Neuropath Mini Course Gdm Jan 2011

8/7/2019 Neuropath Mini Course Gdm Jan 2011

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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 neurons is____________________________.

2. Axonal injury may result in what change in the distribution of this material ?3. What is the location of the inclusion body of Parkinson's disease? of rabies infection?4. Neuronophagia results in______________________ and is carried out 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 of these cells have processes in additionto their cell bodies. The neuronal processes are called axons and dendrites.

In the peripheral nervous system, there are no glia. There are Schwann cells which surround the axons and producemyelin in the same manner as the oligodendroglia of the CNS. Interestingly, the Schwann cells also becomephagocytes, devouring the debris from injured peripheral nerves, and this property is not shared by theoligodendroglia.

NEURONAL CELL BODY

The image above is an example of a normal anterior horn nerve cell. The normal anterior horn cell serves as a goodillustration of a normal neuron. The nucleus is centrally placed and contains a large, prominent nucleolus. In thecytoplasm, large clumps of blue-black material are seen which represent the prominent aggregates ofribonucleoprotein (RNA). This material is often called Nissl substance, after the man who devised special stains for

staining it. One such stain, cresyl violet, has been used in this image.


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The image above, with the more routine hematoxylin and eosin stain, also discloses Nissl substance, which is a shadeof purple. Although the neurons illustrated in this image are typical of large neurons, please remember that neurons ofall sizes exist in the central nervous system.

The image above illustrates central chromatolysis. In response to transection or destruction of the axons, whether bymechanical trauma or by other means, a characteristic change known as central chromatolysis occurs in the neuronalcell body. The nucleus moves to an eccentric position, the Nissl material is visible only peripherally, and the centralarea of the neuron is free of stainable material. This is a reversible change and electron microscopy shows that the

ribonucleoprotein is dispersed rather than aggregated as in the normal neuron. The normal appearance of manyneurons, especially in the brain stem, resembles that of central chromatolysis.

The reversible movement of RNA within the cell body in response to axonal injury is apparently related to the call onthe 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 the central nervous system.When the demand for increased protein synthesis is ended, the Nissl substance returns to its normal position.

When the axon is injured very close to the cell body, or in instances of direct injury to the cell body, whatever the


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cause, the cell body may be irreversibly damaged and simply disappear. Disappearance is a frequent end result ofischemic and/or anoxic damage. Prior to disappearance, the cell body may show vascular degeneration or becomesurrounded by or covered by microglial cells (neuronophagia).

The image above is an example of neuronophagia. Neuronophagia is very common after viral infection of the CNS, butits occurrence is not restricted to viral diseases. The stain is H&E so the microglia are represented only by elongate ,nuclei stained with hematoxylin.

Viral infection is often accompanied by the presence of inclusion bodies, either within the nucleus or the cytoplasm ofthe neuron. In this case the patient had rabies and the inclusions are called Negri bodies.Thesel cytoplasmicinclusions are illustrated by the red ovoids as seen in the image above (arrows).


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

An even larger body, also surrounded by a clear halo, is characteristic of myoclonic epilepsy and is illustrated in theimage above. They are called Lafora's bodies.


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In storage disease, the neuronal cell body may become tremendously distended by the storage product. Some of thedistended cell bodies on the image above are demarcated by arrows.

When treated with special silver stains, elongate black neurofibrils can be demonstrated within the normal neurons asillustrated on this image. They extend down the entire length of the axon. The function of the fibrils is not known, butthey may represent artifactually clumped tubules which, in turn, (hypothesis), may serve as conduits for the movementof intracellular materials from 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 of our neurons. They will becomeclumped and twisted into odd shapes like tennis rackets or skeins of wool. In Alzheimer-type dementia, tremendousnumbers of these neurofibrillary tangles are seen. In this image, arrows point to a neuron filled with such a tangle.Perhaps this leads to interruption of transport down the axon and this in turn is related to deteriorating intellectualfunction.


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

Another change accompanying aging is an increase in the amount of yellow-brown lipofuscin pigment in the neuronalcytoplasm.

In addition to lipofuscin, some neurons contain neuromelanin. This material is an end product of catecholaminemetabolism and is found in the neurons of the substantia nigra (images below), imparting a black appearance to thisstructure when seen in a sliced midbrain and presenting as dark brown granules in the neurons observed under themicroscope.


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IThe neurons of the substantia nigra degenerate and disappear in Parkinson's disease. Their pigment is phagocytosedby macrophages which carry it away. The substantia nigra 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 the cell body known as the axon. When theaxon is severed or irreversibly injured, all of the axon degenerates distal to the site of injury. The entire axondegenerates at once, as does its myelin sheath. This form of degeneration is called Wallerian degeneration, afterWaller, the man who first described it.

Axonal injury is readily manifest by special silver stains and is indicated by axonal swelling, disintegration, and finally,disappearance. Myelin stains reveal degeneration and then loss of myelin all along the affected axon. Walleriandegeneration can occur in either the central nervous system or in the peripheral nerves. During the process of myelindegeneration 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 wrapped around the axon of the peripheral nerve toform the myelin. The analagous cell of the central nervous system is the oligodendroglia. Unlike the Schwann cell, theoligo does not become a phagocyte when myelin breaks down. Instead, in the central nervous system, phagocytosis ofmyelin debris is performed by mesodermal elements, like monocytes entering from the blood.

In the peripheral nervous system, axons can successfully regenerate after Wallerian degeneration. In the CNS,regenerative sprouts may appear but will fail to continue growth and/or to make renewed functional connections withtheir original targets.


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When Wallerian degeneration occurs in a large number of axons, running together in a compact "tract," tractdegeneration is readily demonstrated on myelin stains. The image above displays a spinal cord stained with Luxol fastblue. Pallor of the lateral columns (pyramidal tracts) indicates lack of myelin in these columns or tracts. Walleriandegeneration 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 microglia. Astrocytes and oligodendroglia are

neuroectodermal derivatives. The astrocyte is the principle cell responding in a non-specific way to injuries of thenervous system. A major function of the oligodendroglia is to produce myelin. Microglia are members of themononuclear phagocyte system (formerly called Reticulo Endothelial System). There is a fixed population whichcomes from bone marrow and seed the brain during fetal life. Additional monocytes enter the brain from the bloodespecially after various destructive insults. Generally the tissue macrophages come from these monocytes. The lattermay present antigens. Some people think that the fixed population of microglia can become macrophages. Otherfunctions of microglia are being actively investigated, e.g., cytokine release, antigen presentation.

In the peripheral nervous system there are no glia. There are Schwann cells whose nature was discussed in the


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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 again in different disease settings. Thus,after reviewing this chapter, the student should be prepared to approach other chapters dealing with specific disease

entities.

ASTROCYTES

This image illustrates several normal astrocytes stained with a special gold stain named after Cajal. This and otherspecial stains disclose the starfish like processes of the normal astrocyte. Often, as is the case of several astrocytes inthis image, the processes attach to capillaries and are called foot processes or "sucker feet." The latter term impliedthat the foot processes serve as conduits for 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 and hypothesized functions are continually beingexpanded. They include: removal of potassium ion from vicinity of firing neurons; removal of glutamate, the principalexcitatory transmitter, from vicinity of firing neurons; metabolism of glutamate to lactate which is then liberated from theastrocyte and may serve as partial energy source for neurons; production of diverse cytokines with diverse purposes;release of molecules that signal nearby capillaries to express and translate structural and functional proteins requiredto produce and maintain barriers to proteins and other solutes [i.e. these make up a variety of so-called "blood brainbarriers"].

Not all astrocytes have long slender processes. Some, predominantly in grey matter, have shorter processes withmore frequent thorn-like side branches. Considerable confusion has arisen because the latter type of astrocyte hasbeen called "protoplasmic" while the former has been called "fibrous." These terms do not refer to the shape of the cellbody or its processes. They refer instead to the presence, or relative absence of delicate fibrils within the cell body andprocesses. These are best seen with a different stain, phosphotungstic acid hematoxylin (PTAH). Normal fibrousastrocytes have large numbers of intracytoplasmic fibrils; normal protoplasmic astrocytes do not. The intracytoplasmicfibrils may represent bundles of intermediate filaments. In any case, such filaments, seen with the electronmicroscope, are characteristic of normal astrocytes, are more prevalent in fibrous astrocytes, increase in number whenastrocytes react to injury, and contain an epitope that is stained by an antibody to glial fibrillary acid protein (GFAP).This antibody labels astrocytic cytoplasm for light microscopy.

Now you may wonder why we have emphasized special stains for astrocytes. That is because when astrocytes are


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normal, their cytoplasm does not stain with ordinary stains like hematoxylin and eosin. Only the nucleus stains, and, infact, the same is true for the other two types of glia. Thus, the normal astrocyte is recognized on routine stains by itsoval, vesicular nucleus, while the oligodendroglia is distinguished by its smaller, more perfectly round, and very darklystaining nucleus. Some of the latter are indicated by arrows on the image shown later in this chapter.. The microgliahas a small elongated or cigar-shaped nucleus. Now let us review the features and nomenclature of normal astrocytes:

Now you may wonder why we emphasize normal astrocytic features. We do so because several of these changedramatically when astrocytes respond to injury of the nervous tissue. Astrocytic reaction is the most importantevidence that "something is wrong" with the brain or cord.

Astrocytes respond to injury by (1) multiplying, (2) increasing the length of their processes, and (3) changing theirstaining characteristics so that their cytoplasm, normally unstained by H&E, now becomes eosinophilic. Not all of thesechanges need occur. When the cytoplasm does become stainable with eosin, the nucleus is often displaced to theperiphery and the cell looks plump or fat. 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 normalastrocytes with few intracytoplasmic fibrils. In fact, both protoplasmic astrocytes and fibrous astrocytes can react totissue injury. When they do so, they both may show an increase in intracytoplasmic fibrils. The eosinophilia

THE FIGURE SHOWS REACTIVE ASTROCYTES STAINED WITH H&E. NOTE VESICULAR NUCLEI AND PINKCYTOPLASM. THE PINK MESH BETWEEN CELL BODIES IS REALLY PART OF THE CELL AND REPRESENTSCELL PROCESSES.

THE FIGURE SHOWS GOLD STAINED REACTIVE ASTROCYTES WHICH ARE INCREASED IN NUMBERCOMPARED TO NORMAL.


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

This image shows the edge of a so called glial "scar." It is a dense tangle of delicate astrocytic processes stained, inthis case, by PTAH. Please remember this so called "scar" does not consist of collagen, and unlike collagen, which isan extracellular material produced by fibroblasts, the glial processes or fibers are cytoplasmic extensions of the cellsthemselves. Also note that when CNS tissue 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 of glial fibers.

In hepatic failure, astrocytes proliferate without developing eosinophilia. Known as Alzheimer Type II astrocytes, theyare characterized by irregularly shaped nuclei with exaggerated vesicular appearance. They may reflect theimportance of astrocytes in ammonia metabolism. Ammonia is elevated in liver failure and can elicit formation of theseastrocytes.

OLIGODENDROGLIA

Oligodendroglia are glial cells with few processes, hence the prefix "oligo." These processes may wrap around axonsto form myelin like the Schwann cell of the peripheral nervous system. Thus, in diseases characterized by myelin loss,


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there may be a great diminution in the numbers of oligoglia. This will be especially noticeable in white matter asopposed to grey, since in the latter axons and their myelin sheath are normally separated by cell bodies of neighboringneurons and glia, while in the white matter there are no neuronal cell bodies, so that the myelinated axons formcompact bundles which normally stain quite intensely.

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

In addition to being located along axons where they function as formers of myelin, oligoglia are often located next toneuronal cell bodies as "satellites" or adjacent to capillaries. Their function in these locations is uncertain, howeversome evidence exists to suggest that oligoglial satellites may play a metabolic role connected with the needs of theneighboring neuron.

MACROPHAGES AND MICROGLIA

The macrophage in the CNS looks like the round, foamy, or vacuolated macrophage found in any organ. In the CNS,the macrophage is sometimes called a "Gitter" cell. In many conditions these macrophages come from circulatingmonocytes. This is particularly true in destructive lesions of the brain such as traumatic lesions or in infarction.However some workers report that in other sorts of brain injury macrophages may develop from resident microglia.These microglia are "cousins" of the macrophage/monocyte and share some CD sites with them. They can be stainedwith a special silver stain and with antibodies directed against some lectins. . They arrive in the brain from bonemarrow progenitors either during fetal/neonatal life or later. Thus, they represent a resident population of reticuloendothelial (mesenchymal) cells within the CNS. They may present antigen, release cytokines and have otherfunctions identical to that of related RES cells in other organs. Sometimes, rather than becoming macrophages , themicroglia simply proliferate and their cell bodies elongate. They are then called "rod cells". One form of tertiarysyphillis--so called "general paresis" or "paralysis of the insane" is characterized by huge numbers of these rod cellsthroughout the brain. A few of these rod cells are illustrated in the silver stained image shown below.


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THE FIGURE SHOWS MICROGLIA STAINED WITH THE HORTEGA STAIN [SILVER CARBONATE]. THESEMICROGLIA 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 AFFLICTED WITH TERTIARY SYPHILIS AND SHOWSTHE HUGE NUMBER OF PROLIFERATING 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
http://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#infarcts%23infarctshttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#infarcts%23infarctshttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#hem%23hemhttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#edema%23edemahttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#edema%23edemahttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#infarcts%23infarctshttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#hem%23hemhttp://www.pathology.vcu.edu/WirSelfInst/cerebrovasc.html#edema%23edema


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1. What are the gross and microscopic differences between a hemorrhage and an infarct?2. What is the difference between hemorrhagic infarct and hemorrhage? What underlying conditions can

predispose to hemorrhagic infarcts? Are hemorrhagic infarcts frequently multiple and sometimes notonly multiple but also of the same age? Why?

3. Describe the progression of gross and microscopic changes as an infarct 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 for most cerebrovasculardiseases. The major categories of cerebrovascular disease are caused either by rupture of a blood vessel, orby anoxia in its broadest sense. We will begin with the latter.

ANOXIA

Anoxia of cerebral tissue can be produced by lung disease with generalized anoxia; by poisons like carbonmonoxide, which binds to hemoglobin; by poisons like cyanide, which prevents oxygen in the blood streamfrom being utilized by the brain cell; by hypotension or cardiac arrest, which diminishes the amount of bloodreaching the brain; by anemia, and by narrowing or blockade of a cerebral blood vessel or of the majorvessels in the neck supplying the brain. The blockade of arteries is produced by emboli or thrombi. Thrombi

form over atherosclerotic plaques. Emboli and thrombi produce infarcts, the prototype of the anoxic lesion.

CEREBRAL INFARCTIONIf death occurs within a few hours, no gross or morphologic changes may be observed at the site ofinfarction. After about l2 hours, neuronal cytoplasm may begin to turn eosinophilic and nuclei are pyknotic(image below) by 24 hours, definite softening and some discoloration may be noted in the gross tissue.Accompanying breakdown of the blood-brain barrier permits edema fluid (plasma) to enter the tissue.


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In a jaundiced individual, bilirubin may brightly discolor the edema around recent cerebral infarction (imagebelow).

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


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In the image above, virtually every cell is a macrophage, though only two are labeled with arrows. They thenremain in large numbers for a variable period after which they decrease greatly (cyst formation). During thesecond week or so (and all of these dates are approximate and overlapping), astrocytes begin to respond tothe infarction in all of the ways described in the chapter concerning the cytopathology of the glia. Reactiveastrocytosis reaches a peak somewhat later than does the increase in macrophages, and large numbers ofreactive astrocytes may remain "forever" at the site of infarcts (rarified zone or cyst).

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

The image below show reactive astrocytosis in the form of dense PTAH stained astrocytic processes at themargin of a cyst.


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The image below shows cysts representing old infarcts.

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

A cyst is the endstage of any mass destruction of the brain irrespective of cause. The reactive astrocytesserve as suppliers of diverse cytokines whose role in the injured brain is yet to be understood. In additionastrocytes produce a substance[s] that induces formation of proteins in capillary walls. These proteinsdetermine various aspects of the blood brain barrier[s]. Newly formed vessels at sites of damage do not havethese new properties and one role of astrocytosis is apparently to transform these leaky new vessels intomore normal brain capillaries with their blood brain barriers. This occurs as the astrocytic end feet apposethemselves to the capillary. But it is not the physical barrier of the endfoot which makes the barrier but ratherthe diverse structural and chemical changes in the capillary endothelium whose expression is triggered bysubstances released from the endfeet.

PLEASE REMEMBER THE GENERAL RULES FOR DATING INFARCTS.


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PINK NEURONS 12-18 HOURS

NEUTROPHILS 24-96 HOURS

MACROPHAGES PEAK AT 7-14 DAYS

ASTROCYTOSIS BEGINS AFTER A PERIOD OF DAYS AND PEAKS AFTER SEVERAL WEEKS

PHAGES BEGIN CLEARING OUT AFTER SEVERAL WEEKS, LEAVING REACTIVE ASTROCYTES

BEHIND, INITIALLY IN GREAT NUMBERSo THUS LOTS OF ASTROCYTES AND RELATIVELY FEW PHAGES MEANS A LESION THAT IS

MANY WEEKS OR EVEN MONTHS OLD

A LESION WITH SHEETS OF PHAGES AND RELATIVELY FEW REACTIVE ASTROCYTES IS 1-2 WEEKSOLD

THESE RULES ABOUT MACROPHAGES AND ASTROCYTES ALSO APPLY TO OTHER DESTRUCTIVELESIONS 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 microscope. But a hemorrhagic appearance

may not be present on gross inspection unless large amounts of red cells have passed through the damagedvessels. Only infarcts with grossly demonstrable hemorrhage are called "hemorrhagic." This is more likely tooccur in infarcts produced by emboli rather than those produced by thrombi. However, red blood cells may beseen even in infarction produced by thrombi. It should be stressed that no matter how large the"hemorrhagic" component of a "hemorrhagic" infarct, the red cells do not form large aggregates or clotswithin the tissue, but instead remain dispersed and finely mixed with the intervening necrotic tissue. This ismost important because it is so different from the character of a true intracerebral hemorrhage with which theinfarct must not be confused. The picture below shows a large empty space which is artifact produced when atrue hemorrhage--a big blood clot which displaced surrounding brain--fell out of the brain slice. the otherlesions are hemorrhagic infarcts--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 is often one of several infarctshaving a similar age. The multiplicity of the infarcts plus their hemorrhagic character helps one arrive at theconclusion that the infarcts were embolic.

Sources of the emboli may vary from the heart or aorta, to the carotid or vertebral arteries in the neck or justentering the skull. Atrial fibrillation is a common cause of hemorrhagic infarcts since embolic atrial breaks off


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from thrombi that often form in the atrium or atrial appendages. This is a major reason for anticoagulatingpersons with persistent fibrillation.

TRANSIENT ISCHEMIC ATTACKS (TIA)

Emboli may fragment or lyse within occluded vessels before they have produced permanent damage to brainor brain blood vessels. Such episodes can produce periods of symptoms lasting only a few hours. Symptomsare often similar from one attack to the next because emboli may lodge repeatedly at the same site. Recentserial imaging studies indicate that a permanent lesion is often--but not always-present in an area producing atransient symptom[s]. It is unclear whether this lesion was present but silent before the TIA . If so it may havebeen simply functionally enlarged but not structurally enlarged by another embolis to the same vessel[s] orby a transient episode of hypotension or hypoxia which affected an already compromised site. It is alsopossible 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 neck vessels will play a role in thedevelopment of embolic phenomena affecting the brain. Atherosclerotic plaques in these vessels mayprovoke local thrombosis especially if the plaque has eroded. Aggregated platelets are an important

component of the local thrombus and these as well as other portions of the plaque may embolize from thethrombus to lodge downstream and produce occlusions that are transient [TIA's] or permanent [infarction] orboth. In addition, pathology in these large vessels or in arteries of the Circle of Willis by thrombi and thusproduce cerebral infarction. Complete occlusion does not always lead to infarction, especially when theocclusion is of a vessel in the neck. That is because the other vessels take over the flow of the occludedvessel, and the large anastomoses of the Circle of Willis permits all regions of the brain to be adequatelyperfused. Large numbers of older persons may be walking around with one vertebral or carotid arteryoccluded. In such cases, the occluded vessel (or vessels) become an "Achilles heel" or point of weakness inso far as the effects of future occlusions, severe narrowings, or drops in blood pressure are concerned. Undersuch circumstances, the presence of one or more already occluded vessels may have exhausted the capacityof the collaterals, and the next 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 a normally functioning brain. Insuch cases, an infarct may occur in the distribution of the vessel with the old occlusion, since this is the

vascular territory with the least collateral reserve.

The importance of atherosclerosis and its complications in neck arteries has led to carotid endarterectomy asa treatment for persons with TIA. The TIA are a warning sign of impending permanent infarction which occursin a disproportionate fraction of such patients as compared with persons without TIA. If an artery is at least70% occluded and the artery is on the side of the lesion producing the TIA, then the patient is an acceptablecandidate for endarterectomy provided the surgical team has a track record with less than 6% combinedmorbidity and mortality from the procedure. In such cases the reduction of future infarcts makes theprocedure statistically worth while. Medical treatment of persons with TIA or persons who have had an infarctfollowing TIA is also worthwhile. This prevents future infarction in a significant proportion of treated patients.Anti-platelet drugs are the drugs of choice with aspirin being the first drug found useful for this purpose.

HYPOXIC ANOXIA OR GLOBAL ISCHEMIA

Unlike thromboemboli plugging individual arteries, hypoxic anoxia produced by respiratory arrest, poisons ortransient total ischemia as seen during cardiac arrest, may produce infarcts in many areas of the brain atonce. Since both cerebral hemispheres will be simultaneously deprived of oxygen by these insults, theinfarcts will be bilateral, and of similar age. Sometimes the basal ganglia and/or thalamus are selectivelyinfarcted. To these hallmarks of global anoxia are added the peculiar pattern of cortical involvement. Ratherthan the wedge-shaped infarct involving both cortex and white matter, which is characteristic of emboli orthrombi, the infarct which follows global anoxia spares (at least relatively) the outermost and innermostcortical layers. Thus, a linear portion of the mid-zone of the cortex is involved, and this pattern of necrosis has


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been called pseudolaminar.

You have now completed the portion of this chapter which concerns cerebral infarction. Before proceeding tothe section concerned with hemorrhage, review the appropriate questions in the pretest and see if you knowthe answers.

CEREBRAL HEMORRHAGEUnlike cerebral infarcts which are caused by blockade of a vessel or by anoxia or ischemia, cerebralhemorrhages are caused by rupture of a vessel or vessels. Among the causes of vessel rupture, trauma andhypertension are probably first on the list. Hypertension may produce hemorrhage by increasing the pressurewithin a pre-existing anatomic defect or by causing damage to the walls of small arteries that make themsusceptible to rupture.

The most common defects are "berry" aneurysms and vascular malformations. The latter may consist ofmasses 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 at points of branching in the arterialtree, usually in the Circle of Willis or at its major branch points. These out-pouchings are thought to occur atplaces where the media and elastica of the vessel display a congenital defect. The aneurysms may vary in sizefrom less than a millimeter to many centimeters in diameter. The larger the aneurysm the more likely torupture. They increase in incidence during the first three decades of life, and are often multiple. Althoughhypertension may increase the incidence of rupture, these aneurysms often rupture in the absence of highblood pressure. The picture below shows the arteries at the base of the brain. The patient had three berryaneurysms [red arrows].

The picture below shows a microscopic section of a berry aneurysm at the neck of the aneurysm. The slidewas stained with a trichrome stain which stains connective tissue blue and smooth muscle red. The normalwas is in the left half of the figure. The aneurysm wall , devoid of smooth muscle, is in the right half of thefigure. The intima of the aneurysm is greatly thickened by an atherosclerosis-like process. This oftenhappens.


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The figure below shows the same aneurysm neck in a section stained with the Verhoef van Giessen stain forelastic tissue. The wavy, black, internal elastic lamella is seen close to the lumen of the vessel wall on the left.It ends abruptly where the aneurysm begins. This change in structure is the key to proving that an aneurysmis truly a berry aneurysm and not simply saccular dilation at a site of atherosclerosis.

The site of aneurysm formation may be determined in part by hemodynamic factors in the circle of Willis--forexample a rudimentary communicating artery which forces more blood to go elsewhere through the Circle.

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

Subarachnoid hemorrhage often leads to an accompanying infarct. The reason why subarachnoid


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hemorrhage causes cerebral infarction is not altogether clear, but may involve interruption of blood supplydue to rupture of vessels, kinking of vessels by the hemorrhage, and spasm of the vessels because of thepresence in the blood of some vasospastic material. Indeed progressive spasm, demonstrable onangiograms, can occur following subarachnoid hemorrhage and/or its surgical treatment. The presence ofsevere generalized spasm is a bad prognostic sign.

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

INTRACEREBRAL HEMORRHAGE

We have mentioned that hypertension may increase the incidence with which berry aneurysms rupture, andmay contribute to rupture of vascular malformations. Hypertension appears to be more directly involved,however, in the major cause of intracerebral hemorrhage, rupture of a small arteriole within the brain.

Hypertension causes fibrinoid necrosis of these penetrating arterioles. The massive intracerebral hemorrhagewhich is a complication of hypertension, arises from rupture of a necrotic arteriole or from rupture of a minute

"miliary" aneurysm formed at the site of necrosis. These aneurysms were first described by CHARCOT andBOUCHARD. The frequency of fibrinoid necrosis and miliary aneurysm formation in vessels within basalganglia and thalamus accounts for the frequency of intracerebral hemorrhage in those locations. Fibrinoid isidentified by its structureless or sometimes granular red appearance on H&E stain and by the fact that , unlikehyalinized smooth muscle which is also eosinophilic, the fibrinoid areas stain with stains for fibrin such asPTAH or Putz stain or with certain trichrome stains. The fibrinoid change in these vessels was calledlipohyalinosis by Miller-Fisher in a very influential series of articles. However that term is confusing becausehyalinized arteries are arteries whose media has undergone a pathologic change which is not fibrinoidnecrosis and which by itself does not lead to rupture. Indeed hyalinized arterioles are common inhypertension. The term lipohyalinosis stresses the presence of fat in the degenerate arteriolar wall but againthis change is not the hallmark of the arterioles that are in danger of rupturing or forming miliary aneurysms.The fibrinoid change is the critical change in these diseased arteriolar segments looks and stains just like thefibrinoid seen in renal and other arterioles in malignant hypertension. The important point to remember is that,

for unknown reasons, the brain arterioles can undergo fibrinoid necrosis even in so-called benignhypertension--that is in patents with only modest blood pressure elevation. For that reason it is important totreat even benign hypertension. The series of pictures below illustrates the pathologic processes that canlead to rupture.

The picture below shows the wall of an arteriole stained with H&E. The amorphous pink [eosinophilic] materialin the wall could be either fibrinoid or amyloid [see section on amyloid angiopathy later in this chapter]. Toprove that it is firbrinpoid the section or its close neighbor should be stained with any one of severaltechniques that stain fibrin [e.g. Putz stain-blue; or the PTAH stain-blue; or a trichrome stain such as the azocarmine stain; the azo carmine is particularly good because it distinguishes fibrinoid from garden varietyhyalinization by staining fibrin/fibrinoid red while staining collagen or hyalinized collagen blue.].


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The section below was stained with azocarmine. An arteriole in the subarachnoid space has an amorphousred material occupying a good portion of its wall. This is fibrinoid. Fibrinoid is frequently segmental indistribution so that the entire circumference may not be involved and other areas along the length of thevessel may also be spared.

The slide below was also stained with azocarmine. The arteriole wall is replaced by red fibrinoid and displaysaneurysmal dilation.


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Sometimes a miliary aneurysm thrombosis rather than ruptures. It then appears as a fibrous ball which maybe separated from the parent vessel due to the plane at which the section has been cut. If the section is closeto the parent arteriole there will be elastic tissue at the margin of the ball. This elastic tissue stains black withthe VVG stain in the pictures below.;


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The pathologist got lucky when the section below was taken. Here a miliary aneurysm that has neenconverted to a fibrous ball or globe is shown in longitudinal section still connected to the parent arteriole by athin neck.

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


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Thus, if the clot were to be dislodged as it sometimes is at the autopsy table, a large cavity is left behind(image below). In this picture there are other hemorrhagic lesions. These are hemorrhagic infarcts. Note thatthe brain, albeit infarcted, is still present in these areas into which there has been leakage of large amounts ofred blood cells.

Necrotic tissue is present at the periphery of the clot, but not within it. The necrosis at the periphery ishistologically identical to that seen in infarcts, and is produced by interruption of the blood supply due tobroken blood vessels, and compression of tissue. When the hemorrhage itself resolves, it does so via the

macrophage, which carries away the blood pigment as hemosiderin.

As resolution occurs, the mass or clot becomes smaller and smaller, and the edges of the displaced tissuearound the clot begin to come closer together. Finally, a linear slit will remain as the only sign of what was alarge oval hemorrhage (image below).


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Residual, hemosiderin-laden macrophages may impart an orange color to the wall of the slit or cyst. In otherwords, if the original hemorrhage is compatible with survival of the patient, the actual tissue damage andresidual symptoms may be considerably less than those produced by an infarct of comparable size, since theinfarcted mass is all dead brain, while the original hemorrhage destroys brain only along the path cleaved bythe hemorrhage and at the periphery of the mass of blood.

LOBAR HEMORRHAGE

In hypertensive hemorrhages the hemorrhage is generally in the basal ganglia or pons. The arteries to theseareas are short branches from more major vessels and so the pressure within them is relatively high. Thus thelocation of the microvascular changes in these portions of the vascular tree suggests that blood pressurelevel has something to do with the fibrinoid degeneration. In contrast, there are hemorrhages in the peripheralportions of the various "lobes" of the cerebrum--e.g. frontal lobe or occipital lobe. These hemorrhages are

called lobar to distinguish them from more centrally located hypertensive hemorrhages. Their cause is usuallydeposition of beta A4 amyloid--the same amyloid as is deposited in Alzheimers disease. They tend to occur inindividuals over 60 years old. Fibrinoid has also been reported in adjacent vessels in such cases. Suchreports deny the presence of hypertension in these people. If true, then this would represent the only entitiyother than hypertension in which arterioles of the brain have undergone fibrinoid necrosis.

TEST YOUR KNOWLEDGE ABOUT HEMORRHAGE BY REVIEWING THE PERTINENT QUESTIONS IN THEPRETEST AT BEGINNING OF CHAPTER.

Unfortunately, death often results from intracerebral hemorrhage during its acute or subacute stages. Thisdeath is caused by the increased intracranial pressure produced either by the hemorrhagic mass itself or bythe associated cerebral edema. The final common pathway to death (increased intracranial pressure) is thenidentical to that often seen in infarction, brain trauma and tumor. Since increased intracranial pressure

produced by edema is often the ultimate cause of death in cerebral vascular disease, and since edema is, initself, a basically vascular phenomenon, it seems appropriate to discuss it here in greater detail.

CEREBRAL EDEMATYPES OF EDEMA--There are 2 major types of edema--cytotoxic or intracellular on the one hand andvasogenic on the other. Since edematous tissue must show a net increase in water to meet the definition ofedema, cell swelling alone cannot cause edema unless the volume of the swollen cells occurs withoutequalizing diminution of the extracellular space, as might occur if the swollen cells encroached upon and


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squeezed that space. Animal studies suggest that cellular swelling of that magnitude can occur and thiswould be true cytotoxic edema. Cell swelling, presumably of both astrocytes and neurons begins within 30seconds of hypoxia due to disabling of ionic pumps by the energy shortage produced by hypoxia. It is unclearwhether cytoxic edema by itself can produce significant increases of intracranial pressure during infarction. Inany case within hours the venules and capillaries become leaky and both protein and water leak into the

extracellular space. This is vasogenic edema. It is responsible for the morbidity and mortality of infarction,hemorrhage, infections, etc. because the increased intracranial pressure compromises the brains function asexplained in the section below concerning herniations.

Present therapy of edema consists primarily of infusion of hypertonic solutions into the blood stream. Thesesolutions contain large molecules which cannot easily leave the blood stream. The rationale for this therapy isthe idea that such fluids will retard the leakage of vasogenic edema fluid from the vessels and cause edemafluid to move from the tissues back into the vascular compartment. However, oncotically active substanceslike mannitol will leave the leaking vessels, therefore the actual removal of brain water in patients treated withthese solutions, is from the areas with intact vessels. Because the skull is relatively sealed this removal ofwater will reduce overall intracranial pressure. In addition. it has been found in experimental studies, thatsuch fluids may reduce intracranial pressure by another means: hemodilution, which decreases hematocrit,blood viscosity and shear. Decreased shear reduces the release of dilating local hormones [e.g nitric oxide]

from the endothelium This reduction in local dilators causes vasoconstriction and thus decreasesintravascular volume within the skull. The decreased intravascular volume decreases intracranial pressure.

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

CONSEQUENCES OF EDEMA:

As suggested above, the most common cause of edema that produces brain swelling with a clinicallyimportant elevation of intracranial pressure is either endothelial injury in capillaries and venules or moremassive damage to blood vessels. This edema is VASOGENIC edema. For reasons that are not definitelyestablished, the edema fluid, which is initially comparable to blood plasma, passes predominantly into whitematter, rather than grey. This is true even when the lesion is in the grey, so that the edema fluid enters thebrain at that point. The fluid may travel considerable distances in the white matter.

The image above illustrates some inportant points about vasogenic edema. Fortuitously the edema in the picture has been


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stained green by bilrubin in the plasma which leaked out of the vessels. Formalin changed it to biliverdin which is green.Note the color appears to spare [almost] the arcuate zones [arrows] of white matter which underlies the cortex. We are notsure why the arcuate zone is relatively spared by vasogenic edema. In any case, edema can not only cause brain swellingbut, by interfering with white matter nutrition, it can cause degeneration of the affected white matter. If the patientsurvives, the affected areas of white matter become rarified or cystic and the borders of the original lesion, for example aninfarct or a contusion, are extended by the adjacent zone of damage produced by the edema. These areas of extension are

characterized by the fact that they occupy the deeper white matter coniguous with the original lesion and spare the arcutezone--also known as the "U" fibers.Vasogenic edema is the only basic pathophysiologic process known to distribute itselfin the deep white matter with relative sparing of "U" fibers.So when we see a cystic or semicystic lesion whoseboundaries 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 is surrounded by greatly expanded whitematter, the expansion of which was caused by edema fluid entering where blood brain barrier broke down near theabscess, and spreading great distances between myelinated white matter axons.

The image above shows a great increase in white matter mass especially on the right. There is a brain tumorin this hemisphere but most of the tumor is in adjacent slices. The edema fluid is spreading through whitematter remote from the source which is at leaky vessels within the tumor. The increased mass within the


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edematous hemisphere causes a bulging and flattening of the cerebral surface, unless a defect is present inthe skull. In the latter case, the surface beneath the defect simply protrudes through the defect, while theremainder flattens against the inner aspect of the intact skull.

HERNIATIONS

Not only can an edematous brain herniate through a hole in the skull, but shifts of cerebral tissue can alsooccur within the skull. When one hemisphere is swollen, it may be displaced toward the opposite side of theskull and a portion of the cingulate gyrus may be forced under the falx. Similarly, the temporal lobe may beforced downward and a portion of its medial aspect may be forced under the tentorium. This portion of thetemporal lobe is called the uncus, and the term "uncal herniation" is applied to this lesion. Prior to the stageof herniation, the uncus may be pushed against the sharp edge of the tentorium causing the tentorium tomake an "uncal groove" along the medial surface of the temporal lobe. A swollen hemisphere may also forcethe brainstem toward the opposite side of the skull producing a notch in the contralateral peduncle where it iscompressed against the edge of the tentorium. This is known as Kernohan's notch. These compressions arenot merely morphologic alterations, but are accompanied by malfunction of the compressed tissue. Inaddition, cranial nerves or vessels may be compressed by the swelling or displaced brain. For example,compression of posterior cerebral arteries may produce infarcts in the distribution 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 the consequences of an accompanyingedema, produce a second infarct in a distant part of the brain. Increased intracranial pressure can also causethe brain stem to herniate downward in an attempt to relieve pressure through the foramen magnum. Whenthis occurs the vessels to the stem are stretched and tear. This produces secondary brain stem hemorrhage.The hemorrhage and/or related damage to vital cardiorespiratory centers in the brain stem results in deathand this is frequently the ultimate cause of death in patients with infarct, hemorrhages, traumatic injuries, etc.which originally affected only the cerebrum.

THE FIGURE ILLUSTRATES A SECONDARY BRAIN STEM HEMORRHAGE.

TEST YOUR KNOWLEDGE ABOUT CEREBRAL EDEMA BY REVIEWING PERTINENT QUESTIONS IN THEPRETEST.DEMYELINATING DISEASES; LEUKODYSTROPHIES; STORAGE DISEASES INVOLVING MYELIN OR NEURONS


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This chapter contains four interrelated sections. They are related because some diseases of myelin are storagediseases and some storage diseases involve 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 enzyme normally found in lysosomes, orsometimes in peroxisiomes. Each enzyme deficiency disease is characterized by its own enzyme deficiency, but thefact that lysosomal enzymes are involved has led many writers to lump these diseases together as lysosomal

disorders. The problem with this method of classification is that it loses the distinction between diseases primarilyaffecting grey matter [neuronal cell bodies] and diseases primarily affecting white matter [myelin]. Since this anatomicdifference helps make a diagnosis when the brain is examined by imaging or at autopsy and also has some effect onearly symptoms, we prefer to emphasize the older classification of white matter diseases [ADE, MS andleukodystrophies] on the one hand and the other storage diseases which have been called neuronal lipidoses on theother. Indeed a traditional term for the neuronal storage diseases has been the term "lipidoses". Because of thepathogenetic similarity between some of the leukodystrophies [white matter lipid storage or lysosomal disorders ofwhite matter] and the neruonal lipidoses [lysosomal disorders] we have included a section concerning the latter in thischapter.The other three sections are:

Section 2 - Multiple SclerosisSection 3 - LeukodystrophiesSection 4 - Neuronal Lipidoses

Section 1: Acute Disseminated Encephalomyelitis (ADE)

PRETEST: Answers in text of this section

1. Describe the microscopic hallmark of ADE.2. What type of cells are present in the infiltrate?3. What are some causes of the disease?

PATHOLOGYAcute disseminated encephalomyelitis and postvaccinal encephalomyelitis are apparently identical entities, sometimesalso known as postinfectious encephalomyelitis. As these names indicate, the disease sometimes occurs followingvaccinations (e.g., for small pox) or after viral infections. Although it is not entirely clear, the lesions in both cases areprobably produced by some immunologic mechanism involving a neural antigen and an antibody. In the case of thepostvaccinal variant, the body's exposure to the antigen will occur if the vaccine was prepared in neural tissue. Thelesions are demyelinating, hence, if the immunologic theory is correct, the antigen is probably a component of myelin.The demyelination in acute disseminated encephalomyelitis occurs in a perivenular distribution. Thus, in cross orlongitudinal section, lesions have a venule in their center. This is seen in the image below which is stained blue-blackfor myelin, and which displays the lesions as unstained zones of pallor (x's). The lesions may be confluent, and asindicated in the image, a mononuclear infiltrate is found around the vessels. This infiltrate of monocytes andlymphocytes participates in the immunologic events that produce the disease.
http://www.pathology.vcu.edu/WirSelfInst/MS.htmlhttp://www.pathology.vcu.edu/WirSelfInst/leukodys.htmlhttp://www.pathology.vcu.edu/WirSelfInst/lipidoses.htmlhttp://www.pathology.vcu.edu/WirSelfInst/MS.htmlhttp://www.pathology.vcu.edu/WirSelfInst/leukodys.htmlhttp://www.pathology.vcu.edu/WirSelfInst/lipidoses.html


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EXPERIMENTAL ALLERGIC ENCEPHALOMYELITISAn experimental model of the disease may be provided by experimental allergic encephalomyelitis (EAE), ademyelinating disease produced in animals by immunizing them with neural tissue. In addition to EAE, a disease of theCNS, produced in response to CNS antibodies, a demyelinating disease of peripheral nerve can be produced inanimals by immunizing them with antigens derived from peripheral myelin. This experimental disease is calledexperimental allergic neuropathy (EAN). In EAE and EAN it has been shown that the demyelination can be preventedor arrested by agents that kill macrophages (monocytes) or inhibit some of the proteases released from activatedmacrophages. Others have shown that EAN is enhanced by increasing the permeability of blood vessels to cells whichcan 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?

PATHOLOGY1. Demyelinating, but axonal injury is also important2. CNS only - not peripheral nervous system - reason unknown but probably reflects different antigenic makeup of theperipheral vs central myelin.

3. Preservation of axons is relative, but important in progressive disease. The lesion of myelin loss with relative axonpreservation is well circumscribed and is called a plaque.


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4. On gross inspection, plaques are circumscribed, grey or translucent, often juxta ventricular.Myelin stains display these areas, called plaques, as circumscribed unstained zones of pallor (image below).Oligodendroglia are markedly diminished within the mature plaque [arrows demarcate loss of myelin below].

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

In "young" plaques with active demyelination, the myelin debris is present in macrophages, which then stain for fats.The fat-laden macrophages carry away the fat by passing into the perivascular spaces (Virchow-Robin), which areextensions of the subarachnoid space. As plaques grow, their centers may be free of macrophages which then appearonly at the actively expanding perimeter of the lesion. Quiescent plaques contain no lipid-laden macrophages. Duringor following myelin breakdown, astrocytes proliferate within the plaque and astrocytic processes increase in length andnumber. The ultimate degree of astrocytosis is quite variable. Marked astrocytosis imparts a firmness to the plaque inthe 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 the contrast between the plaque and the densely


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myelinated normal background, plaques also occur in grey matter since all CNS axons are myelinated along theirentire course.Perivascular infiltrate of lymphocytes and monocytes is found in fresh or actively growing plaques.Axon degeneration also occurs in plaques and may begin early. Progression of disease is related to increasingamounts of axonal damage.PATHOGENESISSome workers believe the lymphocytes and monocytes participate in the destruction of the myelin, which is mediatedby an antibody bound to the mononuclear cell and directed against a myelin antigen. Indeed the presence of a venulewith a monocytic\lymphocytic perivascular infiltrate near the center of fresh plaques bears a resemblance to the lesionof acute disseminated encephalomyelitis, a known immunomodulated demyelinating disease of CNS. This similarityhas been used to support the hypothesis that MS is an immuno disease.

Moreover certain immuno-modulating drugs have been affective in slowing or arresting disease progression. On theother hand, much circumstantial evidence suggests a ling to some infectious agent, possibly a virus. This evidenceincludes a geographic distribution favoring a vector--such as an insect--which likes temperate as opposed to tropicalclimates. In addition, MS patients and their close relatives have been found to have excessive antibody titers toseveral different viruses including measles. Similar populations have also been reported to have characteristic patternsof histocompatibility markers which might explain persistent antibody in such people. These facts--sometimes disputedas 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 which shares epitopes with the virus and so isattacked by the persistent antibody to the virus;[3] or the attack is on some other cell which releases [or the attacking cell releases] cytokines that attack meylin--aninnocent "bystander" theory.

Some support for molecular mimicry concept comes from a peripheral nervous system disease. That disease is oneform of Guillain Barre disease in which the patients have had a preceding infection with campylobacter jejuni. Theorganism has a ganglioside that mimics one in the peripheral nerve leading to an immuno attack on the latter as thebody fights the infection.

Some support for the innocent bystander concept comes from a demyelinating disease or peripheral nervous systemthat devastates flocks of chickens. This is Marick's disease where cells attacking one site in the nerve releasecytokines that attack innocent adjacent Schwann cells.

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

REMISSIONSMS is usually characterized by remissions and exacerbations. The reason for remissions is not well understood butagain may have something to do with the interweaving of the pathogenic pathways discussed above. The ability toremit may depend upon preservation of axons and possibly on minimal remyelination sufficient to restore the capacityto conduct. However, inflammation in early plaques is accompanied by local leaks from vessels and edema. Thewaxing and waning of edema in and around the plaque had been thought by some workers to account for the ups anddowns of the clinical picture but MRI studies have failed to find the correlation between edema or leaking vessels and


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clinical status.

It is also possible that inflammatory cells release substances that impair transmission and wax and wane. In addition,an increased number of sodium channels develops after axons lose their myelin. These axons then resembleunmyelinated axons and can conduct electrical impulses. However, if an adaptive increase in sodium channels

accounts for remissions in MS, we have no explanation for recurrence of identical symptoms unless (A) they are reallydue to new plaques, or (B) there is an intermittent factor which inhibits transmission.

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

Two other diseases are thought to be related to MS or to be variants of that disease.DEVIC'S DISEASEThe first of these, Devic's disease or syndrome, is also known as neuromyelitis optica, a name which emphasizes thepreferential distribution of the lesions in the spinal cord and optic nerve. Pathologically, in many cases, the lesions areindistinguishable from those of MS. However, in a subgroup of cases, the lesions differ from the usual MS lesions inthe following respects: axons are destroyed as well as myelin, and a marked acute inflammatory cell infiltrate(polymorphonuclear cells) is present. Some workers believe that these lesions 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 supposedly described it. The same disease namehas also been applied to a form of leukodystrophy [adrenoleukodystrophy] which leads to confusion. In the context ofMS, the term Schilder's disease should be dropped and one should simply speak of hyperacute MS.

The hyperacute disease is characterized by massive degeneration of white matter--both myelin and axons, withprofound astrocytosis. We can only relate this to MS by observing, in the same patients, relatively spared areas ofCNS that have more typical MS plaques.

This chapter contains four interrelated sections. They are related because some diseases of myelin are storagediseases and some storage diseases involve 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 enzyme normally found in lysosomes, orsometimes in peroxisiomes. Each enzyme deficiency disease is characterized by its own enzyme deficiency, but thefact that lysosomal enzymes are involved has led many writers to lump these diseases together as lysosomaldisorders. The problem with this method of classification is that it loses the distinction between diseases primarilyaffecting grey matter [neuronal cell bodies] and diseases primarily affecting white matter [myelin]. Since this anatomicdifference helps make a diagnosis when the brain is examined by imaging or at autopsy and also has some effect onearly symptoms, we prefer to emphasize the older classification of white matter diseases [ADE, MS andleukodystrophies] on the one hand and the other storage diseases which have been called neuronal lipidoses on the

other. Indeed a traditional term for the neuronal storage diseases has been the term "lipidoses". Because of thepathogenetic similarity between some of the leukodystrophies [white matter lipid storage or lysosomal disorders ofwhite matter] and the neruonal lipidoses [lysosomal disorders] we have included a section concerning the latter in thischapter.The other three sections are:

Section 1 - Acute Disseminated EncephalomyelitisSection 2 - Multiple SclerosisSection 4 - Neuronal Lipidoses
http://www.pathology.vcu.edu/WirSelfInst/ADE.htmlhttp://www.pathology.vcu.edu/WirSelfInst/MS.htmlhttp://www.pathology.vcu.edu/WirSelfInst/lipidoses.htmlhttp://www.pathology.vcu.edu/WirSelfInst/ADE.htmlhttp://www.pathology.vcu.edu/WirSelfInst/MS.htmlhttp://www.pathology.vcu.edu/WirSelfInst/lipidoses.html


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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 which leukodstrophy.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] or dysfunctional [in other cases] larylsulfatase. As a result, sulfatides are not broken 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 hasgiven the disease its name.

In fully developed lesions, oligoglia are sparse or absent. Presumably they were adversely affected by the metabolicdefect and/or storage of sulfatide. The injury to oligoglia is thought to account for the disappearance or absence ofmyelin, since these glial cells normally form the myelin.

In addition to myelin loss, axon loss is often severe (presumably a secondary effect of myelin loss or glial injury) andastrocytosis is marked.

KRABBE'S DISEASE OR GLOBOID LEUKODYSTROPHY

Krabbe's disease is characterized by deficient galactosidase and accumulation of galactocerebroside in some cells.

However, unlike typical storage diseases, overall tissue levels of the affected lipid are not increased, and this factprovides us with one additional reason for maintaining the leukodystrophies as a separate nosologic entity.

Moreover, the accumulating cerebroside may not be the cause of tissue destruction. Instead, levels of psychosine, atoxin, are increased during the abnormal metabolism and may be responsible for the damage.

As in other leukodystrophies, cases of Krabbe's disease display degenerated white matter, with absence or diminutionin myelin, loss of axons, loss of oligodendroglia and astrocytosis.

The galactocerebroside is stored in macrophages which may cluster together or fuse to form diagnostic "globoid"bodies (image below) which give the disease its name. Arrows delineate such a body on the image below. Injections ofcerebroside into the brains of animals produce similar bodies. This effect is not produced by injections of other brainlipids.

Recently doctors have successfully treated infants at risk for globoid leukodystrophy by intravascular injection of cordblood 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 treat enzyme deficiency diseases by injecting the patient with enzyme. In thelatter situation enzyme may not pass the blood brain barrier and, moreover, the recipient may develop antibodies tothe protein thereby nullifying its effect.


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CANAVAN'S DISEASE

The next disease we will discuss is Canavan's disease or spongiform leukodystrophy. This disease involves all thewhite matter, but particularly the "U" fibers or arcuate zone which lies immediately beneath the cortex. The affectedarea is demarcated by Xs in the image below. An enzyme defect has been uncovered in this very rare disease. Thedeficient enzyme , acetylaspartase, breaks down N-acetylaspartic acid. The latter is an important constituent ofneurons. Since the enzyme which breaks it down is missing, the aspartate builds up in the neurons. However, theaspartase is not localized in the neurons. Instead it is found in the oligodendroglia. Hence the aspartate is normallytransported down the axons, and in some way is made available for breakdown by the oligodendroglial enzyme. Whythe absence of the enzyme in the latter should lead to myelin breakdown is not known. But it has been postulated thatthe accumulation of the aspartate in the white matter leads to increased osmotic pressure there with consequentdrawing of water into the surrounding tissue. It has been further postulated that in some way this leads to thedegeneration of the myelin.

The disease is presented because it illustrates the fact that all leukodystrophies are not caused by intraneuronal or


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intraglial storage per se and because its pathology 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 becomingwidely separated. An electron microscopic picture of the large spaces between widely separated myelin lamellae isshown above. The large spaces appearing between the billowing lamellar sheets are the cause of the spongyappearance seen with the light microscope. It is the sponginess of the tissue that has given the disease one of itsnames.

ALEXANDER'S DISEASE

The last disease we will discuss is Alexander's disease. This rare leukodystrophy exists in several forms, dependingupon the age of onset. In several forms abnormalities in the gene coding for glial fibrillary acidic protein have beenfound. This is the first disease in which the gene for GFAP has been implicated. This may explain a characteristicfeature of the disease which is the accumulation in the degenerated white matter of large numbers of Rosenthal fibersand eosinophilic granular bodies. These structures are large accumulations of astrocytic processes "clumped"together.

However, they are not specific for this disease and also accumulate in conditions where there has been prolongedproliferation of astrocytes--for example in slow growing or benign astrocytomas like pilocytic astrocytomas where theyhelp the pathologist to make the diagnosis. In Alexander's disease the relationship, if any, of the astrocytic abnormalityto the degeneration of myelin or its failure to form normally, or to the selection of white matter as the preferential targetof the disease, has not been elucidated.

PEROXISOMAL DISORDERS

The peroxisome is another ultrastructural cytoplasmic organelle that contains catabolic enzymes. The deficiency ofone of these enzymes leads to adrenoleukodsytrophy. This disorder is characterized by characteristic curvilinearbodies in affected adrenal cells and brain cells which are swollen contain stored very long chain fatty acids.

TESTING PATIENTS AND PROSPECTIVE PARENTS

Discovery of the enzymatic defect is extremely important. These defects are expressed in many cells, e.g., white bloodcells or cells in amniotic fluid. Examination of these cells provides a rapid, definitive means of diagnosing the diseaseand often its carriers. These facts provide a basis for genetic counseling and for informed decisions concerning


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termination of pregnancy.

Section 4: Neuronal Lipidoses


1. What is the most common lipidosis involving the brain and what enzyme 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 which are characterized by progressiveneurologic and mental deterioration, often with a fatal prognosis. Recent discoveries have provided understanding ofthe pathogenesis of these diseases and have also provided a means for detecting carriers 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 to leukodystrophies and their enzyme defects or perhaps to lysosomal and also peroxisomaldiseases with their enzyme defects. The latter method of classification emphasizes the fact that the missing ordefective enzymes in lipidoses and in leukodystrophies are almost always in either the lysosomes or peroxisomes.

This image below illustrates the appearance of neurons in a neuronal lipidosis. The cell bodies are ballooned orswollen by the poorly stained lipid. Sometimes they may appear to be almost empty. Special stains may sometimesdistinguish one type of storage disease from another, but with ordinary hematoxylin and eosin staining as illustratedhere, 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 ofJews of European origin has resulted in virtual disappearance of the disease in America due to the benefits of geneticcounseling based upon diagnosis of carriers or of affected fetuses. The test looks for the enzyme hexoseaminidase A,whose deficiency results in storage of a GM2 ganglioside.

Electron microscopy reveals lamellated bodies within the neuronal cytoplasm. These are formed by the stored lipidand vary somewhat in appearance depending upon the disease. In Tay-Sachs disease, they take the form of the


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concentric rings shown in this image.

CHERRY RED SPOT

One clinical sign of great notoriety is the "cherry red spot" in the retina of patients with Tay-Sachs disease and someother neuronal lipidoses. It is produced when ganglion cells, filled with lipid, degenerate, thereby exposing the vascularchoroidal tissue behind these cells. The blindness ("amaurosis") produced by retinal involvement, together with themental deterioration produced by destruction of other neurons, has given Tay-Sachs disease the name "amauroticidiocy."

MEDICAL GENETICS

Most lipidoses appear to have a high familial incidence. Recent discoveries concerning the enzymatic basis of thesediseases have provided a means not only 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 fortesting. This is true for all the lipidoses and leukodystrophies for which there is a defined enzyme deficiency. Theenzymatic activity of heterozygote materials is intermediate between that of normal subjects and the very low levels ofhomozygotes, who are, of course, symptomatic, or in the case of affected fetuses, doomed to get the progressivelethal 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
http://www.pathology.vcu.edu/WirSelfInst/INF%20PT2.htmlhttp://www.pathology.vcu.edu/WirSelfInst/INF%20PT3.htmlhttp://www.pathology.vcu.edu/WirSelfInst/INF%20PT4.htmlhttp://www.pathology.vcu.edu/WirSelfInst/INF%20PT2.htmlhttp://www.pathology.vcu.edu/WirSelfInst/INF%20PT3.htmlhttp://www.pathology.vcu.edu/WirSelfInst/INF%20PT4.html


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PRETEST: Answers can be found in the text of this section1. What are the coverings of the brain?2. What are the portals by which infectious organisms can enter the brain 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 or meninges. The thin (or "lepto")meninges are the innermost coverings and consist of two distinct membranes.

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

The second component of the leptomeninges is the arachnoid membrane. This membrane is external to the pia materand connected with it by delicate trabeculae. The space between the pia mater and the arachnoid is called thesubarachnoid space. This space is filled with cerebrospinal fluid, and it is this fluid which is sampled when a spinalpuncture is performed. The surface blood vessels 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 the leptomeninges. It is known as the dura materand is tightly applied to the bones of the skull. Over the spinal cord, the dura is separated from the vertebral column bya space which contains adipose tissue and blood vessels. For this reason, epidural abscesses occur more readily herethan inside the calvarium. In addition to the leptomeninges and the dura, the bony coverings of the brain and spinalcord and the skin form the outermost defenses of the central nervous system.

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. In addition, monocytes enter the wound orlesion and form macrophages which carry away the necrotic debris.

The astrocytes may increase in number, may become larger, and may increase the length and numbers of theirprocesses. However, astrocytic processes do not 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 down collagen to form a wall aroundbacterial invaders. Thus, abscesses within the brain 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 smoldering subacute or chronic infections of thesubarachnoid space and can actually impede or block flow of CSF to the point of producing hydrocephalus.Hydrocephalus may also be produced by a ventriculitis, which may cause inflammation, necrosis, and desquamationof the ependyma (the cells lining the ventricular system) at the level of the aqueduct of Sylvius.

In such cases, the inflammation produces hydrocephalus by causing aqueductal stenosis, thereby reducing drainageof CSF from the lateral ventricles and third ventricle, and increasing the cerebrospinal fluid pressure in theseventricles. Since the communication between the anterior and posterior portions of the ventricular system iscompromised by aqueductal stenosis, the rise in pressure may not be detected by a spinal puncture because such a


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puncture enters the subarachnoid 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 CNS infection. Otitis media may still be the leadingcause of brain abscess. Spread of infection 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 thecalvarium from the scalp may also occur via the emissary veins.

Another common direct source of infections results from trauma such as bullet 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 enterthe 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 for the majority of CNS infections.

THE PURULENT REACTION

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


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LEPTOMENINGITIS

A brain with severe meningitis is shown in the image above. Note that the creamy pus completely obscures theunderlying cortex in some areas. Pus also tends to collect in the cisterns at the base of the brain. Purulent meningitisis by far the most common CNS infection. Though antibiotics have not materially decreased its incidence, they havemarkedly increased survival and reduced the complications of this disease.

COMPLICATIONS OF MENINGITIS

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

This fibrosis may also cause CSF to loculate into arachnoid cysts which may produce pressure effects like a tumor.


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The cranial nerves may be involved with infection or strangled by reactive connective tissue.

BRAIN ABSCESS

The incidence of brain abscess has been markedly lowered since the antibiotic era. As would be expected, they are

found more frequently in individuals who are susceptible to general infection such as diabetics, alcoholics, debilitatedand immunosuppressed patients, and the elderly. They are also noted with increased frequency in infants withcyanotic heart disease.

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

The image above shows a large abscess in the brain. The purulent center is surrounded by a capsule. Often a zone ofhyperemia is present adjacent to the wall and there is marked swelling of the adjacent brain tissue.

The evolution of the abscess is as follows:

An area of cerebritis begins, in which polymorphonuclear leukocytes are attracted to the invading bacteria.

Liquefaction of brain tissue rapidly ensues, and at the periphery, a thin rim of granulation tissue composed ofnew capillaries and fibroblasts is formed.

With time, a connective tissue capsule is formed by collagen laid down by infiltrating fibroblasts. Often this ismore perfectly formed on the outer aspect of the abscess, presumably due to the contribution of the reservoirof potential in the adjacent meninges.

Due to the poor encapsulation of the medial aspect of an abscess, which abuts upon or is located within thecerebral white matter, the infection tends to form daughter or satellite abscesses medially which may

eventually rupture into the ventricular system. Such rupture may lead to rapid death, and in any event, is usually followed by severe ventriculitis and massive

meningitis as infected CSF pours into the subarachnoid space.

Antibiotic therapy greatly decelerates the growth of an abscess, and may allow time for a complete capsule to formafter which the abscess may be removed surgically.


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The image above reviews the basic structural features of a brain abscess from the histologic point of view. It illustrates(A) the purulent, necrotic center, (B) the thin 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 treponema pallidum?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 paras

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