Infections of the central nervous system in malignant hemopathies

Central nervous system (CNS) infections in immunocompromised hosts are often accompanied by subtle disorders because immunosuppression usually decreases the inflammatory response. CNS infections in immunocompromised patients are usually caused by organisms different from those found in the general population. The organism causing CNS infection in an immunocompromised host can often be predicted if the type of immune abnormality of the patient is known. The common causes of CNS infection in immunocompromised hosts are reviewed here. Meningitis in patients with neutropenia is usually due to enteric Gram negative bacilli that live in the patient's own digestive tract. Pseudomonas aeruginosa is most common and is followed by E. Coli, Klebsiella, Enterobacter and Proteus. A major risk in patients with abnormal immunoglobulins or splenectomy is infection with encapsulated bacteria, particularly Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Meningitis caused by any of the encapsulated bacteria can be fulminant. Listeria monocytogenes is the most common cause of bacterial meningitis in patients with impaired cellular immunity. Nocardia asteroides is a leading cause of brain abscess in patients with hematologic malignancy. Most patients have evidence of concomitant pulmonary lesions. Fungi are among the most common organisms involving the CNS in immunocompromised hosts. Susceptible patients include those with lymphoma or leukemia and those who receive therapies aimed at suppressing delayed hypersensitivity. Cryptococcus neoformans is a common fungal cause of CNS infection in immunocompromised hosts. The primary site of infection is the lung. Spread to the CNS is via the blood stream. The clinical course is highly variable: meningitis, meningoencephalitis and focal mass lesions. Candida causes meningitis or meningoencephalitis characterized by multiple small abscesses in neutropenic hosts. Organisms reach the CNS via the blood stream usually from the digestive tract or infected intravenous catheters. Aspergillus causes brain abscess, cerebral infarction and focal meningitis in patients with neutropenia. The primary infection is in the lung. The parasites that infest the CNS of immunocompromised patients are usually those that exploit a T-lymphocyte, mononuclear phagocyte host defect. The most common are Toxoplasma gondii and Strongyloides stercoralis. There have been a few cases of amebiasis with dissemination to the brain in patients with hematologic malignancies. Toxoplasma gondii causes major CNS disease in immunocompromised hosts: meningoencephalitis or mass lesions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cerebral mycosis: 7‐year retrospective series in a tertiary center

This study focuses on the epidemiology, clinical manifestations, risk factors, diagnosis and outcome of all cases of central nervous system (CNS) fungal infections in a tertiary center. Medical records of 18 patients of culture‐proven CNS fungal infections were retrospectively reviewed from 2000 to 2007, including 12 isolated from the cerebrospinal fluid (CSF) and seven from tissue biopsy. Patient demographic data included 10 males and eight females. The mean age was 55 years (range: 24–89 years). All but one patient were immunocompromised. Fungal organisms isolated from CSF included: Cryptococcous neoformans (8 patients), Coccidioides immitis (3 patients), and Aspergillus versicolor (1 patient). Histopathology of seven biopsy cases revealed groups of pigmented golden‐brown fungal forms in three cases; three cases showed septate fungi, two of which had melanin in their walls; and one case showed multiple round spherules. These cases on microbiological cultures grew Coccidioides immitis (1 patient), Aspergillus fumigatus (1 patient), Cladophialophora bantiana (2 patients), Fonsecaea monophora (1 patient) and Scedosporium apiospermum (2 patients). Five of the seven fungal organisms isolated from tissue biopsies were dematiaceous fungi. Twelve patients died after a period of a few weeks to months, two were lost to follow‐up, and four are alive with severe neurological sequelae. CNS fungal infections in our cohort were more common in patients post‐transplant and with hematologic malignancies. In our series, rare dematiaceous fungi are emerging agents for cerebral mycosis. The outcome of CNS fungal infections is poor despite vigorous antifungal therapy.     

Pathobiology of fungal infections of the central nervous system with special reference to the Indian scenario

Ubiquitously present fungi in the environment find a nidus in the human body and adopt its metabolic machinery to be in symbiosis or become pathogenic. Immunocompromised states like human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), systemic neoplasia and organ transplantation have enhanced the frequency of fungal infections. High-risk behavior, IV drug abuse and air travel have led to the emergence of new fungal infections hitherto geographically localized. The pathology in the central nervous system (CNS) is dictated largely by the size of the fungus - the yeast forms, by virtue of their small size enter the microcirculation to cause meningitis and microabscesses, while hyphal forms invade the vasculature to manifest as large pale or hemorrhagic infarcts. The growth kinetics of fungi, the antigenic character of the capsule. the proteases secreted by the mycelial forms and the biochemical milieu in the host also determine clinical manifestations. A hospital-based analysis of the available information from India suggests that in the non-HIV patient population, hyphal forms like Aspergillosis and Zygomycosis are the most common pathogens, while yeast forms like Cryptococcus and Candida are the prime pathogens in cases of HIV/AIDS, the altered macrophage function acting in synergy with suppressed cell-mediated immunity. In Northeastern states, systemic infection by Penicillium marneffei is reported in association with HIV though CNS involvement is not recorded. Although fungal infections of the CNS are reported from various hospitals in India, studies are limited by non-availability of relevant microbiological studies and the reported prevalence data is biased by the surgical practices, availability of postmortem and microbiology and laboratory support. Detailed clinical and mycological investigations related to the interaction between the fungus and host environment is a fertile area of research to understand the basic pathogenetic mechanisms.     

Fungal meningitis

Fungi provide many benefits to humans. However, some of these fungi have the ability to become human pathogens. All the major fungal pathogens can produce meningitis. From the common cryptococcal meningitis to the rare fungal meningitis caused by a dimorphic or filamentous fungus, medical issues are discussed in this review on a fungus-specific basis. Both primary (Cryptococcus, Blastomyces, Histoplasma, Coccidioides, and other dimorphic fungi) and secondary (Aspergillus, Candida, and a series of molds) fungal pathogens can produce life-threatening central nervous system infections. These infections require immediate and precise diagnosis and carefully selected management strategies to optimize outcomes. In this review, we examine the epidemiology, pathogenesis, clinical manifestations, and treatment for fungal meningitis in all the major fungal groups.     

Bacterial and fungal brain infections in AIDS

Many bacterial and fungal pathogens can infect the central nervous system (CNS) in patients also infected with human immunodeficiency virus (HIV). Most of these organisms cause meningitis, and this is sometimes accompanied by focal parenchymal infection. More virulent pathogens, such as Mycobacterium tuberculosis hominis, can cause disease in individuals with mild degrees of HIV-associated immunosuppression. Less virulent pathogens, such as Cryptococcus neoformans, tend to affect individuals with more advanced immunosuppression. This review focuses on the clinical manifestations, diagnosis, and treatment of the more common bacterial and fungal CNS infections.     

Fungal infections of the central nervous system.

This review discusses a practical approach to the patient with possible fungal infection of the central nervous system (CNS). Difficulties in establishing the diagnosis come from the nonspecific clinical syndromes (subacute meningitis, meningoencephalitis, and brain abscess) and the low isolation rate of fungi from cerebrospinal fluid (CSF). Helpful diagnostic clues often come from knowledge of the patient's geographic travels, risk factors, evidence of systemic organ infection, and fungal serologic tests. Standard and new antifungal agents are evaluated and the initial and suppressive drug management of the common fungal infections is presented.     

Cerebrospinal fluid in infection of the central nervous system by yeasts of the genus Candida: analysis of 11 cases

This study is based on the analysis of 44 cerebrospinal fluid (CSF) samples from 11 patients with central nervous system (CNS) Candida infection. Risk factors for CNS fungal infection were present in all patients. Five had a chronic meningitis syndrome; two had acquired immunodeficiency syndrome (AIDS); two had cranial trauma followed by chronic meningities; one had intravascular disseminated coagulation syndrome and sepsis; and one had systemic candidiasis after kidney transplant. Etiological diagnosis was made in all by the CSF examination. Nine cases had positive CSF culture for Candida. Two patients presented the yeast in the direct examination, and one of them had reagent complement fixation test for Candida in three successive samples of CSF. Changes found in the CSF composition are discussed in order to evaluate the inflammatory response to CNS infection by Candida.     

Neurologic complications of systemic lymphoma.

Lymphoma denotes a heterogeneous group of neoplasms derived from lymphoreticular tissues. It can cause neurologic symptoms by infiltrating into the meninges or brain parenchyma. Alternatively, lymphomas may metastasize to bone or infiltrate into the epidural space via intervertebral foramina to cause neurologic dysfunction by compressing adjacent CNS structures. These direct effects can occur at any time during the disease process; most distressingly, meningeal infiltration may be the initial site of relapse after a complete remission. Diffuse and more undifferentiated lymphomas are much more likely to be responsible for producing either meningeal infiltration or intraparenchymal lesions. Direct CNS invasion by lymphoma is associated with significant patient morbidity and short survival despite intensive therapy; whether this manifestation of lymphoma can be prevented by prophylactic CNS treatment remains uncertain. CNS complications may also occur as a result of indirect effects of lymphoma. Therefore, CNS dysfunction may develop as a result of infections that occur secondary to immunosuppression, as a result of antineoplastic therapies, or as a result of true paraneoplastic syndromes. It is important to distinguish between these indirect effects and tumor progression because their recognition permits frequently available appropriate treatment modalities to be administered.     

Cerebrovascular disease in central nervous system infections

Cerebrovascular disease is a complication of a variety of infections affecting the central nervous system (CNS). Infection may cause vasculitis affecting primarily the vessels at the base of the brain in the setting of meningitis; an immune-mediated parainfectious process leading to vasospasm or thrombosis; or a hypercoagulable state in combination with endothelial dysfunction resulting from activation of inflammatory and procoagulant cascades. Although systemic signs and symptoms may be present to aid in the diagnosis, cerebral infarction secondary to infection may be indistinguishable from more typical causes of stroke. Confirmation of an infectious vasculitis may also be challenging, as brain biopsy, the gold standard for diagnosis, is rarely pursued. In many CNS infections, vascular complications portend a poor prognosis as they are often associated with devastating neurologic outcomes, including death, underscoring the importance of early recognition and appropriate therapy. In this review, we address bacterial, viral, fungal, and parasitic causes of cerebrovascular disease.     

Fungal infections of the central nervous system: A review of fungal pathogens and treatment

Multiple factors influence the outcome of fungal infection of the central nervous system (CNS). The host and the pathogen in concert with drug delivery across the blood-brain barrier and drug activity are key factors in outcome. Drug costs can be prohibitively expensive. Drug toxicity with standard antifungal agents such as amphotericin B (infusion rate toxicity) can be reduced using simple techniques such as slower infusion and appropriate saline loading. Continuous infusion can allow relatively large doses of amphotericin B (up to 2 mg/kg/day, remaining below 0.08 mg/kg/hour) to be given with toxicity profiles comparable to expensive lipid formulations of amphotericin B. Dedicated peripherally inserted central catheters can remain in situ for weeks to months and are safe and relatively inexpensive. Correction of metabolic pathology in the case of mucormycosis and resolution of neutropenia are essential to effective treatment of filamentous fungal infections such as Mucor, Aspergillus and Scedosporium. The pharmacology and pharmacokinetics of the current major antifungal agents used to treat fungal infections of the CNS are reviewed. Tables that provide information about achievable CNS drug levels, antifungal susceptibilities and the likelihood of intrinsic drug resistance of significant fungal pathogens have been included to help the clinician with therapy. Treatment recommendations for Cryptococcal and Candida meningitis and for rhinocerebral infection with Mucor and Aspergillus have been included.     

Dissemination of C. neoformans to the central nervous system: role of chemokines, Th1 immunity and leukocyte recruitment

Cryptococcus neoformans is a fungus that possesses two properties unique for yeast: (1) production of a polysaccharide capsule and (2) neurotropism. The natural route of infection by C. neoformans is the respiratory tract; thus, factors that regulate the development and recruitment of memory Th1 cells and monocytes into the brain are critical for an effective response against disseminated C. neoformans infection. Production of TNFalpha prior to day 7 is required to prevent colonization of the central nervous system (CNS). Th1 type immunity is required to clear established foci. In contrast, Th2 type immunity is ineffective at eliminating the infection in the brain and results in decreased survival. C. neoformans infection of MIP-1alpha and CCR5 knockout mice has highlighted the complex role that some chemokines may play in different organs. MIP-1alpha knockout mice have decreased leukocyte recruitment and cryptococcal clearance from the brain compared to wild-type mice. Thus, the host defence mechanisms that clear C. neoformans from the CNS appear to be similar to those in the lungs: via a Th1 cell-mediated inflammatory response that requires chemokines for the recruitment of effector cells.     

MHC class II-positive perivascular microglial cells mediate resistance to Cryptococcus neoformans brain infection

Acquired resistance to the CNS pathogen Cryptococcus neoformans is mediated by CD4(+) T lymphocytes primed by exposure to antigen in the context of major histocompatibility class II (MHC II) molecules. In mouse brain, parenchymal and perivascular microglial cells may express interferon-gamma (IFN-gamma)-inducible MHC class II marker and thus interact with CD4(+) T cells. Primed effector T cells are retained in the infected CNS if antigen is encountered in proper MHC context and may deliver signals that potentiate microglia to enhanced fungistasis. Vaccinated C57BL6/J mice resist an ordinarily lethal C. neoformans rechallenge, but identically treated congenic Abeta(o/o) mice (MHC class II-deficient; CD4(+) T-cell-deficient) do not. Nor can Abeta(o/o) mice be adoptively immunized by infusion of lymphocytes from vaccinated C57BL6/J donors, as are severe combined immunodeficient (SCID) mice (MHC class II-intact, lymphocyte-deficient). Chimeric (C57BL/6J:Abeta(o/o)) mice with class II expression likely on perivascular microglia only were, like SCID mice, capable of adoptive immunization against C. neoformans brain infection. To the contrary, chimeric mice with class II expression likely only on parenchymal microglia were not capable of effective adoptive immunization against C. neoformans brain infection. Therefore, in order to mediate resistance to infection, primed CD4(+) T cells must interact with the replenishable perivascular microglial subset that lies in close proximity to cerebral vasculature. Although T cells may supply help in the form of inflammatory cytokines to parenchymal microglia, expression of class II on these cells appears unnecessary for antifungal activity.     

Emerging epidemic viral encephalitides with a special focus on henipaviruses

In the last few decades, there is an increasing emergence and re-emergence of viruses, such as West Nile virus, Enterovirus 71 and henipaviruses that cause epidemic viral encephalitis and other central nervous system (CNS) manifestations. The mortality and morbidity associated with these outbreaks are significant and frequently severe. While aspects of epidemiology, basic virology, etc., may be known, the pathology and pathogenesis are often less so, partly due to a lack of interest among pathologists or because many of these infections are considered “third world” diseases. In the study of epidemic viral encephalitis, the pathologist’s role in unravelling the pathology and pathogenesis is critical. The novel henipavirus infection is a good example. The newly created genus Henipavirus within the family Paramyxoviridae consists of two viruses, viz., Hendra virus and Nipah virus. These two viruses emerged in Australia and Asia, respectively, to cause severe encephalitides in humans and animals. Studies show that the pathological features of the acute encephalitis caused by henipaviruses are similar and a unique dual pathogenetic mechanism of vasculitis-induced microinfarction and parenchymal cell infection in the CNS (mainly neurons) and other organs causes severe tissue damage. Both viruses can cause relapsing encephalitis months and years after the acute infection due to a true recurrent infection as evidenced by the presence of virus in infected cells. Future emerging viral encephalitides will no doubt continue to pose considerable challenges to the neuropathologist, and as the West Nile virus outbreak demonstrates, even economically advanced nations are not spared.     

Candida tropicalis brain abscess in a neonate: An emerging nosocomial menace

Fungi are a relatively uncommon cause of brain abscess in neonates and early infancy. They are usually associated with predisposing factors like prematurity, low birth weight, use of broad-spectrum antibiotics, and prolonged stay in the intensive care unit. Candida tropicalis (C. tropicalis) is rapidly emerging as a nosocomial threat in the neonatal intensive care settings. This case report describes a neonate with C. tropicalis brain abscess who was diagnosed early and managed aggressively with a favorable outcome. Inadvertent use of intravenous antibiotics can have serious complications such as invasive fungal infection. Correct microbiological diagnosis is the key to successful treatment of deep-seated pyogenic infection. Fungal etiology should always be studied in relevant clinical settings.     

The association between central nervous system (CNS) infections and epilepsy: Epidemiological approaches and microbiological and epileptological perspectives

The causal association between central nervous system (CNS) infections and epilepsy is predictable but poorly documented due to constraints in epidemiological, epileptological, and microbiologic methods. The large number of CNS infections with varied geographic distributions means that epidemiological studies in many different regions are required in order to establish their association with epilepsy. Whenever infectious diseases occur in the community, the majority of the infected cases are either asymptomatic or develop only mild symptoms. Those with neurological involvement and hence at risk of developing epilepsy constitute the tip of the iceberg. Furthermore, there is no one-to-one relationship between surrogate markers of infection used in epidemiological studies (e.g., seropositivity or brain imaging abnormalities) and neurological involvement (and hence epilepsy). As a result, there are individuals in the community who have no neurological symptoms but may either be seropositive or demonstrate imaging abnormalities compatible with the neurological infectious disorder and conversely, those who have seizures (or epilepsy) but may be seronegative. Relevant to the epidemiological study of seizures and epilepsy in relation to CNS infections is the classification of seizures as provoked and unprovoked . Accordingly, seizures that occur during the active stage of infection are considered provoked and those that occur later are unprovoked . Finally, with the burden of infections being concentrated in the less-developed countries, epidemiological studies are required to be carried out in these locations, which present logistic, financial and technical barriers for them to be accomplished.     

Fungal infections of the CNS

Most CNS fungal infections can be divided into those that occur in normal hosts and those that occur in the immunosuppressed host. Cryptococcal infection, however, is common in both groups. The usual clinical presentation of a CNS fungal infection is chronic headache and mental status change. The CSF shows a lymphocytic meningitis with low sugar and high protein. Amphotericin B remains the drug of choice for most CNS fungal infections.     

Intracerebral mass lesion diagnosed as cryptococcoma in a patient with sarcoidosis, a rare opportunistic manifestation induced by immunosuppression with corticosteroids

Cryptococcal infection of the central nervous system (CNS) typically affects patients with HIV infection. In addition, opportunistic infections can also occur during immunosuppressive therapies. Some patients develop cryptococcal meningitis. Cryptococcomas, however, are rarely observed. A 42-year-old patient with sarcoidosis known for 2??years presented with a cerebral mass lesion primarily thought to be CNS sarcoidosis. Stereotactic biopsy and extensive micro- and macrobiological investigations revealed a cryptococcoma which had emerged from cryptococcal meningitis despite 3 months of treatment. Differential diagnosis of cerebral cryptococcoma is difficult due to the unspecific findings in the CSF analysis if C. neoformans fails to be detected using Indian ink staining or PCR studies. In this case, stereotactic biopsy and pathohistological examination revealed C. neoformans causing intracerebral mass lesion. Intensive treatment with antifungal drugs was followed by remission of all symptoms. In conclusion, cryptococcoma of the CNS represents a very important indication of mass lesions in patients suffering from sarcoidosis and treated with corticosteroids.     

Imaging features of central nervous system fungal infections

Fungal infections of the central nervous system (CNS) are rare in the general population and are invariably secondary to primary focus elsewhere, usually in the lung or intestine. Except for people with longstanding diabetes, they are most frequently encountered in immunocompromised patients such as those with acquired immunodeficiency syndrome or after organ transplantation. Due to the lack of inflammatory response, neuroradiological findings are often nonspecific and are frequently mistaken for tuberculous meningitis, pyogenic abscess or brain tumor. Intracranial fungal infections are being identified more frequently due to the increased incidence of AIDS patients, better radiological investigations, more sensitive microbiological techniques and better critical care of moribund patients. Although almost any fungus may cause encephalitis, cryptococcal meningoencephalitis is most frequently seen, followed by aspergillosis and candidiasis. The biology, epidemiology and imaging features of the common fungal infections of the CNS will be reviewed. The radiographic appearance alone is often not specific, but the combination of the appropriate clinical setting along with computed tomography or magnetic resonance may help to suggest the correct diagnosis.     

Fungal infections of the central nervous system: comparative analysis of risk factors and clinical signs in 57 patients

Risk factors and clinical manifestations of fungal infections of the CNS were analyzed in 57 autopsied patients. Aspergillosis occurred in 16, candidiasis in 27, and cryptococcosis in 14. Nine of 31 variables studied showed significant difference (p less than 0.01). Cryptococcosis was community-acquired in 93%; whereas, aspergillosis and candidiasis were nosocomial in more than 95%. Focal neurologic deficits developed in 50% with CNS aspergillosis, but in only 4% with candidiasis. Meningeal signs occurred in 86% with CNS cryptococcosis, but in only 6% with aspergillosis and 7% with candidiasis. Discriminant analysis demonstrated that CNS aspergillosis was most frequently a nosocomial infection with focal neurologic deficits, pulmonary infiltrates, and hypercortisolemia. Cryptococcosis was generally a non-nosocomial infection with meningeal signs presenting in an ambulatory population. CNS candidiasis was a clinically occult nosocomial fungal infection with generally no deficits or meningismus, occurring most frequently in the neonate, the elderly, and surgical patients. The discriminant functions, which correctly classified 91% of these CNS fungal infections, may be applicable in clinical diagnosis.