Aspergillosis of the central nervous system: clinicopathological analysis of 17 patients

The clinical, laboratory, and pathological features of aspergillosis of the central nervous system (CNS) were studied in a series of 17 autopsied patients. Two groups were defined. Group A consisted of 8 patients with diseases commonly associated with CNS aspergillosis: leukemia, lymphoma, aplastic anemia, and renal transplantation. Group B contained 9 patients with various illnesses not generally known to be associated with CNS aspergillosis. CNS aspergillosis was diagnosed and treated before death in only 1 patient. Patients in Group A received cytotoxic drugs, often had granulocytopenia, less commonly had focal neurological deficits, and seldom had seizures. Group B patients were not granulocytopenic, received no cytotoxic agents, underwent nontransplant surgery, and more frequently had focal neurological deficits. Eleven of the 17 patients (65%) had focal deficits, most of them hemiparesis. Meningeal signs were rare, but the cerebrospinal fluid was usually abnormal. The principal neuropathological process was Aspergillus invasion of blood vessels causing hemorrhagic infarction. Focal clinical deficits correlated neuroanatomically with Aspergillus lesions. In 2 patients, such lesions were detected by 99mTc-DTPA or cerebral angiography before computed tomographic scanning. The lungs were the usual portal of entry, but isolated CNS lesions occurred in 2 patients. CNS aspergillosis should be considered as a cause of new onset of focal neurological deficits in patients with illnesses that are more diverse than has generally been appreciated.     

Fungal infections of the central nervous system: the clinical syndromes

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.     

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.     

CNS aspergillosis in organ transplantation: a clinicopathological study.

The clinical characteristics and neuropathological findings of 22 organ transplant recipients with CNS aspergillosis were reviewed. Thirteen patients had liver, six kidney, two heart and one had cluster transplants. The most frequent neurological symptoms were alteration of mental status (86%), seizures (41%) and focal neurological deficits (32%). Meningeal signs were less common (19%). Aspergillus spp invasion of the blood vessels with subsequent ischaemic or haemorrhagic infarcts, and solitary or multiple abscesses were the predominant neuropathological findings. The lungs were the probable portal of entry; however, isolated CNS aspergillosis was seen in two patients. Antemortem diagnosis of the infection was made in half of the patients. Concomitant diabetes mellitus was noted in 59% of the patients and bacterial or other severe infections in 86%. No specific clinical or pathological pattern could be identified among patients with different types of organ transplants. In addition CNS aspergillosis was preceded by organ rejection and the need for intense immunosuppression and retransplantation in the majority of the patients.     

Central nervous system infections in cancer patients.

In the immunocompromised patient, even mild forms of any combination of headache, meningismus, altered mental status, or focal neurologic signs should initiate an evaluation for possible CNS infection. The limited signs and symptoms of acute CNS infection are not due to specific organisms but to pathologic changes at the neuroanatomic site of infection. The initial clinical history, examination, laboratory, and neuroradiographic data will narrow the problem to one of several groups of agents, although it may not be possible to specify a single causative agent. It should be remembered that several concurrent infections (i.e., CMV and toxoplasmosis, aspergillosis, and bacterial sepsis) may be present. Thus, the clinician should rely on broad antibiotic coverage appropriate to the suspected causative agent or agents at the site of infection. It may be necessary to offer broad-spectrum antibiotic coverage for a CSF presentation that is subsequently found to result from a viral illness or from a noninfectious cause. However, one should avoid undertreating those infections for which specific therapy can be offered, and broad-spectrum treatment usually will not be regretted. Uncertainty in diagnosis following noninvasive procedures should lead to a brain biopsy. Although many of the infections discussed in this article have a poor prognosis, some of the most common pathogens, such as Cryptococcus, Listeria, and Toxoplasma, have effective specific therapies to which the patient should have access as rapidly as possible. The clinician who has successfully treated a patient with CNS infection should remain vigilant for late sequelae or recurrence of infection. Chronic treatment of some infections, such as toxoplasmosis or aspergillosis, may be necessary. The reintroduction of steroids for the treatment of an underlying cancer may reactivate previously treated disease, such as cryptococcosis, and periodic CSF surveillance is appropriate under these circumstances. Recurrence of the symptoms should raise the suspicion of recurrent or new infection, and the patient also should be evaluated with CT or MRI for the development of hydrocephalus or for new metastatic disease. In patients who have had varicella-zoster infection, postherpetic neuralgia and delayed arteritis may develop. Seizures, hearing loss, and neuropsychologic sequelae may follow any meningoencephalitis. The patient should always be reevaluated for the possibility of infection with a different opportunistic organism. CNS infections remain a major cause of morbidity and mortality in immunosuppressed patients with malignancies. In one series, 60% of such patients died as a result of their CNS infection, many at a time when the underlying disease had an otherwise good prognosis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cerebrospinal fluid in acquired immunodeficiency syndrome. Analysis of 50 cases

Cerebrospinal fluid (CSF) was analysed in 50 AIDS patients in this investigation. CSF analysis included: pressure, aspect, colour, cytology (cell number, cytomorphology, and lymphocyte subpopulations), proteins concentration and their electrophoretic distribution, chloride and glycosis concentration, GOT and LDH activity, immunology for cysticercosis, syphilis and toxoplasmosis, bacteriology, and mycological examinations (direct, cultures, Cryptococcus neoformans antigen test). Diagnostic changes were: lymphoma cells in one patient, cryptococcosis in 10, toxoplasmosis in 4, candidiasis in 1, and syphilis in 3. Cryptococcosis occurred in association with toxoplasmosis in one patient who developed syphilis in the follow-up; oligoclonal distribution of gamma globulins occurred in this case. In another case of cryptococcosis, candidiasis appeared during the course of the disease. Changes in the CSF composition observed are discussed in order to evaluate: aspects of CSF inflammatory response in report to immunodeficiency; blood-brain barrier involvement; CNS damage; intracranial mass effects.     

CSF in 85 patients with AIDS and CNS cryptococcosis.

In an eight years time period (July 1984-June 1992) CSF samples of 40718 patients were studied, and 610 were from patients with AIDS clinically diagnosed and immunologically confirmed through HIV antibodies detection. Among opportunistic infections detected in them 85 were CNS cryptococcosis. For the purpose of this study the CSF of these 85 patients are the AIDS group of CNS cryptococcosis. For comparison, CSF data from 50 patients with CNS cryptococcosis but without AIDS were taken (non-AIDS group); in this group, 22 patients were immunosuppressed after renal transplant. In AIDS group, the more frequent CSF findings were: yeast presence at direct exam (Fuchs-Rosenthal cell counting chamber), growing of the yeast in cultures, and gamma globulins increase. In non-AIDS group were more frequent: hypercytosis, neutrophil cells presence, and total protein increase. Differences between the two groups are discussed taking into account CNS/CSF immune changes induced by HIV infection. It is concluded that in CNS cryptococcosis of patients with AIDS the CSF evidenced more extensive signs of the fungal opportunistic infection than signs of inflammatory response to the infection. The latter were more prominent among patients of the non-AIDS group of CNS cryptococcosis.     

Acquired immune deficiency syndrome in childhood

Central nervous system (CNS) involvement is very frequently observed in pediatric AIDS. Clinical manifestations include encephalopathy, cognitive deficits, acquired microcephaly, neurological signs, myelopathy, and peripheral neuropathy. Neurological complications can be related to opportunistic viral infections such as encephalitis, atypical aseptic meningitis, progressive multifocal leukoencephalopathy, and myelitis. Nonviral syndromes include: toxoplasmosis, cryptococcal meningitis, candidiasis, Mycobacterium tuberculosis meningitis, and Mycobacterium avium subacute encephalitis. Bacterial infections, tumors, cerebrovascular complications, and peripheral neuropathies are not frequently observed in pediatric AIDS. The most severe complications of HIV infection is encephalopathy resulting from HIV infection of brain tissue. Direct HIV invasion of the CNS has been demonstrated. Clinical features of HIV encephalopathy are classified into three categories: (1) normal neurological findings; (2) static encephalopathy; and (3) progressive encephalopathy. AIDS dementia complex can be differentiated from the predominance of behavioral and cognitive disabilities.     

Spectrum of fungal infection in a neurology tertiary care center in India

There is a paucity of studies on spectrum of fungal infections in neurology care. This study reports clinical, MRI and outcome of patients with central nervous system (CNS) fungal infections. 39 patients with CNS fungal infections treated in neurology service during the last 3?years were included and a detailed medical history and clinical examination were undertaken. Cranial MRI including paranasal sinuses were carried out and the location and nature of abnormalities were noted. Fungal infection was confirmed by CSF examination or histopathology. Death during hospital stay was noted. The median age was 37 (8–72)?years and 8 were females. The clinical features included altered sensorium in 31, focal motor deficits in 13, visual loss in 12, seizures in 10, diplopia in 7, and papilledema in 9 patients. 28 patients had the following predisposing conditions: HIV in 15, diabetes in 8, corticosteroid in 2 and alcohol, immunosuppression, neutropenia and analgesic abuse in 1 patient each. On CT or MRI scan, 5 patients had meningeal enhancement, 7 sinusitis, 10 each granuloma and infarction, 4 hydrocephalous and 1 cerebral venous sinus thrombosis. 28 patients had cryptococcal meningitis, 7 zygomycosis, 2 aspergillosis and 1 each candida and phaeohyphomycosis. Death was related to the type of fungal infection; all patients with zygomycosis and candida infection died. Rhinocerebral form of fungal infection due to zygomycetes has poorer survival compared to meningitis group which was mainly due to cryptococcal infection.     

Neurologic complications of bone marrow transplantation

Among 78 patients who died after bone marrow transplantation, neurologic complications were present in 55 (70%) and were the cause of death in 5 (6%). Metabolic encephalopathy occurred in 29 patients (37%). CNS infections included aspergillosis (3), herpes simplex encephalitis (2), and Listeria monocytogenes meningitis (1). Six additional patients had neuropathologic changes possibly due to cytomegalovirus infection. Cerebrovascular complications occurred in five patients (two hemorrhages and three infarcts). All infarcts were associated with endocarditis. The rate of nonbacterial thrombotic endocarditis was significantly higher (p less than 0.001) than in the general autopsy population. CNS leukemia and therapy-induced injury were rare. There was no evidence of graft-versus-host disease involving the CNS.     

Neuropathology of heart transplantation

The neuropathology of 18 cardiac transplant recipients was reviewed with the clinical findings. Pathological changes were noted in the central nervous system (CNS) in 94% of the patients, the most frequent being cerebral vascular in origin (72%). Eight patients (44%) had multiple cerebral infarcts and morphologically, a large number of these antedated the transplantation. In addition 4 patients had acute focal ischemic changes which occurred after transplantation. Intracranial hemorrhage was noted in 5 patients (28%), including one case of fatal intracerebral hemorrhage following an acute hypertensive episode after the transplantation. While systemic infection was common (10 patients), there were only 5 cases of intracranial infection; including 3 cases of cytomegalovirus infection, one of candidiasis and one of aspergillosis. Post-transplant seizures, occurring in a third of the patients, were related to a variety of causative factors such as sepsis, intracranial hemorrhage, cerebral ischemia, metabolic encephalopathy and cyclosporin neurotoxicity. Of note in this series was the absence of CNS lymphoma or other systemic lymphoproliferative disorder.     

Central nervous system fungal infections: Observations from a large tertiary hospital in northern India

Objective

To report our observations regarding fungal infections of the brain over two years from a large tertiary hospital in northern India. To identify fungal infections in immunocompetent and immunocompromised patients and to compare the two groups with respect to their age of occurrence, demographic data, clinical profile, radiological findings, response to treatment and outcome.

Methods

All consecutive cases of central nervous system (CNS) fungal infections admitted to the hospital over two years were included in this study. The patients were categorized as immunocompetent and immunocompromised, the predisposing factors, symptoms and clinical presentation were studied in detail and the outcomes of the two groups were compared.

Results

Of the 50 cases, 25(50%) were that of mucormycosis, 17(34%) were cryptococcosis and 8(16%) cases were that of aspergillosis. 14(28%) cases were immunocompetent and 36(72%) were immunocompromised. The outcome studied was as follows: 28% died of which 4% were HIV positive, 12% were diabetics with severe rhinorbital involvement, 2% had idiopathic thrombocytopenic purpura (ITP), 6% had advanced cancer and 4% had no predisposing illness.

Conclusions

We observed fungal infections of the brain in both immunocompetent and immunocompromised patients. In immunocompetent patients, early diagnosis and appropriate treatment frequently leads to recovery from the illness. The mortality and morbidity of fungal infections are less in the immunocompetent group of patients.     

Pathology of the central nervous system in patients infected with the human immunodeficiency virus (HIV): a Report of 252 autopsy cases from Brazil

The central nervous system (CNS) was studied in 252 HIV-infected patients from the States of Rio de Janeiro and Sgo Paulo in Brazil, the regions with the highest incidence of AIDS in the country. We compared the frequency and morphology of opportunistic infections and CNS changes caused by the HIV, with those described in other series and briefly analysed the risk factors involved in our cases. There were CNS lesions in 230 cases (91.3%), 30 (11.9%) with multiple infections and/or turnours. Most infections were opportunistic (65.4%), including 15.4% viral and 50% bacterial, fungal or protozoal infections. The most frequent was toxoplas-mosis (34.1%), followed by cryptococcosis (13.5%), cytomegalovirus (CMV) infection (7.9%) and nodular encephalitis (6.7%). Primary lymphomas were observed in 4% of the cases and HIV encephalitis or leukoencephalopathy in 10.7%. Other opportunistic and HW associated lesions were present in a limited number of cases and there were also vascular and non-specific lesions. Our study confirms the high frequency of CNS lesions in HIV infected patients. They are morphologically similar to those previously described. However, the higher incidence of toxoplasmosis and cryptococcosis, a lower incidence of viral opportunistic and HIV-associated lesions, and the presence of rarer lesions such as histoplasmosis and chagasic encephalitis, differ from other series, and may reflect geographical and/or socio-economic factors.     

Nervous system infections in patients with cancer

The diagnostic approach to the patient with cancer with suspected CNS infection depends on an analysis of the patient's immune defect, the time course of development of manifestations of infection, and the type of clinical syndrome with supportive evidence for a specific diagnosis coming from laboratory and neuroradiographic data. Most patients with CNS infections can be grouped into those with signs of meningitis or meningoencephalitis and those with focal mass lesions. A smaller group presents with stroke-like onset. Except for the group with strokes, those with focal deficits usually present in a more indolent fashion, whereas those with meningitis and encephalitis present more acutely [63]. Patients with B-lymphocyte dysfunction are susceptible to encapsulated bacterial pathogens. Patients with T-lymphocyte impairment develop CNS infections that are caused by intracellular pathogens, particularly viruses (HSV, JC, CMV, HHV-6), Nocardia, Aspergillus, and Toxoplasma. Many noninfectious entities, such as drug treatment complications, radiation effects, recurrent tumor, and paraneoplastic syndromes, can mimic CNS infections. Although cryptococcosis, bacterial meningitis, and some viral infections are easily diagnosed from Gram's stain, culture, or PCR, patients with mass lesions may require tissue biopsy to confirm diagnosis. Patients with cancer differ from normal hosts in the distribution of pathogens, and there is a wider range of differential diagnostic issues, both infectious and noninfectious, for the relatively few clinical syndromes that present as potential CNS infections.     

Mycoses of the central nervous system. Anatomopathological data of cryptococcosis and cerebral aspergillosis

The pathological findings of the cerebral involvement in deep-seated fungal infections in routine autopsy is reported. In 42 cases of mycotic infections studied among 3.966 autopsies, there were 8 cases of cryptococcosis and 2 of aspergillosis of the brain, showing a very low frequency of central nervous system involvement, occurring in a proportion of 1:400 autopsies. The histopathological findings of the brain in cases of cryptococcosis showed the spectrum of inflammatory reactions already described, although most of the cases presented with mild to severe meningitis with large number of giant cells, and slight degree of involvement of the nervous tissue. The cases of aspergillosis showed a pattern of severe necrotizing meningo-encephalitis with large number of fungi. The paper points out the role of the histological examination in the identification of the fungi in tissues and their morphologic reactions.     

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.     

Central nervous system involvement in patients with acquired immune deficiency syndrome (AIDS)

Central nervous system involvement occurred in 28 of 121 patients with acquired immune deficiency syndrome (AIDS). The major risk factor in this AIDS population was intravenous drug abuse (64%). A neurologic symptom or disability was the principal reason for hospitalization in 16 cases (57%). Three patients had primary lymphoma of the brain and the remainder had opportunistic infections. Patients with focal neurological features usually had toxoplasmosis. Progressive headache and meningeal signs occurred with cryptococcosis. A progressive subacute dementia was probably due to cytomegalovirus. Other infections included atypical mycobacteria, candida, herpes zoster and possible progressive multifocal leukoencephalopathy.     

Infections of the central nervous system in the immuno-compromised

Infections of the central nervous system (CNS) can be caused by a variety of pathogens, depending on whether the number and function of T-cells or monocytes are impaired (as in HIV patients) or whether the number and function of polymorphonuclear granulocytes are reduced or impaired, as typically seen in patients on immunosuppressive therapy, post transplantation, etc.. The first part of the chapter deals with CNS infections associated with reduced or abnormal T-cell (or monocytic) function and number, mainly seen in HIV patients, such as cerebral toxoplasmosis, CNS cryptococcosis, cytomegalovirus encephalitis, and progressive multifocal leukoencephalopathy. The clinical presentation, diagnostic procedures, as well as therapeutic and prophylactic management of these diseases are described in detail. The second part of the chapter deals with diseases usually seen in patients with impaired or reduced number and function of polymorphonuclear granulocytes. Such CNS infections are frequently caused by viral, bacterial, or fungal pathogens and are described in their clinical presentation, their diagnostic procedures and the best possible therapeutic and prophylactic management.     

Cerebrospinal fluid abnormalities in 170 cases of AIDS

Cerebrospinal fluid (CSF) was analysed in 170 AIDS patients. All of them showed HIV positive serological tests. All of them showed neurologic syndromes related to AIDS. The time period of the investigation was July 1984-April 1989. In 8 cases (4.7%) CSF composition was normal. Lymphoma cells were observed in three cases. Aseptic meningities occurred in 34 cases (20.1%). Aetiological diagnosis of associated infection was established in 88 cases: cryptococcosis in 28 (35.9%); toxoplasmosis in 20 (25.6%); syphilis in 10; candidiasis in 3; Chagas disease in 2; tuberculosis in 1; nocardiosis in 1; schistosomiasis in 1. Antibodies for other virus were detected in 7. Bacteria were isolated in 5 cases. Anti-HIV antibodies were tested in CSF samples of 55 cases: they were found in 48 (87.3%). Two or more associated infections were observed in 15 cases. Changes of CSF composition in AIDS are discussed taking into account changes reported.     

Early penetration of the blood-brain-barrier by HIV

CNS dysfunction occurs frequently in patients with HIV infection. To better define the role of HIV in the pathogenesis of neurologic dysfunction, HIV isolation and antibody studies were investigated from the CSF in 52 seropositive patients, 29 with and 23 without neurologic signs and symptoms, in various stages of disease development ranging from asymptomatic to ARC to AIDS. HIV was recovered from the CSF of 5 of 29 (17%) patients with neurologic signs and symptoms and 5 of 23 (22%) neurologically asymptomatic patients. All patients with positive CSF HIV cultures had antibodies directed against HIV p24 and gp41 in serum and CSF by Western blot analysis and elevated intra-blood-brain-barrier total IgG and HIV-specific IgG synthesis rates. The frequency of CSF HIV isolation from the group of seropositive patients without AIDS, 9 of 32 (28%), exceeded that of patients with AIDS, 1 of 20 (5%) (p less than 0.05). These findings indicate that HIV infects the CNS early in the course of viral infection and prior to the development of HIV-associated neurologic abnormalities.