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  Table of Contents    
REVIEW ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 135-145
Non-granulomatous inflammatory lesions of CNS: Approach to diagnosis


Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

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Date of Submission30-Jan-2022
Date of Decision27-Feb-2022
Date of Acceptance28-Feb-2022
Date of Web Publication11-May-2022
 

   Abstract 


Infections constitute an important and common category of diseases, particularly in less developed countries. Infections present with a broad spectrum of clinical and radiologic features dictated by the cell and tissue tropism and host response elicited, posing a considerable diagnostic challenge. Early diagnosis and treatment are crucial in preventing mortality and morbidity. Recourse is often made to biopsy for ascertaining the diagnosis, and hence the pathologist plays a vital role in patient management. Therefore, knowledge of the histopathologic changes is necessary to recognize the histological changes and guide the diagnostic workup and management. Each microbial agent elicits a distinctive pattern of inflammatory tissue response, which can serve as a clue to the etiological agent. Based on the causative organism, microbial, and host factors, the inflammatory response may be acute or chronic, necrotic or non-necrotic. The inflammation can be of varied patterns – lymphohistiocytic, granulomatous, inflammatory demyelinating, fibrosing, or showing minimal inflammation. The pattern of necrosis also differs based on the causative organism. Typically, pyogenic bacteria are associated with suppurative inflammation, tuberculosis with caseous granulomatous, and fungi with suppurative granulomatous inflammation. Viral infections are associated with lymphohistiocytic non-necrotizing inflammation and, based on cell tropism, can cause demyelination (e.g., JCV) and/or viral inclusions. Parasitic infections (protozoal or metazoal) display a broad spectrum of inflammatory changes that overlap with other types of infections. This review briefly describes pathological patterns and associated pathogens and provides an algorithmic approach based on pattern recognition that may be useful for the practicing pathologist.

Keywords: Encephalitis, inclusions, necrosis, neuroinfections, suppurative, toxoplasmosis, viral

How to cite this article:
Nandeesh B N, Rao S, Mahadevan A. Non-granulomatous inflammatory lesions of CNS: Approach to diagnosis. Indian J Pathol Microbiol 2022;65, Suppl S1:135-45

How to cite this URL:
Nandeesh B N, Rao S, Mahadevan A. Non-granulomatous inflammatory lesions of CNS: Approach to diagnosis. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:135-45. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/135/345048





   Introduction Top


Inflammation is a response of vascularized tissues to limit the invading pathogen's survival and proliferation, eliminating the pathogen and promoting tissue survival, repair, and recovery.[1] The inflammatory reaction may be triggered by various stimuli, including infections (bacterial, viral, fungal, parasitic), toxins, foreign tissue bodies, and immune responses (hypersensitivity and autoimmune). Infections are the most common and medically important cause of inflammation.[1],[2],[3] Although various microbial agents can cause infection, the morphologic pattern of tissue/cellular response is relatively distinct and unique to each category of the organism, serving as an important clue to its diagnosis. A common approach used in histopathological assessment includes recognition of the pattern of tissue response and demonstration of the organism. The review below focuses on the pattern of tissue response to aid the diagnosis.

From the Central Nervous System (CNS) perspective, the tissue response can be broadly categorized based on the presence of necrosis into (A) Necrotising type (B) Non-necrotising type.

Necrotizing inflammation can have various patterns.

  1. Suppurative
  2. Granulomatous inflammation with caseous necrosis
  3. Suppurative granuloma
  4. Necrotising (Unclassified/patternless)
  5. Angiocentric/vasculocentric
  6. Extensive necrosis with minimal inflammation


  1. Suppurative (Purulent) Inflammation – This pattern of inflammation is characterized by prominent vascular permeability and a dense leukocytic infiltration, chiefly comprising neutrophils. The release of bacterial products, especially from extracellular gram-positive cocci and gram-negative bacilli, is a powerful chemoattraction for neutrophils.[2],[3] The dense neutrophilic response leads to tissue necrosis (liquefactive type) admixed with dead neutrophils and cellular debris form pus, and is referred to as abscess in tissues. This can range from small micro abscesses to large abscesses depending on the tissue/host factors and the microbe. Some of the most critical and common pyogenic bacteria include S. pneumonia, S. aureus, H. influenza, N. meningitides, K. pneumoniae.[2],[3]
  2. Granulomatous inflammation with caseation: This type of inflammatory response is typically seen with the Mycobacterial group of infections, primarily Mycobacterium tuberculosis. However, many other infections and non-infectious agents (immune-mediated, foreign body) can also cause granulomatous inflammation.[4] This is discussed in detail in the article by Sundaram C in this edition.
  3. Suppurative granulomatous inflammation: This combination of suppuration with a granulomatous response is typically seen with fungal infections that include Aspergillosis, Phaeohyphomycosis, etc. The other causes include parasitic infections, especially hydatid cyst, cysticercosis when they lose their viability, atypical bacterial infections like Actinomycosis, Cat scratch disease, infections due to Nocardia and Brucella. This category includes atypical mycobacterial infections, tuberculosis (TB) with vasculitis, and granulomatous amoebic infections.[2],[3] The inflammation is dominated by neutrophils. Although histiocytes exist in good numbers, the granulomas are not well-formed (ill-defined) and usually lack giant cells.
  4. Necrotising inflammation of No special type (Unclassified/patternless): Necrosis can exist in a pattern-less form accompanied by a minimal cellular response. This generally occurs in immunocompromised patients not capable of mounting an immune response. The common pathogens include tuberculosis, fungal infections, protozoal infections like Toxoplasmosis, amoebic infection, and less commonly viral infections, especially cytomegalovirus (CMV). Necrosis is also noted in other viral infections belonging to the Herpes group-Herpes simplex and Varicella zoster. Some toxin-related tissue injuries such as following radiation/chemotherapy can cause necrosis with minimal/tissue response. Finding an angiocentric/vasculocentric pattern of inflammation should suggest protozoal infections, especially Toxoplasmosis, Amoebic encephalitis, Malaria, and Varicella zoster infection.


  5. B. Non-necrotising inflammation includes the following patterns:


  1. Lymphohistiocytic inflammation

    In this category, the inflammatory pattern is predominantly lymphohistiocytic with a perivascular or diffuse distribution in the brain. It may include microglial cells that form nodular aggregates or a perivascular/diffuse microglial infiltration. This is typically seen in viral infections. Some of the viral infections may demonstrate a cytopathic reaction, caused by intracellular replication of viruses that form aggregates of viral components (virions/viruses) and inclusion bodies (e.g., herpesviruses or adenovirus) or cause cellular fusion to produce multinucleated cells referred to as polykaryons (e.g., measles virus or herpesviruses).[1] In some of the viral infections, inflammation may be significantly less. This is exemplified by rabies encephalitis. In the immunocompromised host, viral infections like CMV encephalitis, and toxoplasmosis, may be characterized by necrosis without significant inflammation. Viruses can cause a diffuse parenchymal inflammation (e.g., measles causing SSPE) or be focal, for, e.g., multifocal demyelination caused by the John Cunningham (JC) virus.
  2. Demyelination with inflammation: Certain viral agents that selectively infect oligodendroglia can result in demyelination like JC virus, a papovavirus causing progressive multifocal leukoencephalopathy (PML). The release of inflammatory cytokines toxic to myelin supporting cells or myelin membranes can lead to demyelination. Alternatively, demyelination can be secondary to an immune-mediated process, either post-infectious/post-vaccinal/perivenous encephalomyelitis, following a preceding systemic virus infection. This can occur with measles, mumps, rubella, influenza, vaccinia, smallpox virus infections, and vaccinations through molecular mimicry of virus proteins and myelin proteins.[4],[5],[6]
  3. Inflammatory pathology with minimal inflammatory cell infiltrates is generally seen in an immunocompromised host. In addition, viruses like Rabies and HIV elicit only a minimal inflammatory response.
  4. Inflammation with fibrosis: As a part of tissue repair, chronic inflammation elicits angiogenesis and fibrosis in the late stages. Some of the long-standing chronic inflammatory processes cause extensive fibrosis. This can mimic a growth or neoplasm. This fibrosis/scarring can compromise the function of the tissue or cause a secondary effect on other tissues, as in obliterative arteritis. Pachymeningeal involvement leads to extensive fibrosis because of the fibrous nature of the tissue with minimal vascularity.


All these patterns of tissue response provide an essential clue for determining the causative agent. But in reality, the types of tissue response can occur in combination or possess atypical features, particularly in the immunocompromised host, posing diagnostic challenges. Non-infectious conditions such as immune-mediated demyelination can mimic an infectious pathology adding to the diagnostic dilemma. Hence, confirmation requires demonstration of the organism by immunohistochemistry/molecular tests. However, the tissue reaction guides the pathologist to select special stains/immunohistochemistry to identify the pathogen [Table 1].
Table 1: Patterns of inflammation and associated pathogens

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A brief note on some of the important infections

Pyogenic Infections causing suppurative inflammation [Figure 1]: Bacterial infection can cause (a) Pyogenic meningitis, (b) Subdural and Epidural Empyema, (c) Brain abscess (intraparenchymal).
Figure 1: (a-c) Pyogenic meningitis with an exudate covering the superolateral surface of brain (a) as a result of lymphohistocytic infiltrates in the subarachnoid space (star, b, c, H and E, x12.5, x100). (d-f) Chronic abscess with central necrosis (star, D, Masson trichrome, x40) surrounded by inflammatory granulation tissue (e, H and E, x100) and fibrous capsule (f, H and E, x100)

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Route of entry and spread: Bacterial infections of CNS occur through (a) Hematogenous route following bacteremia/septicemia from a distant source (lung abscesses, bronchiectasis, subacute bacterial endocarditis, osteomyelitis and pelvic infections) (b) Direct spread from an adjacent infectious source like sinusitis, mastoiditis, otitis media, and dental abscesses (c) Penetrating traumatic skull injuries (d) Diagnostic (lumbar and ventricular puncture) and therapeutic procedures (ventriculoperitoneal shunt) (e) In Neonates, through the amniotic fluid or from maternal genital tract during parturition and in fetuses by transplacental transmission. One-third to half of the parenchymal bacterial infections are secondary to direct spread from contiguous sources. One-fourth occur from hematogenous spread of distant infective foci like lung abscess/bronchiectasis. The remaining may be due to trauma, procedural or other situations.[7],[8] Bacterial (pyogenic) meningitis is common in infants and young children.[9] Exudate in the subarachnoid space causes a hazy appearance of the leptomeninges [Figure 1]a, [Figure 1]b, [Figure 1]c. [Table 2] shows some of the common etiologies of bacterial meningitis in different age groups.
Table 2: Etiology of bacterial meningitis in different age groups

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Pathology of Brain abscess: Four important stages are recognized in brain abscess formation. The pathology starts as cerebritis with an ill-defined area of inflammation. In the early cerebritis stage (1–3 days), neutrophilic infiltration predominates, and in the late cerebritis (4–9 days) phase, there is ensuing tissue necrosis and foamy macrophage infiltration [Figure 1]d. It constitutes an organized abscess when the process gets localized or walled off by a fibrous capsule [Figure 1]f. This organization goes through an early capsule (10–13 days) stage consisting of granulation tissue with mixed inflammatory cells, followed by a late capsule (beyond 14 days) stage where the vascularity reduces with fibroblast ingrowth and thick fibrous capsule formation. The fibrous capsule gets remodeled with more collagen that replaces the inflammatory cells with time. Along the periphery, the astrocytes proliferate to wall off the abscess from the healthy tissue.[10],[11] Since the brain parenchyma lacks fibroblasts, the fibroblasts for the capsule are mainly derived from the leptomeninges and the adventitia of the larger blood vessels. Hence the capsule is generally well formed on the superficial cortical aspect and thinner along the deeper aspect. Hence there is always a risk of extension along the deeper aspect to enter the ventricle. The capsule is poorly formed in immunocompromised/debilitated elderly individuals, and multiple disseminated embolic microabscesses can form. The capsule appears as a ring, which may be hyperattenuated on precontrast computed tomography (CT) compared with the central region of necrosis and peripheral edema. The ring enhancement indicates a vascularized capsule, which subsides in due course of treatment.[10],[11]

Diagnostic workup: CSF Gram stain and culture are essential in meningitis where lumbar puncture is performed. But the sensitivity of Gram staining is variable (25–90% depending on the organism and the bacterial load), which dramatically reduces with antibiotic exposure. Similarly, although bacterial culture has high specificity, the sensitivity depends on the pathogen and reduces with antibiotic exposure. Blood culture is helpful but has variable sensitivity (35-60%).[12] PCR can be beneficial in atypical infections like Borrelia, Bartonella, mycoplasma, and spirochetes (Leptospira and Treponema).[12] Generally, lumbar puncture is contraindicated in cerebral abscess, and diagnosis is often suspected based on radiological findings. Tissue and even blood cultures are necessary for a definite diagnosis and identifying the causative organism and its antibiotic sensitivity. Surgical intervention is both diagnostic and therapeutic. Management is not successful until the primary source of infection is recognized and treated adequately.

Fungal infections

Important fungi that cause CNS disease include (a) Yeasts (Candida, cryptococcus); (b) Moulds/filamentous fungi (Septate – Aspergillosis; Aseptate – Mucorales, dematiaceous/pigmented – Cladophialophora; (c) Dimorphic fungi (Blastomycosis, Histoplasma, Coccidioidomycosis).

The tissue response is usually granulomatous and is covered in detail in article on Diagnostic approach to granulomatous lesions of CNS by Sundaram C in the same issue.

Fungal stains (Gomori methenamine silver or periodic acid Schiff) are essential in the histopathological workup. Mucin stains (Alcian blue and Mucicarmine) are helpful in the diagnosis of cryptococcus. Cryptococcal meningitis requires an India Ink study. Serum capsular polysaccharide antigen detection or latex agglutination test in CSF is useful for cryptococcosis. CSF cultures are often non-diagnostic from fungal brain abscesses. Serological tests (immunofluorescence based) have varied sensitivity (38–92%) depending on species. Fungal antigens (like galactomannan from Aspergillus spp) can be detected using commercially available kits. Fungal PCR, especially for invasive aspergillosis, has excellent sensitivity.[13]

Protozoal infections [Figure 2]
Figure 2: (a-d) A case of toxoplasmosis with coronal slice of brain showing multiple hemorrhagic necrotising lesions in the temporal, frontal, and basal ganglia regions (a); these lesions are seen around occluded vessels with bradyzoites (c, arrow, H and E) which are highlighted along with tachyzoites on immunohistochemistry with toxoplasma antigen (d). (e-h) A case of amoebic encephalitis with necrotic lesions (E, arrows) which reveal histiocytic response (f, H and E), trophozoites and cysts (g, arrow and arrowhead, Periodic acid Schiff), with a defined cyst wall and karyosome (h, arrow, Masson trichrome). (i-k) A case of malaria with ball and ring hemorrhages (i and j, star, H and E) with parasitized red blood cells (k, H and E). Magnification = scale bar

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Toxoplasmosis: Toxoplasmosis is one of the important opportunistic infections caused by the protozoan Toxoplasma gondii, often associated with acquired immune deficiency syndrome (AIDS), post-transplant status, and other immunocompromised situations.[14],[15],[16] This can present as a solitary or multiple parenchymal peripheral/ring-enhancing lesion/s with hemorrhage and extensive perilesional edema.

Pathogenesis: The entry route involves the ingestion of oocysts or tissue cysts (bradyzoites) from undercooked meat, contaminated soil and water; oocytes are shed in cat feces, and cat is the only source of infectious oocysts (only definitive host). From the ingested oocyst in humans or animals, sporozoites are released in the intestine, which enters the circulatory system and spreads hematogenously. Once the sporozoite gains access to the cell, it transforms into tachyzoites. Tachyzoites form tissue cysts containing bradyzoites if conditions are unsuitable. Direct infection involves the endothelial cells causing vasculitis and vascular occlusion, producing characteristic endarteritis with hemorrhage and infarction. T cells and macrophages participate in the inflammation with interferon-gamma, TNF alpha, and IL -12, perpetuating the necrosis.

Pathology: The clinicopathological lesions include (a) Mass lesion, characterized by ring-enhancing lesions on MRI – involving basal ganglia, thalamus, grey-white junction, brain stem and cerebellum causing hemorrhagic necrotizing lesions. The morphological forms include acute necrotizing encephalitis stage (1st week), organizing abscess (2nd week of illness), and chronic abscess (>4 weeks). These necrotic lesions in the acute stage are generally poorly circumscribed, with hemorrhage and surrounding edema. Histologically, the lesions consist of coagulative necrosis, Toxoplasma cysts, and numerous free tachyzoites with usually minimal host inflammatory response, along with small arteries which reveal fibrinoid necrosis, endothelial damage, thrombosis [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The lesions are characterized by central eosinophilic, acellular, coagulative necrosis, walled off by a peripheral zone of histiocytes containing lipid and hemosiderin, variable inflammation, astrocytosis, and microglial proliferation. Free tachyzoites are less frequent and identified in the inflamed wall along blood vessels by immunohistochemistry using tachyzoite-specific antibodies.

(b) Periventricular inflammation with hydrocephalus: This is an infrequent presentation with periventricular necrosis, petechial hemorrhages, or hemosiderin, with minimal inflammatory response, mimicking CMV ventriculitis. Numerous free tachyzoites of Toxoplasma may be observed.

(c) Diffuse encephalitic pattern with microglial nodules throughout grey and white matter mimicking a viral infection. Multifocal cysts and free tachyzoites may be detected. There may be necrotic yellow exudate and periventricular petechiae.

Histologically, these three morphological patterns can coexist in the same patient. Congenital toxoplasmosis can occur, frequently showing ocular involvement and acquiring in utero.

There is a mild to subclinical meningoencephalitis form in the immunocompetent, with the disease resolving spontaneously without clinical sequelae.

Serial serologic tests on serum and CSF are helpful but have been largely supplanted by the availability of PCR.[12],[17] CT and MRI are useful in recognizing the lesions, which can display a ring or homogeneous enhancement with calcifications.[18]. Eccentric target sign on contrast-enhanced MRI and concentric target sign on T2WI is highly suggestive of toxoplasmosis, and its histological correlate was described in our group.[19] Periventricular involvement is common.[14],[20]

Amoebic encephalitis

Free-living amoebae and parasitic amoebae can rarely cause CNS infection. Free-living amoebae cause two types of disease – an acute primary amoebic meningoencephalitis (PAM) caused by Naegleria fowleri and a subacute or chronic granulomatous subtype, caused by Acanthamoeba and Balamuthia species.[14] As in all protozoal infections, these amoebae exist in two forms – the actively replicating trophozoites capable of causing disease and the “cyst” phase that is the resting, non-infectious form induced when conditions are unfavorable.

Pathology: PAM caused by Naegleria fowleri is typically seen in young immunocompetent males with a history of swimming in stagnant pools in summer. When temperatures rise, the amoebic cysts in contaminated water get converted into the infective trophozoite stage. They enter through the olfactory route and cause florid necrotizing, hemorrhagic meningitis with parenchymal involvement, predominantly involving the orbitofrontal cortices, closely mimicking Zygomycotic infection. It is a fulminant disease with dense neutrophilic exudate and hemorrhagic necrosis secondary to angiitis and perivascular hemorrhages [Figure 2]f. Numerous trophozoites are found surrounding blood vessels. The trophozoites measure about 10-15 um trophozoites with a less prominent karyosome. Unlike granulomatous amoebic encephalitis (GAE), no cysts are seen.[21] Unlike PAM, GAE affects immunocompromised individuals, and brain involvement occurs following hematogenous spread. Despite the name, well-formed granulomas are infrequent. The aggregates of histocytes with erythrophagocytosis and vascular destruction are central to the pathology. Granulomatous response with giant cells is reported more frequently in Balamuthia infection, especially if the host is immunocompetent. There is prominent complement activation, cytokines, proteases released from trophozoites that induce microvascular damage and cause parenchymal pathology. The trophozoites exhibit erythrophagocytosis and are highlighted on the PAS stain [Figure 2]g.

Cerebral malaria

Plasmodium falciparum causes cerebral malaria, which has a high mortality rate of close to 50% when untreated. This is common in endemic areas (Tropical and subtropical regions). Seizures in a patient with malaria indicate CNS involvement. Cerebral malaria often leads to acute tubular necrosis, acute respiratory distress syndrome, disseminated intravascular coagulation, persistent hypoglycemia, worsening seizures, and coma.[22]

Pathogenesis: The infection causes a generalized encephalopathic state. Obstruction of microcirculation by infected red blood cells causes endothelial dysfunction and damage with pericapillary ring hemorrhages and small infarcts [Figure 2]i, [Figure 2]j, [Figure 2]k. Clusters of microglial cells in the microinfarcts/ring hemorrhages region are termed as Dürck granulomas. Hemorrhages, either punctate or ring hemorrhages at the grey-white junction and in deep white matter, as well as Dürck granuloma, are important diagnostic clues for the pathologist. Tissue damage is mediated by cytokines like tumor necrosis factor-α nitric oxide.[23]

The parasites remain sequestered within capillaries, ingest and catabolize host hemoglobin as nutrition and release hemoglobin breakdown products (hemozoin or malarial pigment, an iron–porphyrin–proteinoid complex), seen as small dark brown refractile pigment granules. In tissues, it can mimic hemosiderin or formalin pigment. It can be distinguished easily from hemosiderin as it does not react with a Prussian blue stain. Hemazoin pigment can be removed from tissue sections by a saturated alcoholic solution of picric acid. It is birefringent under polarized light (red-yellow color). Advanced techniques like spectroscopic (with fluorescence and chemiluminescence), magneto-optic (linear dichroism), densitometric, optical scattering, and nonlinear optical methods can detect and quantify the hemozoin pigment.[24],[25],[26]

Diagnostic workup: Peripheral blood examination is needed to diagnose cerebral malaria. Given sequestration of RBCs within capillary microcirculation of organs or prior treatment with antimalarial drugs, peripheral smear can be negative in some cases.[27] Repeat testing every 6–8 hours for at least 48 hours is recommended. Point of care diagnostic test is available with varying sensitivity and specificity, some of which detect histidine-rich protein (HRP-2) produced by Plasmodium falciparum. Tests detect aldolase or parasite lactate dehydrogenase enzymes (pLDH) which may be pan-specific (all species) or species-specific, and employ lateral flow immunochromatography to detect Plasmodium antigens in a finger-prick sample of blood. A rapid result is obtained, and the kits are very simple to use. However, because of the high mortality, presumptive treatment is initiated.

Viral infections [Figure 3][28],[29]
Figure 3: Photomicrographs show oligodendroglial intranuclear inclusions (a, H and E, x400) which are immunopositive for measles antibody (b, immunoperoxidase, x200) in a case of subacute sclerosing panencephalitis. Characteristic Negri bodies in pyramidal neurons of the cerebellum (c, d, H and E, x200, x400) confirmed immunohistochemically for Rabies (e, x40). Necrolytic lesion in a case of Japanese encephalitis (f, H and E, x40), Cowdry type A intranuclear inclusions of cytomegalovirus (g, H and E, x100) confirmed on immunohistochemistry (g, inset). A case of Herpes simplex encephalitis with intranuclear inclusion (h, arrow, H and E, x400) with immunopositivity for antigen (i, arrow, x200)

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General features: Several viruses are neurotropic with an affinity for neural tissue. The viral infections of CNS can be sporadic or can cause epidemic outbreaks affecting all ages. The routes of entry include respiratory, oral, sexual contact, cutaneous inoculation, transplacental, animal, or insect/tick bite. Following replication at sites of entry, there ensues a primary viremia during which there may be transient aseptic inflammation of the leptomeninges. In the secondary viremic phase, neurotropic viruses lodge in the CNS. Viruses can remain latent without exposure to systemic immune responses. When reactivated by immunosuppression, they can produce either an acute inflammatory or a slowly progressive inflammatory/demyelinating disease. Certain viruses are teratogenic and produce malformations in the fetuses of infected mothers.

Diagnostic workup in viral meningitis: CSF study shows mild to moderate pleocytosis (lymphocytes), the moderate elevation of protein, and generally glucose is normal, hence referred to as aseptic meningitis. The gold standard for diagnosis is viral isolation in permissive cell lines, but this is not freely available and is time-consuming. Thus, for a definite diagnosis, serology (IgM/rising titers of IgG antibodies) or viral-specific DNA and RNA in CSF and/or blood by PCR assay is preferred. The useful diagnostic tests for viruses like Adenovirus, CMV, EBV, HSV-1, HSV-2, HHV-6, VZV, JC virus, arbovirus, HIV include CSF PCR and serology. PCR from the skin (nuchal) or brain biopsy (IHC) can be considered for rabies. Immunohistochemistry or in-situ hybridization can be performed in tissues for some important common viruses, including SSPE.

Viruses are broadly classified into RNA and DNA viruses based on the nucleic acid type. The important RNA viruses affecting the CNS include:

  1. Enteroviruses: Poliovirus, Coxsackie, and Echovirus
  2. Paramyxoviruses: Measles, Mumps, Parainfluenza, Nipah virus
  3. Toga viruses: Rubella virus
  4. Arboviruses: Japanese virus, Western and Eastern encephalitis, West Nile virus, Chikungunya, and Dengue virus
  5. Rhabdoviruses: Rabies virus
  6. Retroviruses: HIV.


Pathology of viral encephalitis

Grossly, there is diffuse cerebral edema with congestion. Histologically perivascular mononuclear cell infiltrations, neuronophagia, and microglial nodules should make one suspect viral encephalitis. One of the important clues to etiologic agents is a cytopathic change in the form of inclusions in neurons and glial cells. The inclusions can be cytoplasmic as in Rabies (Negri bodies) or nuclear, which can be of two types: Cowdry Type A and Cowdry type B. Cowdry type A causes an eosinophilic large intranuclear inclusion seen typically in CMV (with cytomegaly) and HSV.[30] Cowdry type B inclusions are small, often multiple, and lack a halo.[31] Cowdry type B inclusions may be seen in polio and adenovirus. Generally, the DNA viruses show distinct intranuclear inclusions, with measles being an exception. Some viral infections may have a cytopathic change resembling an atypical/neoplastic cell (e.g., PML and EBV). Hemorrhagic necrosis points toward the herpes group (HSV and VZV). Apart from these general features, there are characteristic pathological features specific to certain viruses.

Poliovirus that causes poliomyelitis is acquired via the fecal-oral route and colonizes gut lymphoid tissue, replicates and disseminates to nervous tissue via the bloodstream. The motor neurons of the spinal cord, brainstem and variably, the cortical motor neurons are specifically involved in giving rise to flaccid paresis or paralysis of the extremities. The survivors of the acute illness will have a residual weakness.[32]

Pathology: During the acute phase of the infection, perivascular lymphocytic infiltrations may be seen in the leptomeninges, spinal cord, and brainstem. Neuronophagia and microglial nodules are seen in the anterior horns of the spinal cord and brainstem grey matter. Cortical motor, thalamic, hypothalamic, and cerebellar neurons are less frequently affected. Chronic cases show loss of neurons in the anterior horns is depleted with gliosis.[33]

Measles is an important neurotropic virus that causes a broad spectrum of CNS pathologies.[34] These include

  1. Aseptic meningitis – complicates acute infection.
  2. Postinfectious perivenous demyelinating encephalomyelitis (immune-mediated) – develops 1 to 2 weeks following an acute infection.
  3. Subacute measles inclusion body encephalitis – occurs in immunocompromised
  4. Subacute sclerosing panencephalitis, primarily affect children and adolescents several years after an early childhood infection and characterized by behavioral changes, slowly progressive mental regression, seizures, myoclonus, and focal neurologic deficits. CSF shows increased IgG levels with oligoclonal bands, and raising measles antibody titers will be observed in CSF and serum.[35]


Pathology of SSPE: There is atrophy of the cerebral cortex with hemispheric white matter appearing greyish and firm, reflecting demyelination and gliosis. Microscopically, there is panencephalitis with widespread perivascular lymphocyte and plasma-cell infiltrations in the cerebral hemispheres and brainstem with variable neuronal loss. Distinct eosinophilic intranuclear inclusions are observed in the neurons and oligodendrocytes [Figure 3]a; diffuse myelin degeneration in the hemispheric white matter is accompanied by dense astrocytic gliosis, and neurofibrillary tangles containing measles genetic material may be seen in some neurons.[34],[36]

Arboviruses are arthropod-borne (mosquito and tick bite related) and are major causes of epidemics in particular geographic areas. The viruses reach the nervous tissue through the bloodstream and cause aseptic meningitis or meningoencephalitis. The prognosis is less favorable among children and elderly individuals. Histologically, there will be prominent perivascular lymphocytic cuffing comprising mainly CD4 (+) and CD8 (+) T cells with occasional B cells. Microglial clusters neuronophagia of infected cells is observed. Prominent brain stem involvement is seen terminally in addition to spinal anterior horns (myelitis). Characteristic necrolytic lesions are seen in thalamic and basal ganglia in Japanese encephalitis [Figure 3]f. Viral inclusions are not detectable. Immunohistochemistry is available for some of these infections.[37],[38]

Rabies virus of the Rhabdovirus family enters the body from the bites of infected animals, commonly dogs, and less commonly cats, raccoons, or bats. The virus reaches the brain along the axons of the peripheral nerves. It exhibits both a centripetal (periphery to CNS) and centrifugal spread (CNS to peripheral structures like salivary glands, head and neck skin, organs with autonomic innervation). The incubation period ranges from several days to months and causes acute, rapidly progressing fatal encephalomyelitis and radiculoganglionitis. Histologically, eosinophilic viral inclusions (Negri bodies) are noted in the cytoplasm of the neurons, most conspicuous in the large neurons like pyramidal neurons of the hippocampus and cerebellar Purkinje cells [Figure 3]c, [Figure 3]d, [Figure 3]e.[39],[40],[41] Despite widespread brain involvement, inflammation and cerebral edema are inconspicuous (unlike most viral infections). Two clinical forms of rabies occur, encephalitic (furious) form (70-80%) with pathology mainly in the limbic cortex, cerebellum, brainstem, and the Paralytic (dumb) form (20–30%) restricted to lower brain stem and spinal cord with peripheral nerve demyelination.

Human immunodeficiency virus[42]

The virus infects CNS tissue early, and CSF abnormalities (raised lymphocyte count and protein, with normal glucose) are seen in up to 20% of untreated HIV-infected individuals even in the absence of CNS symptoms. Primary HIV infection can cause aseptic meningitis or meningoencephalitis during seroconversion, often accompanied by lymphadenopathy and a maculopapular rash. This stage is highly infectious with high viral loads.[43] Neuropathology due to HIV can be due to direct infection or secondary to opportunistic infections (commonly cryptococci, Toxoplasmosis, CMV, TB, PML) and neoplasms (primary CNS B cell lymphoma).

Direct infection: The virus can infect the brain, spinal cord, and peripheral nerves and cause (a) HIV encephalitis, (b) HIV leukoencephalopathy, (c) diffuse poliodystrophy, and in the late stages – AIDS dementia complex (HIV-associated dementia/HIV-associated cognitive motor complex). The risk of HIV dementia correlates with CSF viral loads. CD4 Count below 50/mL has the greatest risk of neurocognitive impairment.

Pathology: In the early stages, the brain appears normal, and in advanced stages, there may be atrophy with bilateral ventricular enlargement (hydrocephalus ex vacuo). Histologically, there is microglial nodular encephalitis with multiple discrete nodules of microglial cells, macrophages, and variable perivascular lymphocytic infiltrates involving the cerebral cortex, white matter, deep gray structures, brainstem, and cerebellum. Distinctive small multinucleated giant cells are seen that contain HIV proteins, including gp120, p24, which is very useful in confirming the diagnosis. There may be evidence of neuronal loss involving the frontal cortex, substantia nigra, cerebellum, and putamen. Basal ganglia calcifications can occur.[44],[45],[46] HIV leukoencephalopathy is characterized by focal/diffuse myelin changes with axonal degeneration and axonal spheroids accompanied by astrocytic proliferation.

HIV-related diffuse Poliodystrophy is characterized by loss of dendritic processes and neurons in the cerebral cortex and deep grey structures. HIV “vacuolar myelopathy” is characterized by spongy degeneration of myelin involving the lateral and posterior columns of the spinal cord.

DNA Viruses: The important DNA viruses that involve the CNS are chiefly Herpes group of viruses and include Herpes simplex type 1 virus (HSV-1), Herpes simplex type-2 virus (HSV-2), Varicella zoster virus (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human herpesviruses 6 and 7.

Herpes simplex virus – 1 [HSV1]

HSV-1 commonly affects young adults. The route of entry is mainly contaminated saliva or respiratory secretion. Initial infection is characterized by nasopharyngitis, which probably migrates to the trigeminal ganglia through a retrograde axonal transport and remains latent in the trigeminal ganglia. Reactivation causes herpes vesicles on lips (cold sore) or oral mucosa following the innervation of the trigeminal ganglia distribution. The virus extends to the brain either by the spread of the virus along the trigeminal nerve roots or dural nerves to meninges or from the nasopharyngeal infection through olfactory nerves to frontobasal and temporal regions.[47],[48] The virus has a predilection for temporal lobes (especially medial and basal), the limbic system, including cingulate gyri, insular, and orbitofrontal cortex.

Pathology: HSV1 causes hemorrhagic necrotizing encephalitis involving the fronto-orbital, cingular, and temporomesial regions, petechial hemorrhages in the leptomeninges and cerebral cortex of the affected regions. These regions show significant edema and congested blood vessels.

Histologically, these regions show dense perivascular and diffuse infiltration by lymphocytes, neutrophils, and macrophages along with pericapillary hemorrhages; neuronal destruction, neuronophagia, necrosis with prominent eosinophilic intranuclear inclusions (Cowdry type A) in the hippocampal neurons and glial cells [Figure 3]h. Chronic lesions show atrophy of the brain and cystic necrosis with gliosis.

Herpes simplex virus-2 [HSV-2]

HSV-2 infection is acquired through sexual contact, and the virus remains latent in the sacral spinal ganglia. Reactivation causes genital herpes. CNS involvement causes aseptic meningitis, myelitis, and radiculitis. In neonates, severe necrotizing encephalitis/myelitis occurs following exposure to an infected birth canal during parturition.

Varicella-Zoster virus infection

VZV infection is through the respiratory route and causes Varicella (chickenpox), a benign exanthematous disease (affecting mainly young children), and Herpes zoster in adults. The clinical course may be more severe in adults and display rare complications like cerebellitis, postinfectious encephalomyelitis, and encephalopathy of Reye's disease.[49] The virus persists in spinal ganglia neurons and causes lesions in the PNS, CNS, skin, and blood vessels with reactivation. Herpes Zoster (shingles) occurs when viruses pass from ganglia to skin along sensory nerves.[50] This mainly affects adults.

The pathology includes (a) radiculoganglionitis with severe cases, showing hemorrhage and necrosis of the ganglia with the extension of the inflammation into the spinal cord; (b) Granulomatous angiitis of large arteries; (c) Vasculopathy of small vessels associated with multiple infarcts and foci of demyelination.[51],[52]

Cytomegalovirus causes a broad spectrum of clinical-pathological presentations, including aseptic meningitis, encephalitis with microglial nodules, ventriculitis (necrotizing) with calcifications; radiculomyelitis/radiculoneuropathy; and retinitis.[53] They infect various cells, including glial cells, ependymal cells, and vascular endothelial cells. The infected cells show cytomegaly with enlargement and characteristic intranuclear (owl's-eye) Cowdry type A inclusions [Figure 3]g. Congenital and neonatal CMV causes microcephaly, mental retardation, seizures, hearing impairment, chorioretinitis, and cerebral malformations.[54]

Progressive Multifocal Leukoencephalopathy (PML) is caused by the JC virus (John Cunningham virus). It mainly affects immunocompromised adults. The virus remains dormant in the reticuloendothelial system and kidney and gets reactivated in immunodeficiency states system.

Pathology: Grossly, the white matter shows multiple, ill-defined, soft, slightly granular lesions. Histologically multiple confluent demyelination with relative sparing of axons will be seen. Important histological findings include giant, bizarre, often multinucleated astrocytes (due to a nonpermissive infection). Enlarged oligodendrocytes are seen in the demyelinated areas with inclusions (permissive infection) that are large, round, with violaceous/amphophilic characters that fill the infected oligodendrocytes' nucleus, maximally seen at the periphery of demyelinating lesions.[55],[56] Lymphocytic inflammation is minimal in immunocompromised patients. Severe inflammation with few viral inclusions may be observed in patients with immune reconstitution inflammatory syndromes (IRIS).[57]

Noninfectious mimics: The inflammation of the CNS may be caused by non-infectious conditions, such as post-infectious, paraneoplastic, or chronic autoimmune disorders. Multiple Sclerosis (MS) is the prototype of demyelinating lesion that can be extensive and chronic with a broad spectrum of neurologic symptoms. Tumefactive demyelination, presenting as a mass lesion measuring >2 cms, with ring enhancement on MR is a close histologic mimic.[58] This is characterized by demyelination with inflammation, many macrophages (especially foamy macrophages), and reactive gliosis. The autoimmune encephalitis includes NMO spectrum disorders (NMO, isolated optic neuritis, or myelitis) and Anti-myelin oligodendrocyte glycoprotein (MOG) associated encephalitis. The paraneoplastic diseases present as a plethora of clinical syndromes, namely, limbic encephalopathy, cerebellar degeneration, stiff-person syndrome, opsoclonus myoclonus, etc. Post-infectious central nervous system inflammation is acute disseminated encephalomyelitis (ADEM), a monophasic demyelinating is an autoimmune disease involving the CNS. Behçet's disease, a chronic, relapsing, autoimmune, multisystem, can cause brainstem, diencephalic, or corticospinal tract dysfunction, and meningoencephalitis. CNS vasculitis (primary or secondary) can mimic many other lesions (infective and neoplastic pathologies). Diagnosis of these requires close clinicoradiologic correlation. Some of these have specific serological tests for confirmation, but majority are a diagnosis of exclusion.

In conclusion, infections of CNS are caused by a broad spectrum of infectious agents and are associated with a significant risk of morbidity and mortality. The infection can affect both immunodeficient and immunocompetent individuals, although the prevalence and severity are greater in the former. They can present with a wide spectrum of clinical and radiologic features, thus posing a great diagnostic challenge. An infective pathology should always be kept in the differential diagnosis of single or multiple mass lesions with prominent surrounding edema. The histopathology and other laboratory tests play a great role in confirming the diagnosis while ruling out the mimickers. An approach to the diagnosis is provided in [Figure 4]. The clue to the histological diagnosis lies in the pattern of tissue response, and the definite diagnosis requires demonstration of the pathogen. Knowledge of pathologic changes is necessary to recognize etiological agents, institute early therapy, and prevent morbidity and mortality.
Figure 4: Algorithm showing the histopathological approach to non-granulomatous inflammatory lesions

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Correspondence Address:
B N Nandeesh
Additional Professor, Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_114_22

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