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REVIEW ARTICLE
Year : 2007  |  Volume : 55  |  Issue : 3  |  Page : 221-225

Fungal infections of the central nervous system: The clinical syndromes


Department of Neurology, The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India

Date of Acceptance30-Aug-2007

Correspondence Address:
J.M.K Murthy
Department of Neurology, CARE Hospital, Exhibition Road, Nampally, Hyderabad - 500 001
India
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DOI: 10.4103/0028-3886.35682

PMID: 17921650

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 » Abstract 

Fungal infections of the central nervous system (CNS) are being increasingly diagnosed both in immunocompromised and immunocompetent individuals. Sinocranial aspergillosis is more frequently described from countries with temperate climates, more often in otherwise immunocompetent individuals. The clinical syndromes with which fungal infections of the CNS can present are protean and can involve most part of the neuroaxis. Certain clinical syndromes are specific for certain fungal infections. The rhinocerebral form is the most common presenting syndrome with zygomycosis and skull-base syndromes are often the presenting clinical syndromes in patients with sinocranial aspergillosis. Subacute and chronic meningitis in patients with HIV infection is more likely to be due to cryptococcal infection. Early recognition of the clinical syndromes in an appropriate clinical setting is the first step towards achieving total cure in some of these infections.


Keywords: Clinical syndromes, fungal infections, rhinocerebral syndromes, sinocranial aspergillosis, skull-base syndromes


How to cite this article:
Murthy J. Fungal infections of the central nervous system: The clinical syndromes. Neurol India 2007;55:221-5

How to cite this URL:
Murthy J. Fungal infections of the central nervous system: The clinical syndromes. Neurol India [serial online] 2007 [cited 2014 Apr 18];55:221-5. Available from: http://www.neurologyindia.com/text.asp?2007/55/3/221/35682


Fungal infections of the central nervous system (CNS) are being increasingly diagnosed. Two main factors contribute to this steady increase of fungal infections, namely the widespread use of antibacterial agents and a rapid increase in the numbers of the immunocompromised population. [1],[2] Modern therapeutic modalities such as cancer chemotherapy and organ transplantation have greatly increased the immunocompromised population who are at a risk of invasive fungal infections. [1],[3] Fungal infections of the CNS account for a significant proportion of opportunistic infections in patients with HIV. [4]

Most of the fungi are aerosolized and inhaled and initiate a primary pulmonary infection which is usually self-limited. Hematogenous dissemination may follow the initial infection, with subsequent involvement of the CNS. Local extension from paranasal sinuses, ear and orbit [5] and rarely trauma [6] also provide the route to intracranial spread. The hyphae or molds (species of Aspergillus , Rhizopus ) generally cause focal disease with hemorrhagic necrosis secondary to vascular thrombosis. The yeasts (species of Cryptococcus ) tend to cause a more diffuse process with the base of the brain being primarily affected.

The clinical syndromes with which CNS fungal infections present largely depends on the pathological reaction elicited by the fungus in the host. This interaction between the organism and the host is a complex one and depends on the virulence of the organism, the antigen makeup of the species and the immune status of the host. The host is frequently, although not always, immunocompromised. [7] Predisposing factors are helpful in defining host defense. Disorders of phagocytic function predispose patients to the development of CNS aspergillosis, mucormycosis and candidiasis. Impairment of cell-mediated immunity predisposes patients to CNS cryptococcal, histoplasmal, coccidioidal and blastomycotic infections. Impairment of granulocyte function predisposes to CNS infection with Candida spp., Aspergillus spp., and Zygomycetes spp. [8] However, fungal infections can occur in otherwise immunocompetent individuals. Most of the patients with CNS aspergillosis reported from the Indian subcontinent are otherwise immunocompetent. [5],[9],[10]


 » Clinical Syndromes Top


The clinical syndromes with which fungal infections of the CNS can present are protean [Table - 1]. These clinical syndromes can occur either alone or in combination. Certain clinical syndromes are specific for certain fungi [Table - 2]. The rhinocerebral form is the most common presenting syndrome with zygomycosis. [11] Because of the contiguous spread of the infection from the adjacent paranasal sinuses and orbit, skull-base syndromes are often the presenting clinical syndromes in patients with sinocranial aspergillosis. [5],[12],[13],[14]

Meningitis

Meningitis and meningoencephalitis can be the presenting clinical syndrome with most of the yeasts ( Cryptococcus spp. Blastomyces spp., Coccidioides spp., Paracoccidioides spp., Sporotrichum spp., Histoplasma spp. and Candida spp.) as they have access to the microcirculation from which they seed the subarachnoid space.

Meningitis is the predominant presenting clinical syndrome of cryptococcal infection. [15],[16],[17],[18],[19],[20] Approximately 5-10% of HIV infected patients will develop cryptococcal meningitis as an AIDS-defining illness. [21] In about 40% of patients, it may be the initial manifestation of HIV infection. [22] Meningitis may be a manifestation of widely disseminated histoplasmosis or an isolated illness. Central nervous system involvement is clinically recognized in 5-10% of cases of progressive disseminated histoplasmosis. [23] Meningitis can be the presenting feature of primary phaeohyphomycosis of CNS (9%), more often in an immunocompetent host. [24] The most significant complication of Coccidioides infection is meningitis. [25] Meningitis caused by Aspergillus spp. is very rare. [26],[27] Recently, a case series of aspergillus meningitis has been reported from Sri Lanka. It was suggested that it could be a post-tsunami effect. [28] Bichili et al . [29] reported a healthy subject with meningitis and granulomatous following zygomycetes infection.

Fungal meningitis tends to be a subacute or chronic process, however, it may be just as lethal as bacterial meningitis if untreated. [30],[31] Fungi that produce a meningoencephalitis usually begin in the meninges as a meningitis and reach the brain by penetrating the brain's Virchow Robin spaces adjacent to the meninges. [32] Meningoencephalitis is associated with altered mental status and seizures. Fungi can also produce meningeal vasculitis with vessel thrombosis and localized brain infarctions. [33] Zygomycetes spp. and Aspergillus spp. are highly angioinvasive causing an arteritis or phlebitis that may result in vessel thrombosis or rarely rupture of the vessel wall with an accompanying cerebral or subarachnoid hemorrhage. [5],[9],[11] The clinical manifestations may include focal neurological deficits and seizures.

Hydrocephalus and elevated intracranial pressure (ICP) are complications of chronic fungal meningitis. Elevated intracranial pressure (ICP) is reported in excess of 50% of HIV-1 infected patients with cryptococcal meningitis without accompanying hydropcephalus or cerebral edema. [17] Importantly, clinical signs of raised intracranial pressure were absent even in those patients with highest opening pressures. [34]

Intracranial mass lesions

Histologically, the parenchymal mass lesions with fungal infections can be either an abscess or a granuloma. Abscess formation is common with certain fungi, Phaeohypomycosis spp., [5],[9],[24],[35] Zygomycetes spp., [5],[11],[36] Candida spp., [5] and rarely with Aspergillus spp. [9]

Intracranial both intra- and extraparenchymal aspergillus granulomas are more frontal and temporal in location and rarely parietal, either with a focus in the paranasal sinuses or with no obvious sources. [5],[9],[10],[14],[37],[38],[39],[40],[41],[42],[43],[44]

Patients with mass lesions present with focal deficits and raised intracranial pressure. Increased intracranial pressure can result from the mass effect of the lesion and/or surrounding cerebral edema. The focal deficits depend on the location of the lesion. [45]

Skull-base syndromes

Cranial and intracranial extension is frequent in patients with invasive type of Aspergillus sinusitis. [5],[10],[12],[13],[46] Basifrontal and basitemporal aspergillus granulomas in otherwise immunocompetent individuals have largely been reported from countries with tropical climate. [5],[9],[10],[13],[14],[43],[47],[48],[49]

Patients with sinocranial aspergillosis may present with skull-base clinical syndromes [Table - 3]. [5],[9],[10],[12],[13],[14] Of the 21 patients with CNS aspergillosis studied by Murthy et al ., [14] 13 presented with skull-base syndromes: cavernous sinus syndrome in five, orbital apex syndrome in three, proptosis with associated limitation of ocular movements in two and cranial neuropathy with or without meningeal signs in three. Of the 89 patients with CNS aspergillosis reported by Sundaram et al ., [5] 64 patients presented with skull-base syndromes: sinocranial in 47, sino-orbito-cranial in nine and sino-orbital in eight.

Rhinocerebral syndrome

The rhinocerebral form is the most frequent presenting clinical syndrome in zygomycosis. [9],[10],[11],[36] Of the 56 patients with cerebral zygomycosis reported from two tertiary care centers in south India, [11] 44 (79%) patients presented with rhinocerebral syndrome. Of the 178 patients with invasive zygomycosis studied in a tertiary care center in north India, 54.5% of patients presented with rhino-orbito-cerebral form. [50] The clinical manifestations of the rhinocerebral form start as sinusitis, rapidly progressing to involve neighboring tissues like the orbit, eye and optic nerve and extend to the brain. Facial edema, pain, necrosis, loss of vision, black discharge along the nasal cavity angle of the eye and proptosis are usual features. As angio-invasion is very frequent, occlusion of the sphenopalatine artery and central retinal artery can occur, mostly effecting blindness. [11],[36]

Stroke syndromes

Fungal infections known to cause cerebrovascular involvement include Aspergillosis, Candidiasis, Zygomycosis, Coccidiodomycosis, Cryptococcosis and Histoplasmosis. Vascular involvement is usually associated with large vessel vasculitis by invasion or embolization. [51]

Cerebral vasculitis due to fungal infections producing thrombosis and large infarcts is extremely uncommon. [52],[53],[54],[55] Very rarely, fungal infections of the CNS with vasculitis can present with subarachnoid hemorrhage. [56],[57],[58] Sometimes both the pathological features can be the presenting features . Endo and colleagues [59] described a case of fatal subarachnoid hemorrhage, with brainstem and cerebellar infarction, caused by Aspergillus infection after cerebral aneurysm surgery. Extremely rarely intracerebral hemorrhage can be the complication of fungal infections of the CNS. Adunsky and colleagues [60] described an elderly patient with Aspergillus flavus meningitis and pontine hemorrhage.

Cardioembolic stroke can be the presenting feature of fungal endocarditis. Fungal endocarditis accounted for 1.3-6% of infective edocarditis. [61],[62] Candida is the most common causative organism of fungal endocarditis in both normal and immunocompromised hosts. [63] Aspergillus is the second most common cause. [63],[64]

Subarachnoid hemorrhage secondary to fungal mycotic intracranial aneurysm is an extremely rare complication. Intracranial aneurysms of fungal etiology are extremely rare and often the diagnosis is established at autopsy. Fungal mycotic intracranial aneurysms are usually found in the setting of disseminated hematogenous infection and fungal endocarditis. [65],[66],[67],[68],[69],[70],[71],[72],[73],[74] Rarely, they can occur following surgery [75] and rarely from contiguous spread from the paranasal sinuses. [76] In the first two settings the host is immunocompromised and in the latter settings the host is otherwise immunocompetent. The majority of intracranial fungal mycotic aneurysms are in the proximal portion of the major arteries at the base of the brain [65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76] and have been described with Aspergillus spp., Candida spp. and Zygomycetes spp. infections. Fungal mycotic aneurismal subarachnoid hemorrhage is often associated with very poor outcomes.

Spinal syndromes

Central nervous system fungal infections can rarely present as myelopathy and myeloradiculopathy. Infectious processes giving rise to spinal cord syndromes range from intramedullary granuloma or abscess, epidural abscess to focal spinal meningitis to frank fungal myelitis. Spinal cord involvement has been reported very rarely with aspergillosis. [77],[78],[79] It may be due to aspergilloma [78],[79] or epidural abscess. [80] Upper thoracic level of spinal cord is most commonly affected, caused by contiguous spread from lung. [79],[80],[81] Koh et al . [82] reported three children with myelopathy resulting from invasive aspergillosis. Spinal arachnoiditis has been described with aspergillosis and Cryptococcus neoformans. [83] reported spinal intramedullary abscess caused by Candida albicans . [84]

Fungal infections of the CNS are being increasingly diagnosed both in immunocompromised and immunocompetent individuals. The clinical syndromes with which fungal infections of the CNS can present are protean and can involve most part of the neuroaxis. Certain clinical syndromes are specific with certain fungi. The rhinocerebral form is the most common presenting syndrome with zygomycosis and skull-base syndromes are often the presenting clinical syndromes in patients with sinocranial aspergillosis. Subacute and chronic meningitis in patients with HIV infection is more likely to be due to cryptococcal infection. Early recognition of the clinical syndromes in an appropriate clinical setting [Table - 3] is the first step towards achieving total cure in some of these infections.

 
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    Tables

  [Table - 1], [Table - 2], [Table - 3]

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