hyperacute disease is characterized by massive degeneration of white

matter--both myelin and axons, with profound astrocytosis. We can only relate

this to MS by observing, in the same patients, relatively spared areas of CNS

that have more typical MS plaques.

This chapter contains four interrelated sections. They are related becausesome diseases of myelin are storage diseases and some storage diseasesinvolve not myelin primarily but the neuron instead. In many cases the storagediseases are related in the sense that they depend upon a lack of an enzymenormally found in lysosomes, or sometimes in peroxisiomes. Each enzyme

deficiency disease is characterized by its own enzyme deficiency, but the facthat lysosomal enzymes are involved has led many writers to lump thesediseases together as lysosomal disorders. The problem with this method oclassification is that it loses the distinction between diseases primarily affectinggrey matter [neuronal cell bodies] and diseases primarily affecting white matte[myelin]. Since this anatomic difference helps make a diagnosis when the brainis examined by imaging or at autopsy and also has some effect on earlysymptoms, we prefer to emphasize the older classification of white mattediseases [ADE, MS and leukodystrophies] on the one hand and the othestorage diseases which have been called neuronal lipidoses on the otherIndeed a traditional term for the neuronal storage diseases has been the term"lipidoses". Because of the pathogenetic similarity between some of theleukodystrophies [white matter lipid storage or lysosomal disorders of whitematter] and the neruonallipidoses [lysosomal disorders] we have included asection concerning the latter in this chapter.The other three sections are:

Section 1 -Acute Disseminated EncephalomyelitisSection 2 - Multiple SclerosisSection 4 - Neuronal Lipidoses

Section 3: Leukodystrophies


1. Name 2 leukodystrophies and their enzyme deficiencies.2. What histologic hallmarks distinguish these 2 diseases.3. What medical benefits have come from the discovery of the

enzymatic defects?

4. Excessive deposition of Rosenthal fibers characterizes whichleukodstrophy.5. Spongiform change especially in the subcortical white matter

distinguishes ___________'s disease.6. What is the most common storage disease produced by a missing

peroxisomal enzyme?

PATHOLOGY

METACHROMATIC LEUKODYSTROPHY

Metachromatic leukodystrophy is characterized by deficient [in some cases] odysfunctional [in other cases] larylsulfatase. As a result, sulfatides are nobroken down and are found in large amounts in astrocytes and macrophages

The sulfatide is metachromatic--that is, it causes a shift in the color of a dye--and this histologic characteristic has given the disease its name.

In fully developed lesions, oligoglia are sparse or absent. Presumably they wereadversely affected by the metabolic defect and/or storage of sulfatide. The injuryto oligoglia is thought to account for the disappearance or absence of myelinsince these glial cells normally form the myelin.

In addition to myelin loss, axon loss is often severe (presumably a secondaryeffect of myelin loss or glial injury) and astrocytosis is marked.

KRABBE'S DISEASE OR GLOBOID LEUKODYSTROPHY


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Krabbe's disease is characterized by deficient galactosidase and accumulationof galactocerebroside in some cells. However, unlike typical storage diseases,overall tissue levels of the affected lipid are not increased, and this fact providesus with one additional reason for maintaining the leukodystrophies as a separatenosologic entity.

Moreover, the accumulating cerebroside may not be the cause of tissuedestruction. Instead, levels of psychosine, a toxin, are increased during theabnormal metabolism and may be responsible for the damage.

As in other leukodystrophies, cases of Krabbe's disease display degeneratedwhite matter, with absence or diminution in myelin, loss of axons, loss ofoligodendroglia and astrocytosis.

The galactocerebroside is stored in macrophages which may cluster together orfuse to form diagnostic "globoid" bodies (image below) which give the diseaseits name. Arrows delineate such a body on the image below. Injections ofcerebroside into the brains of animals produce similar bodies. This effect is notproduced by injections of other brain lipids.

Recently doctors have successfully treated infants at risk for globoidleukodystrophy by intravascular injection of cord blood from normal newborns.Mononuclear cells from the cord blood enter the brain and produce sufficientcerebrosidase to ameliorate the symptoms. This technique--and presumably

stem cells injected intravascularly-overcomes the difficulties of trying to treatenzyme deficiency diseases by injecting the patient with enzyme. In the lattersituation enzyme may not pass the blood brain barrier and, moreover, therecipient may develop antibodies to the protein thereby nullifying its effect.

CANAVAN'S DISEASE

The next disease we will discuss is Canavan's disease or spongiformleukodystrophy. This disease involves all the white matter, but particularly the"U" fibers or arcuate zone which lies immediately beneath the cortex. Theaffected area is demarcated by Xs in the image below. An enzyme defect hasbeen uncovered in this very rare disease. The deficient enzyme,acetylaspartase, breaks down N-acetylaspartic acid. The latter is an importantconstituent of neurons. Since the enzyme which breaks it down is missing, theaspartate builds up in the neurons. However, the aspartase is not localized inthe neurons. Instead it is found in the oligodendroglia. Hence the aspartate isnormally transported down the axons, and in some way is made available forbreakdown by the oligodendroglial enzyme. Why the absence of the enzyme inthe latter should lead to myelin breakdown is not known. But it has beenpostulated that the accumulation of the aspartate in the white matter leads toincreased osmotic pressure there with consequent drawing of water into thesurrounding tissue. It has been further postulated that in some way this leads tothe degeneration of the myelin.

The disease is presented because it illustrates the fact that all leukodystrophiesare not caused by intraneuronal or intraglial storage per se and because itspathology is illustrative of a very unusual type of ultrastructural lesion.

When studied with the electron microscope, the myelin sheath appears to be"unraveling" the lamellae becoming widely separated. An electron microscopicpicture of the large spaces between widely separated myelin lamellae is shownabove. The large spaces appearing between the billowing lamellar sheets arethe cause of the spongy appearance seen with the light microscope. It is thesponginess of the tissue that has given the disease one of its names.

ALEXANDER'S DISEASE

The last disease we will discuss is Alexander's disease. This rareleukodystrophy exists in several forms, depending upon the age of onset. Inseveral forms abnormalities in the gene coding for glial fibrillary acidic proteinhave been found. This is the first disease in which the gene for GFAP has beenimplicated. This may explain a characteristic feature of the disease which is theaccumulation in the degenerated white matter of large numbers of Rosenthafibers and eosinophilic granular bodies. These structures are largeaccumulations of astrocytic processes "clumped" together.

However, they are not specific for this disease and also accumulate inconditions where there has been prolonged proliferation of astrocytes--foexample in slow growing or benign astrocytomas like pilocyticastrocytomaswhere they help the pathologist to make the diagnosis. In Alexander's disease

the relationship, if any, of the astrocytic abnormality to the degeneration ofmyelin or its failure to form normally, or to the selection of white matter as thepreferential target of the disease, has not been elucidated.

PEROXISOMAL DISORDERS

The peroxisome is another ultrastructural cytoplasmic organelle that containscatabolic enzymes. The deficiency of one of these enzymes leads toadrenoleukodsytrophy. This disorder is characterized by characteristiccurvilinear bodies in affected adrenal cells and brain cells which are swollencontain stored very long chain fatty acids.

TESTING PATIENTS AND PROSPECTIVE PARENTS


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Discovery of the enzymatic defect is extremely important. These defects are

expressed in many cells, e.g., white blood cells or cells in amniotic fluid.

Examination of these cells provides a rapid, definitive means of diagnosing the

disease and often its carriers. These facts provide a basis for genetic counseling

and for informed decisions concerning termination of pregnancy.

Section 4: Neuronal Lipidoses


1. What is the most common lipidosis involving the brain and whatenzyme is deficient in that disease?

2. What medical benefits accrue from this knowledge?PATHOLOGY OF LIPIDOSES

The lipidoses are rare and complex diseases usually involving children whichare characterized by progressive neurologic and mental deterioration, often witha fatal prognosis. Recent discoveries have provided understanding of thepathogenesis of these diseases and have also provided a means for detectingcarriers or affected fetuses.

Tables listing the various diseases and their enzyme defects can be found in

standard texts. The same texts will have similar tables devoted toleukodystrophies and their enzyme defects or perhaps to lysosomal and alsoperoxisomal diseases with their enzyme defects. The latter method ofclassification emphasizes the fact that the missing or defective enzymes inlipidoses and in leukodystrophies are almost always in either the lysosomes orperoxisomes.

This image below illustrates the appearance of neurons in a neuronal lipidosis.The cell bodies are ballooned or swollen by the poorly stained lipid. Sometimesthey may appear to be almost empty. Special stains may sometimes distinguishone type of storage disease from another, but with ordinary hematoxylin andeosin staining as illustrated here, one neuronal lipidosis looks like another.

Tay Sachs has been the most common of the neuronal lipidoses. This image is

from such a case. Genetic testing of Jews of European origin has resulted invirtual disappearance of the disease in America due to the benefits of geneticcounseling based upon diagnosis of carriers or of affected fetuses. The testlooks for the enzyme hexoseaminidase A, whose deficiency results in storage ofa GM2 ganglioside.

Electron microscopy reveals lamellated bodies within the neuronal cytoplasm.These are formed by the stored lipid and vary somewhat in appearancedepending upon the disease. In Tay-Sachs disease, they take the form of theconcentric rings shown in this image.

CHERRY RED SPOT

One clinical sign of great notoriety is the "cherry red spot" in the retina opatients with Tay-Sachs disease and some other neuronal lipidoses. It isproduced when ganglion cells, filled with lipid, degenerate, thereby exposing thevascular choroidal tissue behind these cells. The blindness ("amaurosis"produced by retinal involvement, together with the mental deteriorationproduced by destruction of other neurons, has given Tay-Sachs disease thename "amaurotic idiocy."

MEDICAL GENETICS

Most lipidoses appear to have a high familial incidence. Recent discoveriesconcerning the enzymatic basis of these diseases have provided a means noonly for definitive diagnosis of symptomatic patients, but also for detectingcarriers who are heterozygotes.

Leukocytes, cultured fibroblasts, amniotic cells and choroid villus biopsies can

all provide the material necessary for testing. This is true for all the lipidoses and

leukodystrophies for which there is a defined enzyme deficiency. The enzymatic

activity of heterozygote materials is intermediate between that of norma

subjects and the very low levels of homozygotes, who are, of course

symptomatic, or in the case of affected fetuses, doomed to get the progressive

lethal disease.

PATHOLOGY OF CNS INFECTIONS

This chapter contains four interrelated sections. The other three sections are:

Section 2 - Purulent InfectionsSection 3 - Granulomatous InfectionsSection 4 - Viral infections, Rickettsial infections, Prion Diseases

Section 1: General Features


1.

What are the coverings of the brain?2. What are the portals by which infectious organisms can enter thebrain or cranial cavity?

3. What cells proliferate in the vicinity of infectious lesions?4. Do reactive astrocytes wall off abscesses?5. How can hydrocephalus result from infection?

STRUCTURES PROTECTING THE BRAIN

Over the surface of the brain and spinal cord, there are three protective coats omeninges. The thin (or "lepto") meninges are the innermost coverings andconsist of two distinct membranes.


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The first is the pia mater, which is tightly applied to the surface of the brain andspinal cord.

The second component of the leptomeninges is the arachnoid membrane. Thismembrane is external to the pia mater and connected with it by delicatetrabeculae. The space between the pia mater and the arachnoid is called thesubarachnoid space. This space is filled with cerebrospinal fluid, and it is thisfluid which is sampled when a spinal puncture is performed. The surface bloodvessels course in this space. The term "leptomeningitis," or simply "meningitis,"refers to an infection within this space.

The outer most membrane covering the brain is much thicker than theleptomeninges. It is known as the dura mater and is tightly applied to the bonesof the skull. Over the spinal cord, the dura is separated from the vertebralcolumn by a space which contains adipose tissue and blood vessels. For thisreason, epidural abscesses occur more readily here than inside the calvarium.In addition to the leptomeninges and the dura, the bony coverings of the brainand spinal cord and the skin form the outermost defenses of the central nervoussystem.

RESPONSE OF CELLS WITHIN THE BRAIN OR CORD

The astrocytes and the reticulo-endothelial elements of the brain or microglia,are the two types of brain or cord cells which may respond in a non-specific

manner to a wide variety of noxious stimuli including infectious organisms. Themicroglia may simply proliferate while retaining their basic rod-like shape. Inaddition, monocytes enter the wound or lesion and form macrophages whichcarry away the necrotic debris.

The astrocytes may increase in number, may become larger, and may increasethe length and numbers of their processes. However, astrocytic processes donot act well to wall off or impede the advance of infectious organisms. Instead,fibroblasts in the walls of cerebral blood vessels may proliferate, and lay downcollagen to form a wall around bacterial invaders. Thus, abscesses within thebrain can be walled off like abscesses anywhere in the body.

Unfortunately, since fibroblasts are not diffusely scattered throughout the brain,but are only present in vessel walls, and since the only other reservoir of

fibroblasts is the meninges, the wall of a cerebral abscess may be less sturdythan that of abscesses outside the brain.

Leptomeningeal fibroblasts may also proliferate in response to smolderingsubacute or chronic infections of the subarachnoid space and can actuallyimpede or block flow of CSF to the point of producing hydrocephalus.Hydrocephalus may also be produced by a ventriculitis, which may causeinflammation, necrosis, and desquamation of the ependyma (the cells lining theventricular system) at the level of the aqueduct of Sylvius.

In such cases, the inflammation produces hydrocephalus by causing aqueductalstenosis, thereby reducing drainage of CSF from the lateral ventricles and thirdventricle, and increasing the cerebrospinal fluid pressure in these ventricles.Since the communication between the anterior and posterior portions of the

ventricular system is compromised by aqueductal stenosis, the rise in pressuremay not be detected by a spinal puncture because such a puncture enters thesubarachnoid space below the point of blockade.

ROUTES OF ENTRY AND POTENTIAL SOURCES OF CNS INFECTION

DIRECT SPREAD

Sinusitis, otitis media, and mastoiditis are still important sources of CNSinfection. Otitis media may still be the leading cause of brain abscess. Spread ofinfection from the linings of the sinuses occurs through the bone (osteomyelitis)which is tissue paper thin or along veins in a retrograde manner

(thrombophlebitis). Spread of infection through the calvarium from the scalp mayalso occur via the emissary veins.

Another common direct source of infections results from trauma such as bulle

wounds, skull fractures, and surgery. Basilar skull fractures produce defects in

the bony sinuses that will allow the flora of the upper respiratory tract to ente

the CNS.

Section 2: Purulent Infections


1. The principle inflammatory cell for purulent meningitis is the__________.

2. Name a complication of meningitis.3. True or false: the wall of an abscess is generally thickest on the side

facing the ventricle.4. The collagen in an abscess wall comes from ________________5. Purulent infections are caused by pyogenic bacteria and account fo

the majority of CNS infections.

THE PURULENT REACTION

The purulent reaction (image below) is characterized by polymorphonucleacells mixed with fibrin and bacteria. The great abundance of neutrophils impartsa characteristic creamy, yellow-white appearance to the pus which forms thecenter of an abscess or fills the subarachnoid space in meningitis.

LEPTOMENINGITIS

A brain with severe meningitis is shown in the image above. Note that thecreamy pus completely obscures the underlying cortex in some areas. Pus alsotends to collect in the cisterns at the base of the brain. Purulent meningitis is byfar the most common CNS infection. Though antibiotics have not materiallydecreased its incidence, they have markedly increased survival and reduced thecomplications of this disease.

COMPLICATIONS OF MENINGITIS


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The purulent reaction caused by bacteria may involve the vessels of thesubarachnoid space and cause thrombosis resulting in small, cortical infarcts.Thrombosis of the superior sagittal sinus may occur. The underlying brain mayalso be infected by direct spread from the meningitis and abscesses may form.If the meningitis is allowed to smolder, there will be fibrosis of the subarachnoidspace which will impede flow of CSF and cause hydrocephalus.

This fibrosis may also cause CSF to loculate into arachnoid cysts which mayproduce pressure effects like a tumor. The cranial nerves may be involved withinfection or strangled by reactive connective tissue.

BRAIN ABSCESS

The incidence of brain abscess has been markedly lowered since the antibioticera. As would be expected, they are found more frequently in individuals whoare susceptible to general infection such as diabetics, alcoholics, debilitated andimmunosuppressed patients, and the elderly. They are also noted withincreased frequency in infants with cyanotic heart disease.

Brain abscesses are most frequently caused by staphylococcus, streptococcus,and pneumococcus and the primary infections are usually located in the sinuses(ear), lungs, or heart valves.

The image above shows a large abscess in the brain. The purulent center issurrounded by a capsule. Often a zone of hyperemia is present adjacent to the

wall and there is marked swelling of the adjacent brain tissue.

The evolution of the abscess is as follows:

y An area of cerebritis begins, in which polymorphonuclear leukocytesare attracted to the invading bacteria.

y Liquefaction of brain tissue rapidly ensues, and at the periphery, athin rim of granulation tissue composed of new capillaries andfibroblasts is formed.

y With time, a connective tissue capsule is formed by collagen laiddown by infiltrating fibroblasts. Often this is more perfectly formed onthe outer aspect of the abscess, presumably due to the contributionof the reservoir of potential in the adjacent meninges.

y Due to the poor encapsulation of the medial aspect of an abscess,which abuts upon or is located within the cerebral white matter, theinfection tends to form daughter or satellite abscesses medially whichmay eventually rupture into the ventricular system.

y Such rupture may lead to rapid death, and in any event, is usuallyfollowed by severe ventriculitis and massive meningitis as infectedCSF pours into the subarachnoid space.

Antibiotic therapy greatly decelerates the growth of an abscess, and may allowtime for a complete capsule to form after which the abscess may be removedsurgically.

The image above reviews the basic structural features of a brain abscess fromthe histologic point of view. It illustrates (A) the purulent, necrotic center, (B) thethin zone of granulation tissue, and (C) the collagenous connective tissuecapsule.

Section 3: Granulomatous Infections


1. Granulomatous responses are characterized by what type of cells?2. Name three groups of organisms that produce granulomata.3. What disease of unknown etiology produces granulomatous

response in the brain.4. What forms of lesion can be produced by mycobacteria and by

treponemapallidum?5. In addition to t. pallidum what other spirochaete produces lesions

especially of peripheral nerve?6. In addition to general paresis, what two forms of tertiary syphillis can

affect the CNS? In one of them the blood vessels may be affected-how?

7. What is a common parasitic lesion of the brain which can betransmitted via the placenta and may cause as granulomatousresponse with periventricular calcification?

INTRODUCTION

The granulomatous infection is characterized by a chronic exudate omononuclear, histiocytes, epithelioid cells, giant cells and others admixed withconnective tissue. Of these cells the histiocyte is the one that really defines thepresence or absence of granulomatous response. In some instances, there isalso necrosis.

Even when specific antibiotic therapy is available, it is difficult to eradicategranulomata, therefore, granulomatous meningitis frequently leads to fibrosiswithin the subarachnoid space, and blockade of this space with consequenincrease in intracranial pressure and hydrocephalus. In addition to meningitisorganisms causing a granulomatous response can also produce discretegranulomas within the brain or spinal cord, or there may be a more diffusegranulomatous reaction throughout the nervous system.

Granulomatous reactions are caused by a wide range of micro-organisms. Themore important ones which invade the CNS will be covered in the followingparagraphs.

FUNGAL INFECTIONS

Fungal infections are currently the most frequently encountered granulomatousinfections of the CNS and appear to be increasing with our ability to maintaindebilitated patients, the use of immunosuppressive therapy and the advent o

AIDS. Fungi may cause a granulomatous meningitis and granulomata o"abscesses" in the brain.


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The most common fungal invader of the CNS is cryptococcus (Torulahistolytica).These spheroidal organisms (image below) vary from slightly smaller to twicethe size of an erythrocyte and have a thick polysaccharide capsule. They arefound most frequently in the Southern part of the U.S.

I

In man, the lesions are found principally in the CNS where the fungi causeirregular, granulomatous thickening of the leptomeninges and tubercle-likenodules over the base of the brain. In the brain, it produces granulomas, one ofwhich is shown in the image below with giant cells (arrows-image below).

Often, for reasons not completely clear, cryptococcal necrosis may produce aminimal inflammatory reaction. Among other fungi seen are coccidioides

(southwestern U.S.), histoplasma (Ohio River Valley), blastomyces, candida,nocardia, aspergillus and mucormyces.

CNS TUBERCULOSIS

Spread to the brain is frequently miliary and it is thought that tuberculousmeningitis occurs when a miliary tubercle near the surface of the brain burstsinto the subarachnoid space. This chronic meningitis leads to obliteration ofportions of the subarachnoid space and a high incidence of hydrocephalus. Theorganizing meningeal exudate may constrict cranial nerves and causethrombosis of cerebral vessels. Sometimes, miliary tubercles can be seenstudding the subarachnoid space (arrows, image below).

Tuberculomas in the parenchyma of the CNS may behave like slowly expandingmass lesions. One well circumscribed tuberculoma is shown in the cerebellawhite matter in the image below (arrows).

Occasionally, tuberculomas occur as subdural plaques. Epidural tuberculomasin the spinal canal may arise from tuberculous vertebrae (spinal caries) andcompression on the spinal cord produces Pott's paraplegia.

The histologic picture of tuberculosis is seen in the image below. A tubercle isillustrated, with a central core of homogeneous caseous necrosis, surroundedby mononuclear cells, histiocytes, epithelioid cells and giant cells (arrows)

Thus, in the central nervous system, the histopathol

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