Surgical Neuropathology of Non-neoplastic CNS Disorders
Moderators: Teresa Ribalta and Gerard H. Jansen
Section 4 -
Surgical Pathology of Infectious Diseases
Department of Anatomical & Cellular Pathology
The Chinese University of Hong Kong
This review will discuss the practical scenarios encountered for differential diagnosis of infectious
diseases of the brain in the setting of surgical pathology and will focus on the common
rather than the esoteric. It will emphasize main points of diagnosis rather than review individual
disease in details.
Brain biopsy has to be the last resort in the diagnostic workup for infectious diseases. With the
widespread availability of PCR techniques for CNS infections in microbiology /clinical pathology
laboratories, the role of brain biopsy must be carefully weighed in each clinical situation. For
example, detection of herpes viral DNA in CSF by PCR will usually lead to anti-herpes treatment for
herpetic encephalitis rather than necessitating a brain biopsy as in the past. However, the diagnostic
significance of detecting viral sequences in brain tissues is sometimes uncertain and JC (for progressive
multifocal leucocephalopathy) and herpes virus sequences can be detected in apparently normal individuals
as a result of viral latency . Close correlation with clinical and imaging information is necessary
for interpretation of results.
In general, situations requiring brain biopsy for potential infectious diseases is divided into those
with mass lesions, which may be single or multifocal and those with a diffuse process.
Abscesseses, cerebritis or granulomas due to bacterial or fungal infections may closely mimic tumours and
may lead to brain biopsy or resection as focal or mutlifocal lesions. Mass effect, perifocal oedema
and contrast enhancement are present in both tumour and infectious lesions posing uncertainty in clinical
diagnosis. Diffuse Weighted Imaging (DWI) is proving to be a useful diagnostic tool for differentiation
 between infectious focal lesion and neoplastic ones. Under rarer situations, an acute
cerebrovascular event especially in the early phase may also confuse with its imaging findings. The
differential diagnosis of tumour vs infection is particular difficult for immunocompromised patients.
For mass lesions, enhancing intracranial tuberculoma shows nodular or ring-like enhancement similar to
that of primary or metastatic brain tumour. The situation of diffuse disease process requiring a brain
biopsy is difficult. Usually in these patients, imaging or CSF findings are abnormal but insufficiently
specific for a distinct diagnosis. Such patients present usually as progressive cognitive decline. A
major differential diagnosis is prion disease and that will be covered by another lecturer. Other
neurodegenerative diseases are also differential diagnoses. In the context of this presentation,
chronic infections need to be excluded. However, the diagnostic yield in such scenarios is usually low
due to difficulty of targeting the pathologic materials in the procedure and non-specific histologic
changes and these might have to be remembered in any discussion for potential biopsy with clinical
An array of psychiatric presentations may be encountered in diseases such as HIV and neurosyphilis 
. Mass lesions in HIV positive individuals are usually biopsied under stereotatic techniques .
Common focal lesions in HIV positive patients include :
In these situations, cytologic techniques will prove to be an excellent intraoperative technique
- Progressive multifocal leukoencephalopathy
- Syphilitic gumma
- Encephalitis, herpes, CMV or HIV
Meningeal biopsies may be performed in rare occasions . Tuberculosis, Cryptococcus infection
may also present as nodular lesions in the meninges necessitating biopsy  and smooth muscle tumours
of the meninges may present in the setting of HIV individuals . Neurosyphilis may also present as
mass lesions in the meninges in the form of gummas.
In all such scenarios, the biopsy should only be taken after careful clinical and imaging review. The
biopsy should be performed early in the day and early in the week, to allow maximum time for tissue
preparation and preparation for ancillary diagnostic techniques, e.g. microbiologic culture .
Notes on diagnosis of some individual infection
Brain abscess : Patients often have forgotten episodes of sepsis in the paranasal sinus,
middle ear or dental root. 50% of brain abscess is direct spread from head and neck regioin. Streptococcus milleri is the commonest pathogen but often a mixed infecdtion
involving anaerobes. Approximately 25% of brain abscesses is due to haematogenous spread : congenital
heart disease with right to left shunt, septic emboli, bronchiectasis, lung abscess, SBE etc. Head
injuries, even those close head, are predisposing factors. Abscesses are usually located in the frontal
and temporal region though otogenic infection may lead to a cerebellar abscess. Brain abscess is a
serious condition with mortality rate of about 20%.
In terms of histologic evolution when biopsied, in the first three weeks, the histologic picture is
mainly cerebritis. It is only after three weeks when a capsule with granulation tissue and a purulent
centre develops 
Subdural empyema : This can occur 1. by local spread, by sinusitis but more often by cranial
trauma, neurosurgery and 2. haematogenously due to systemic sepsis. In the spinal cord, this can result
in epidural abscess, and the main incriminating organism is Staphylococcus
Toxoplasmosis : The major differential diagnosis is primary cerebral lymphoma in the setting
of HIV positive patients. Both are relatively common in AIDS and may co-exist in the same lesion .
In general, toxoplasmosis is about 2-3 times more common than lymphoma in HIV patients and about 70% of
them are focal . Whereas, about 70% of lymphomas are solitary but are more likely to be multifocal
compared with patients not infected with HIV . The characteristic lesion is cerebritis or
necrotizing abscess. Cysts are difficult to recognize and may resemble those seen in other infections
such as Leishmania donovani, Trypanosoma cruzi,
and so on. Immunohistochemistry and also electron microscopy can be done in doubtful cases 
Herpes simplex encephalitis : Other than what was mentioned above concerning PCR diagnosis,
occasionally herpes encephalitis may be difficult to differentiate from lymphoma when the latter affect
temporal lobe and limbic pathway. It is rarely necessary these days to resort to brain biopsy. When
this needs to be done, the inferior portion of the temporal lobe on the involved side should be advised
upon. Biopsies on occasion have been performed at other sites (e.g. frontal convexity) and have
provided false negative results because herpes simplex virus encephalitis is highly localized to the
inferior frontal and temporal regions .
Biopsy materials should be processed for immunohistochemistry for herpes simplex 1, and also PCR or
in situ hybridization can be performed using paraffin embedded tissues. Intranuclear inclusions are
more easily seen at the periphery rather than the centre of the necrotizing lesions. It should be
noted that herpes simplex genome can rarely be found in temporal lobe by PCR in normal individuals and
close correlation with clinical picture and imaging must be followed.
CMV encephalitis : The majority of CMV encephalitis occurs in the setting of AIDS. There are
no specific imaging findings but ventriculitis and myeloradiculitis in association with encephalitis is
suggestive and CMV PCR is a reliable test when taken into account with the clinical situation. Other
than infecting the macrophage/monocyte, as is typical of viral encephalitis, CMV is also harbored by the
Japanese encephalitis (JE) : JE is an RNA virus which causes an endemic encephalitis in Asian
countries. A mosquito-borne transmission, JE remains a major public health problem in agricultural
societies in these regions. The clinical, imaging and pathological findings are those of encephalitis
and diagnosis is usually suspected on epidemiological ground. A combination of virus isolation,
antigen and antibody detection in serum and CSF and PCR, confirms the diagnosis.
Tuberculosis : In spite of socio-economic advances, tuberculosis is still a problem in any
newly industrialized countries in Asia and has a significant mortality and morbidity rate. The
definitive diagnosis of nervous system tuberculosis, mainly meningitis (TBM), is difficult due to the
extreme paucity of the organism. Rarely the difficulty of establishing a diagnosis TBM may call into
question the need for meningeal biopsy but one must remember that inflammatory exudates much more
exuberant at the base of the brain which is rarely the biopsy site. In a typical TBM reaction, other
than tuberculous granuloma, there will be endarteritis obliterans of the subarachnoid vessels.
Tuberculoma may be found anywhere in the cerebrum and cerebellum but in the spinal cord,
tuberculous infection arises from direct extension of an osteomyelitic focus in the vertebral column,
causing the spinal epidural tuberculosis (the historical Pott's paraplegia).
Cryptococcosis : Cryptococcus neoformans is the commonest form of
fungal meningitis. It also produces cerebral abscesses, or cryptococcoma. Cryptococcal infection is
commonly associated with debilitating diseases, such as lymphomas, leukaemias, sarcoidosis, tuberculosis,
steroid therapy, diabetes mellitus and lupus erythematosus (which is very common in our locality).
Among HIV patients, Cryptococcus ranks third (after HIV and toxoplasmosis) as infectious agents. A
typical "soap-bubble" appearance may be seen in meninges or parenchyma radiologically and appear slimy in
gross appearance due to the mucoid exudates . The faintly basophilic budding yeast forms may be
confused with corpora amylacea and should be stained by PAS or methenamine silver and the thick capsule
stains with mucicarmine or alcian blue.
Aspergillosis : One of the commoner mycosis of the brain. Aspergillus may spread to the
brain from lung abscesses, paranasal sinus, external ear, skin or intrdocued during cardiovascular or
other surgery or trauma. Typically, Aspergillus hyphae invade blood vessels with thrombus formation.
Mucormycosis : This usually occurs as abscesses in the orbital part of the frontal lobes with
extension to nasopharynx, sphenoid sinus, cribriform plate and adjacent skull base. Broad and
non-septae hyphae at right angle to the main hyphae. Rhinocerbral mucormycosis usually starts with
nasal or unilateral facial swelling and hyperaemia and then the infection rapidly extends to the orbit
and meninges. Most patients are diabetic ketoacidotic and infection may spread to cavernous sinus,
arteries of the orbit, internal carotid arteries associated with thrombosis. Occasionally, haematogenous
spread arises from extracrnail sites such as the lungs and predisposing conditions include acidosis due
to diarrhea and dehydration, organ transplantation, immunopression. Very rarely, cerebral mucormycosis
occurs in previously health individuals or complicate cranial trauma or neurosurgery.
Candidiasis : Candida infection of the CNS is usually associated with systemic candidiasis
and is often a late manifestation and are associated with cardiac and renal lesions. Candida species
are budding round or oval yeasts which may cohere after budding to form chains or pseudohyphae.
Amoebiasis : Entamoeba histolytica usually gives rise to
meningitis and only rarely causes cerebral abscesses. Amoebae are difficult to be distinguished from
histiocytes. They are usually a little larger (15-25 Ám) in diameter, more uniform in appearance. Their
nuclei are round, uniform, often have a small central karyosome and slightly thickened peripheral
chromatin. It is usually secondary to a primary septic focus elsewhere in the lung, or intestine.
Infection of Naegleria fowleri is associated with swimming in polluted man-made or fresh water and is not
associated with predisposing medical condition. Infection by Acanthomoebe and Balmuthia occur through a
similar route. These latter three amoebae are more likely to cause meningo-encephalitis than Entamoeba.
The latter two may develop cysts in the tissue (Naegleria does not) and a chronic granulomatous
encephalitis in debilitated patients
Histoplasmosis : Found in certain regions of USA, and in immunocompromised patients. It may
appear as miliary lesions, meningitis or focal cerebritis. Radiologically indistinguishable from
high-grade gliomas. Histology shows multinucleated giant cells with numerous ingested yeast organisms.
Neurocysticercosis : It is endemic in central and South America, Africa and Asia . The most
frequent clinical presentations include epilepsy, meningitis, intracranial hypertension and cognitive
disability. In imaging, the scolex may be seen in a cystic lesion or multiple calcifications and small
cysts. The gross appearance is usually that of a cyst with the scolex. Histologically, each sclex has
a rostellum with four suckers. The cell wall should have an acellular cuticular layer and an inner
reticular layer. Degenerated cysticercotic cysts are hard to be definitively diagnosed as they will
consist of a fibrotic or calcific cysts with multinucleated giant cells and inflammatory reaction .
Anti-Elisa tests are available in some laboratories for diagnosis and also differentiation from
Paragonimiasis and Sparganosis.
Progressive multifocal leucoencephalopathy (PML) : This will probably be dealt with by the
next lecturer too. Typically, focal neurological deficits occur in a background of cognitive decline
with personality change. Other than demyelination with foamy macrophage infiltration, the bizarre and
highly atypical astrocytes may mimic a glioma. Viral inclusions may be seen in glial cells, which can
be confirmed by harbor JC virus by in situ hybridization and electron microscopy.
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