Neuropathology of HIV/AIDS With an Overview of the Indian Scene

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Fungal infections

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ith_an_overview_of_the_indian_scene/

Fungal infections involving the brain in the vast majority are

secondary to a primary focus elsewhere, most often in the lungs or

intestine. But the primary focus remains unrecognized in most of the

cases, and the only evidence of infection at the time of

presentation would be in the nervous system.

Cryptococcal meningitis (CM)'. Among the fungal infections affecting

the CNS, CM due to Cryptococcus neoformans is the most common HIV

associated complication both in developed and developing

countries14'16. Signs and symptoms of CNS cryptococcal infections

are often subtle and nonspecific, evolving over days or weeks with

often only a mild headache as the presenting manifestation. Focal

neurological deficits, signs of meningeal irritation and papilledema

may be lacking and radiological investigations including computed

tomography (CT) and magnetic resonance imaging (MRI) non-

contributory. The importance of being alert to this condition lies

in the fact that it is easily treatable and diagnosis requires only

a simple examination of CSF to demonstrate the budding yeast forms

of the fungus. But if the diagnosis is missed, the patient can

deteriorate rapidly within hours to days. A clinical aphorism often

stated is that headache in advanced HIV disease is cryptococcal

meningitis until proved otherwise. Cryptococcal meningitis

complicates AIDS when the CD4 counts fall below 100 cells/ul. Sex,

race and other opportunistic infectio\ns do not significantly alter

the risk of CM in HIV patients15.

Approximately 5-10 per cent of HIV infected patients will develop CM

as an AIDS defining illness17, and in about 40 per cent patients, it

may be the initial manifestation of HIV infection18. There is

however, a wide geographic variation from 2 per cent in Northern

Europe to 20-30 per cent in Africa and South East Asia19. In a

preliminary analysis of 588 cases of HIV infection (from 1990-2002)

at the Neurological services, National Institute of Mental Health

and Neurosciences (NIMHANS), Bangalore, south India, cryptococcal

infection was detected in 25 per cent of cases, preceded by

neurotuberculosis (30%), with both cryptococcus and tuberculosis co-

existing with toxoplasmosis in 12 per cent of cases (Satishchandra

P, unpublished data). Another clinical series from western India

reported cryptococcal meningitis in 67.4 per cent of cases and

tuberculous meningitis (TBM) in 18.6 per cent of cases20.

On the other hand, in an autopsy series of 134 cases (between 1990-

2004) from NIMHANS, cryptococcal infection of nervous system topped

the list accounting for 31.3 per cent cases, followed by

toxoplasmosis (20.8%) and tuberculous meningitis in 20.1 per cent of

cases as monomicrobial infections (Shankar SK, unpublished data).

The discrepancy between the clinical and autopsy data could be

attributable to systemic cryptococcal infection masquerading

clinically and radiologically as mycobacterial infection and the

clinical bias because of endemicity. Recognition of the entity

of 'cryptococcal primary complex' similar to Mycobacterium

tuberculosis infection can provide an insight into the biology of

this infection. It is likely that cryptococcal meningitis in cases

of HIV could be reactivation of the dormant lesion in the lung

similar to Ghon's focus of pulmonary tuberculosis.

The fungus is a common soil contaminant being excreted in feces of

several birds particularly pigeons. In HIV patients as well as in

other immunocompromised states, cryptococcal infection is caused

almost exclusively by the neoformans variant Infection occurs via

inhalation and primary infection is localized to the lung from where

there is dissemination to other organs including brain. The

resulting lung infection is usually asymptomatic. Spread to the

brain most often causes leptomeningitis very similar to

tuberculosis. The CSF facilitates establishment of infection because

it lacks complement and immunoglobulins and thereby acts as a good

culture medium for the fungus. CNS involvement by the fungus causes

a leptomeningitis and uncommonly a meningoencephalitis.

Cryptococcomas (localized granulomas) are extremely rare.

In addition to nonspecific clinical complaints like fever, altered

mental status, nausea and vomiting, and severe headache, elevated

intracranial pressure (ICP) is reported in excess of 50 per cent of

HIV-1 infected patients with CM21 without accompanying hydrocephalus

or cerebral oedema. A retrospective study of 119 cases of

Cryptococcus with HIV from NIMHANS, south India, the cranial CT

scanning revealed features of cerebral atrophy in 19 per cent and

hydrocephalus in 10 per cent of cases (unpublished data). In the

study from NIMHANS, nearly 90 per cent of cases of cryptococcal

meningitis manifested with " unbearable headache " with or without

mild fever resembling acute subarachnoid haemorrhage. The severe

headache abated spontaneously after two to three weeks of antifungal

therapy, but did not respond to mannitol and steroid therapy

suggesting pathogenetic mechanisms other than cerebral oedema is

responsible for the headache (Satishchandra P, unpublished

observations). Saag et al21 emphasized that elevated intracranial

pressure has been reported in excess of 50 per cent of HIV-I

infected patients with CM but in the absence of accompanying

hydrocephalus or cerebral oedema. An opening CSF pressure of 250-

350 mmH^sub 2^O has been recorded22. Importantly, clinical signs of

raised intracranial pressure were absent even in those patients with

highest pressures. The pathophysiology of this increased ICP in the

absence of associated clinical signs has not been fully

elucidated17. A preliminary pathological study of the brain and the

durai venous sinuses in our autopsied cases (unpublished data)

revealed plugging of the arachnoid villi by masses of cryptococci,

at places almost occluding the venous sinuses. This could be

responsible for impendence to CSF circulation leading to dynamic

hydrocephalic attacks, not recognized in cranial CT scan or MRI in

majority of instances.

Pathological examination of the brain in cryptococcal meningitis

typically shows mucinous exudates covering the superolateral aspect

of the brain, unlike the basal exudates of tuberculous

arachnoiditis. It also produces multiple cystic nongranulomatous

parenchymal lesions in basal ganglia and thalamus, and the cortical

ribbon, which suggest haematogenous spread of the fungus and

entrapment around the endarteries of the pial, lenticulostriate and

thalamostriate vessels especially with relatively long duration of

illness. Inflammatory response to the fungus is characteristically

sparse as the capsule of the cryptococci inhibit phagocytosis and

impair leukocyte migration23. Giant cell reaction to the cryptococci

or granulomatous reaction to produce cryptococcomas are not often

seen. Rarely large plaque like demyelinating lesions resembling

progressive multifocal encephalopathy (PML) on imaging and gross

pathology are seen. This probably represents dispersal of the

organisms along the medullary veins, following blockage of superior

sagittal sinus and venous impedence.

Of the diagnostic modalities available, cryptococcal antigen in CSF

and serum is virtually always positive except in very early stages

of the disease or in cryptococcomas. Sensitivity of India ink test

on CSF is approximately 70 per cent24. Fungal culture is useful only

for speciation of the organism and sensitivity to antifungal agents.

In a comparative study of cryptococcal meningitis with and without

associated HIV from our centre25, it was noted that poor CSF

inflammatory cell response, positive culture of cryptococci from

extraneural sites and systemic dissemination are common when

associated with HIV infection and connote a poor prognosis. Clinical

indicators of poor prognosis include depressed level of

consciousness, development of signs of raised intracranial tension,

markedly depressed CSF glucose, CSF white cell count below 20/mm3,

and cryptococcal antigen titre greater than 1024(15).

Other mycoses: Other mycoses documented in HIV/ AIDS include

aspergillosis which produce multiple abscesses and rarely

granulomas, candidiasis also causing abscesses in brain from

haematogenous dissemination from primary focus in respiratory or

gastrointestinal tract, and coccidioidomycosis presenting as a basal

meningitis causing hydrocephalus or cerebellar or brain stem

abscesses. These are however extremely rare and confined to case

reports. Even rarer is involvement by Nocardia asteroides,

Histoplasma capsulatum causing meningoencephalitis, zygomycosis, and

Cladosporium bantianum. 'Narendra Singh from Manipur reported26

increased incidence of Penicillium marneffei infection among

patients with AIDS next to tuberculosis and Pneuomocystis carninii

pneumonia. Infection by this fungus is commonly reported from

Thailand where it is the third commonest AIDS defining opportunistic

infection. In India, other than from Manipur, there are no reports

of this mycoses from anywhere else till date.