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Neuropathology For Medical Students > Section 3 Granulomatous Infections


Presented by William I. Rosenblum, MD
Materials in This Chapter Provided by MG Hadfield, MD



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

Section 1 - General Features
Section 2 - Purulent infections
Section 4 - Viral infections, Rickettsial Infections,Prion Diseases

Section 3: Granulomatous Infections

PRETEST: Answers can be found in the text of this section or click on link at end of questions

  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 parasitic lesion of the brain which can be transmitted via the placenta and may cause  as granulomatous response with periventricular calcification?



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

Even when specific antibiotic therapy is available, it is difficult to eradicate granulomata, therefore, granulomatous meningitis frequently leads to fibrosis within the subarachnoid space, and blockade of this space with consequent increase in intracranial pressure and hydrocephalus. In addition to meningitis, organisms causing a granulomatous response can also produce discrete granulomas within the brain or spinal cord, or there may be a more diffuse granulomatous reaction throughout the nervous system. 

Granulomatous reactions are caused by a wide range of micro-organisms. The more important ones which invade the CNS will be covered in the following paragraphs.


Fungal infections are currently the most frequently encountered granulomatous infections of the CNS and appear to be increasing with our ability to maintain debilitated patients, the use of immunosuppressive therapy and the advent of AIDS. Fungi may cause a granulomatous meningitis and granulomata or "abscesses" in the brain.

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


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


Often, for reasons not completely clear, cryptococcal necrosis may produce a minimal inflammatory reaction. Among other fungi seen are coccidioides (southwestern U.S.), histoplasma (Ohio River Valley), blastomyces, candida, nocardia, aspergillus and mucormyces.


Spread to the brain is frequently miliary and it is thought that tuberculous meningitis occurs when a miliary tubercle near the surface of the brain bursts into the subarachnoid space. This chronic meningitis leads to obliteration of portions of the subarachnoid space and a high incidence of hydrocephalus. The organizing meningeal exudate may constrict cranial nerves and cause thrombosis of cerebral vessels. Sometimes, miliary tubercles can be seen studding the subarachnoid space (arrows, image below).


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


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

The histologic picture of tuberculosis is seen in the image below. A tubercle is illustrated, with a central core of homogeneous caseous necrosis, surrounded by mononuclear cells, histiocytes, epithelioid cells and giant cells (arrows). Thus, in the central nervous system, the histopathology of TB is identical to that seen in other organs. Caseation is not always found in tuberculous lesions but it is far more frequent than in granulomata of non-tuberculous origin.



Sarcoidosis generally produces a chronic granulomatous meningitis in the CNS. It may be indistinguishable from that of tuberculosis, though caseation is usually absent. It not infrequently involves the hypothalamus and may lead to diabetes insipidus, etc. Although classified here as an infectious disease, no organism has been isolated as the cause of sarcoid and it is not known to be spread from person to person.


The lepra bacillus has a predilection for peripheral nerve and the granulomatous reaction may increase the diameter of the nerve several times so that it is easily palpated. Loss of sensation results in damage to extremities, including loss of digits, etc.


The dementia, psychosis, and spinal cord disease produced by late tertiary syphilis are rarely seen at present, thanks to penicillin. However, the classic picture described here may not represent a curiosity, but rather a specter whose reappearance may follow the current increase of sexually transmitted diseases. Three major types of CNS syphilis will be illustrated. Although we have grouped syphilis with the granulomatous diseases, it will be seen that (except for the particularly rare gumma) the histologic response to the spirochete (T. pallidum) causing this disease is characterized by lymphocytes and plasma cells rather than by the histiocyte or epithelioid cell which predominates in granulomatous reactions.


Here, the involvement is primarily of the meninges, subarachnoid spaces and vessels, while the substance of the brain and cord are relatively spared. There may be a diffuse basilar meningitis and hydrocephalus. The surface vessels may be surrounded by lymphocytes and plasma cells (image below).



The vessels  may show marked endothelial thickening (Heubner's endarteritis obliterans) as well as thickening of the media and adventitia (image below).



In paresis, otherwise known as paretic dementia (or general paralysis of the insane), the brain is shrunken and firm. The frontal convolutions are atrophic and there is diffuse thickening of the leptomeninges. The cerebral atrophy is due to loss of neurons. There is a diffuse astrocytosis. Most characteristically, there is a diffuse increase of the microglia (rod cells). Three of these cells, especially impregnated with silver (Hortega) stain, are shown in the first of the two images below (arrows), but this relatively high power view cannot convey the impression of the tremendous numbers of microglia seen in this condition. Indeed, while not unique to paresis, microglial proliferation is probably more pronounced in syphilis than in other conditions. The tremendous number of microglia are illustrated in the low power view in the second of the pictures




Here the most prominent consequence of the syphilitic attack is seen in the spinal cord where the dorsal columns are demyelinated (image below).


 However, the pathogenesis of the lesion is probably related to an attack by the spirochetes on the dorsal roots rather than the spinal cord itself. The dorsal columns then undergo Wallerian degeneration. Thus, an inflammatory response is sparse or absent within the cord. Due to the loss of the sensory fibers carried in the posterior columns, this patient walked with a typical slapping gait which resulted in severe injury to his knee joint (Charcot's joint).


Subclinical infection in adults is high since this parasite may be acquired by eating raw meat and is present in the excreta of cats and other feline species. The organisms may be passed transplacentally to the fetus. Toxoplasmosis is usually much more severe in infants than in adults. It is typically characterized by foci of calcium (arrows, image below) which can be visualized on X-rays. Histologically, there is a marked granulomatous reaction.


The organism may be seen in cysts within the brain tissue.



Last Updated 15-May-2007