aspergillosis of cns

7/28/2019 Aspergillosis of CNS

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Title: Intracranial Aspergillus Granuloma

Authors:

1. C Sundaram MD, FAMS, FIC PathSr. Professor and Head,

Department of Pathology

Nizams Institute of Medical Sciences,Panjagutta,Hyderabad 500 081, India.E mail: [email protected]

2. J M K Murthy MD, DM, FAMS, FAAN,Chief of Neurology,

The Institute of Neurological Sciences,

Care Hospital, Exhibition Road, Nampally,Hyderabad 500 001, India.

E mail: [email protected]

Corresponding Author:

C Sundaram MD, FAMS, FIC Path

Sr. Professor and Head,

Department of Pathology

Nizams Institute of Medical Sciences,

Panjagutta, Hyderabad 500 081, India.

E mail: [email protected]


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ABSTRACT

Intracranial fungal granulomas are rare and of the histologically verified granulomas,

Aspergillus sp. is the commonest causative fungal pathogen. Most of the reported

large series of aspergillus granulomas are from countries with temperate climate like

India, Pakistan, Sudan and Saudi Arabia. In contrast to disseminated aspergillosis

seen in immunosupressed individuals, most of the intracranial aspergillus granulomas

are reported in immunocompetent individuals. The temperature, humidity, high spore

content in the atmosphere during ploughing and occupation as agricultural worker are

implicated in the pathogenesis. The sinocranial spread is most common route of

intracranial extension. Extracerebral firm fibrotic lesions and skull base lesions are

common. Extensive fibrosis and large number of multinucleated giant cells are the

characteristic histological features and these pathological features have therapeutic

relevance.

Key words: Intracranial fungal granuloma, Aspergillus sp, pathogenesis, temperate

climate.

Text

Introduction:

Fungal infections of the central nervous system (CNS) are more frequently reported

in the last few decades mostly due to increase in the population at risk, increased

awareness, and better diagnostic modalities. [1-4]. However, in the recent years there

has been increase in the number of CNS fungal infections in immunocompetent

individuals [2-12].


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Fungi are ubiquitous in nature but have low virulence and cause disease usually when

the host defenses are compromised. The fungi enter the CNS by hematogenous route

from the systemic focus mostly from lungs or by contiguous spread from paranasal

sinuses (PNS), ear, skull, bone or by direct inoculation during trauma or surgical

procedure. [1-5] The pathology depends upon the route of spread, host immunity, and

type of fungus, hyphae or yeast. The fungi may involve any part of the neuroaxis and

the pathology includes meningitis, encephalitis, meningo-encephalitis, abscess,

granuloma, and vasculitis with associated infarction and hemorrhage and aneurysmal

formation. [1-4,13] The type of pathology, to some extent, determines the presenting

clinical manifestations. This review will discuss the experience with intracranial

aspergillus granuloma.

Epidemiology

The incidence of CNS fungal infections parallels the incidence of systemic fungal

infections. The estimated annual incidences of invasive fungal infections caused by

Aspergillus species are 12-34 per million population. [14] The reported incidence of

CNS involvement associated with invasive aspergillosis is about 4-6%. [15]

Intracranial aspergillus granulomas are rare space occupying intracranial lesions [2-

4,7,9,11,13-19] and most of the reported large series are from countries with

temperate climate like India, Pakistan, Sudan, and Saudi Arabia. [2-4,6-8,10, 12-25].

Among the intracranial fungal granulomas, aspergillus granuloma is the most

commonly reported granuloma. [2-4,13,18-24] (Table 1) The prevalence of

intracranial fungal mass lesions in major neurosurgical centers in India is around one

to two per years [26] and Aspergillus sp. is the commonest causative fungal


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pathogen, accounting for 56% to 69% of the intracranial fungal mass lesions

[2,17,18] whereas it was the causative fungus in 5% of the fungal mass lesions in the

series from USA. [27]

Pathogenesis

Aspergillus sp. is the most clinically significant moulds and is ubiquitous throughout

the world. They are present in soil, water, decaying vegetation, and organic debris.A.

fumigatus causes most disease followed by A.flavus and A. terreus. A flavus is the

commonest agent when the infection extends from PNS to CNS. [1-4]

Brain is remarkably resistant to fungal infections due to the abundant blood supply

and also due to the relatively impermeable blood-brain barrier. Despite the fact that

the brain and subarachnoid space are protected by anatomic and functional barriers,

under special conditions and immune system abnormalities fungal pathogens breach

these barriers. [28] Invasive disease is seen mostly in patients who are significantly

immunocompromised: patients with prolonged neutropenia, hematological

malignancies or advanced AIDS, and hematopoietic stem celltransplant and solid

organ transplant [29,30] Whereas, aspergillus granulomas in countries with

temperate climates, are most commonly reported in immunocompetent individuals.

[2, 7, 13]

The sino-cranial form of CNS aspergillosis is often reported from countries with

temperate climate. [2,7,13] In countries with temperate climate, the temperature and

humidity favor the growth of the fungus. Ploughing during agriculture works or

construction activities result in aerolization of number of spores into the environment.


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High spore content in the atmosphere exposes the agriculture workers and workers in

the construction activity to inhale the fungal spores. The spores are colonized in the

lungs, nose, PNS, mastoid air cells, and ear canal. Closed cavity and anaerobic

atmosphere promotes growth of the fungus. There may be local altered immunity

which promotes the mucosal invasion of the fungus. [1-4] The immunopathogenesis

of CNS fungal infections remains incompletely studied, with most of the knowledge

coming from studies on experimentally infected animals. The activation of brain

resident cells such as microglia, astrocytes, and endothelial cells combined with

relative expression of immune-enhancing and immune-suppressing cytokines and

chemokines may play a determinant role in immunopathogenesis. [28]

Pathology

Mostly these lesions, because of the sinocranial spread of the infection are

extraparenchymal and skull base in location. Skull base location includes anterior

and middle cranial fossae, orbit, orbital apex, cavernous sinus, and rarely posterior

fossa. (Figure 1) Rarely these lesions can be primarily intrapranechymal, involving

frontal and temporal lobes. [17,19] The location of the lesions probably explains the

clinical syndromes. Extracranial mostly skull base lesions with intra-axial extension

should strongly suggest the diagnosis of fungal mass lesion, more so in countries

with temperate climate. This feature can be used to differentiate it from a

neoplastic pathology.

Histologically the granulomas show dense fibrosis and an infiltrate of lymphocytes,

plasma cells and mononuclear cells. The multinucleate giant cells are foreign body

type and contain slender septate, acute angle branching hyphae ofAspergillus sp. The

extracerebral granulomas differ from intraparenchymal granulomas in having

extensive fibrosis. [17-19] Aspergillus granuloma on haematoxylin and eosin staining


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some times may be mistaken for tuberculous granuloma. However, the prominence of

multinucleated giant cells with admixture of neutrophils, plasma cells and eosinophils

and relatively less number of epitheloid cells differentiates tuberculous granuloma

from aspergillus granuloma. Good scanning of the biopsy may reveal fungal hyphae

within giant cells.

Gomoris methenamine silver (GMS) and Periodic Acid Schiff (PAS) stains

demonstrate the slender septate hyphae with acute angle branching of the Aspergillus

sp. in aspergillus granuloma. [17-19] [Figure 2] The extensive fibrosis observed in

the extraparenchymal, sinocranial aspegergillus granulomas has therapeutic

relevance. Extensive fibrosis does not allow effective penetration of systemically

administered antifungal agents. Thus these lesions need extensive radical excision to

achieve cure. [16,17] The other approach to achieve effective therapeutic

concentration of the antifungal agents will be intralesional administration of the

antifungal agents by Omaya reservoir. [16,17] The pathology of haematogenous

dissemination to CNS, because of angioinvasive character of aspergillus, includes

ischemic infarction and haemorrhage and the pathology in the sino-cranial

aspergillosis is characterized by well formed granuloma. [2]

Sinocranial Aspergillus Granuloma - Pathological Features Therapeutic

relevance

The striking pathological feature of aspergillus granulomas reported from the

countries with temperate climate is intense fibrosis. However, the

pathophysiology of this intense fibrosis is unclear. A. flavuscauses majority of

the sinocranial infections. A fumigatuselaborates a substance called fumigallin


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which can cause fibrosis [13]. Many allergens present in A. fumigatusare

present at high levels of homology in A. flavus. A.flavusproduces many allergic

proteins than the two currently known proteins (Asp fl 13 and Asp fl 18) and

may possess an allergen component similar to that ofA. fumigatus [35]. A. flavus

seems to be more virulent and more resistant to antifungal drugs than most of

the other Aspergil lus sp. It is possible that that some of the unidentified allergens

present in A. flavusmay have structural similarity to fumigallin and may be

responsible for the intense fibrosis seen with these granulomas.

The extensive fibrosis observed in the extraparenchymal, sinocranial aspergillus

granulomas has therapeutic relevance. Extensive fibrosis does not allow effective

penetration of systemically administered antifungal agents. Thus these lesions need

extensive radical excision to achieve cure. [8,16,17,29,31] The other approach to

achieve effective therapeutic concentration of the antifungal agents will be

intralesional administration of the antifungal agents by Omaya reservoir. [7,32,33]


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aspergillosis of cns

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