PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM IN 40 CASES OF ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)

The central nervous system was examined in 40 AIDS patients who died between August 1982 and 1987. The cases included two children born to intravenous drug abusers and 38 male adults. The brains of eight patients who had no clinical or radiological evidence of central nervous system involvement showed non-specific changes which included microglial nodules, perivascular mononuclear cuffs, mineralization of blood vessels and granular ependymitis. In 32 brains from patients with neurological symptoms, toxoplasmosis was the most frequent finding (19 cases) manifested by multifocal, necrotic lesions or a diffuse pseudo-encephalitic process. Other opportunistic infections included cytomegalovirus (eight cases), progressive multifocal leucoencephalopathy (two cases), cryptococcosis (one case), aspergillosis (one case), multiple bacterial microabscesses (one case) and Mycobacterium avium intracellulare (one case). Two patients had cerebral lymphoma. Subacute encephalitis with white matter lesions and multinucleated giant cells characteristic of HIV infection was present in 15 cases. Various combinations of all these infections were encountered in the same brain, sometimes in the same area and, occasionally, in the same cell.     

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.     

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.     

Cryptococcosis in AIDS patients: observations concerning CNS involvement

Summary The clinical course and response to therapy of seven patients with cryptococcosis and AIDS were reviewed. One patient was still in the primary stage of cryptococcosis in AIDS, i.e. the stage that is characterized by the sole cultural detection of Cryptococcus neoformans in the respiratory tract. The other six patients were in the secondary stage, where C. neoformans can be detected from the cerebrospinal fluid (CSF), blood, urine, faeces and other body sites. The main presenting features (headache, fever, nausea) were due to central nervous system involvement, although meningism and mental changes were rarely present, and CSF changes were very subtle. Treatment with amphotericin B and flucytosine was very effective, there being no more growth of fungi in cultures in most cases. Adverse reactions to the drugs used occurred frequently and consisted mainly of anaemia, hepatosis and fever. Diagnosis in the primary stage of cryptococcosis may improve the prognosis.     

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.     

The neuropathology of neonatal period: analysis of 1616 autopsies]

The lesions of the central nervous system represent an important cause of morbid-mortality in the neonatal period. This is due to the vulnerability of the brain to several adverse conditions during gestation and after birth. This study analyses the prevalence and pattern of central nervous system lesions in neonates autopsied at Hospital de Clínicas - Curitiba. There were 5743 pediatric autopsies performed in the Sector of Anatomic Pathology from 1960 to 1995 with 2049 cases corresponding to death during neonatal period. These later autopsies were reviewed and all cases with central nervous system lesions were selected and classified according to sex, age and pattern of central nervous system lesion. The central nervous system was affected in 1616 (78,87%) of neonatal autopsies and there was predominance of intracerebral hemorrhages (73,39%), congenital malformations (4,27%) and infections (3,59%). The hypoxic hemorrhages are the most prevalent central nervous system lesions in the neonatal period, affecting mainly premature babies. There was predominance of central nervous system malformations in the female neonates.     

Neuropathological findings in an autopsy series of Italian subjects with AIDS

Lesions of the central nervous system were seen in 13/22 autopsies of Italian subjects affected by the acquired immune deficiency syndrome and including 19 intravenous drug addicts. Multinucleated cells similar to those originally described by Sharer et al. [1985] in response to direct central nervous system lesions by the human immune deficiency virus were seen in five subjects. Isolated or multiple opportunistic infections of the brain including cerebral toxoplasmosis (7 cases), progressive multifocal leukoencephalopathy (4), cytomegalovirus encephalitis (3), and tuberculous meningoencephalitis (2) were recognized. Finally, three cases of primitive cerebral lymphoma of large round cells were found. The central nervous system is a target, like the lymphoid tissue, of direct damage for the human immune deficiency virus, and it is frequently affected by opportunistic infections due to the immunological impairment sustained by the acquired immune deficiency syndrome.     

Epidemiology of central nervous system mycoses

Fungal infections of the central nervous system (CNS) were considered rare until the 1970s. This is no longer true in recent years due to widespread use of corticosteroids, cytotoxic drugs and antibiotics. Immunocompromised patients with underlying malignancy organ transplantations and acquired immune deficiency syndrome are all candidates for acquiring fungal infections either in meninges or brain. A considerable number of cases of CNS fungal infections even in immunocompetent hosts have been reported. A vast array of fungi may cause infection in the CNS, but barring a few, most of them are anecdotal case reports. Cryptococcus neoformans, Candida albicans, Coccidioides immitis. Histoplasma capsulatum are common causes of fungal meningitis; Aspergillus spp, Candida spp, Zygomycetes and some of the melanized fungi are known to cause mass lesions in brain. Few fungi like C. neoformans, Cladophialophora bantiana, Exophiala dermatitidis, Ramichloridium mackenzie, Ochroconis gallopava are considered as true neurotropic fungi. Most of the fungi causing CNS infection are saprobes with worldwide distribution; a few are geographically restricted like Coccidioides immitis. The infections reach the CNS either by the hematogenous route or by direct extension from colonized sinuses or ear canal or by direct inoculation during neurosurgical procedures.     

Cytomegalovirus infection of the brain in AIDS: a clinicopathological study

Based on neuropathological findings, a retrospective case control study of 39 patients with acquired immune deficiency syndrome (AIDS) and confirmed cytomegalovirus (CMV) infection of the brain is presented. Since 1989, the incidence of cerebral infections in AIDS autopsy material has increased progressively and, in 1994, CMV was the most frequent opportunistic central nervous system (CNS) infection. Of the patients with CMV infections of the brain 16 had one or more coexisting secondary opportunistic and/or tumorous lesions in the CNS. Cerebral involvement by CMV was more frequent in patients with multiple extracerebral organ infections, while 7 among the 39 reported cases showed isolated CMV infection of the brain. The evaluation of the clinical records of 21 patients revealed neuropsychiatric signs and symptoms in 10, while these were absent in 11. All of these patients revealed various types of cerebral lesions related to CMV infection: ventriculitis, focal lesions, and microglial nodule encephalitis. The extent and distribution of cerebral lesions showed no significant correlations with clinical, radiological, or laboratory findings. Further clinicopathological studies are warranted to recognize CMV infections of the CNS and to allow earlier and more efficient treatment of this rather frequent complication of AIDS.     

Central Nervous System Aspergillosis; Analysis of 26 Patients

The clinical presentation, risk factors, laboratory data, and neuroimaging and neuropathological findings in 26 patients with autopsy proved central nervous system (CNS) aspergillosis are reviewed. Eleven patients had hematological malignancies (8 underwent bone marrow transplantation), 8 patients underwent liver transplantation, and 3 patients had acquired immunodeficiency syndrome. Four had illnesses resulting in immunosuppression (systemic lupus erythematosus, infected aortic graft, neuroblastoma, and fulminant hepatic failure). The most common presenting clinical symptoms of CNS aspergillosis were fever and a strokelike syndrome. Risk factors for developing CNS aspergillosis included neutropenia, immunosuppressive therapy, low CD4 counts, and retransplantation. Spinal fluid findings were nondiagnostic. Computed tomograms and magnetic resonance scans of the head showed low-density lesions or hemorrhagic infarctions. Most aspergillosis cases occurred in the setting of widely disseminated disease commonly arising from the lung. Pathologically, multiple areas of necrosis throughout the brain were seen. Aspergillus invasion of blood vessel walls was seen microscopically. Amphotericin B with or without flucytosine was not effective treatment.     

Human Zika and West Nile virus neurological infections: What is the difference?

The recent epidemic of West Nile Virus (WNV) infection in the United States was associated with severe neurological disease in immunocompromised hosts, while the emergence of Zika virus infection in the Americas has been notable for an association with increased microcephaly in the fetuses of infected mothers. Rare autopsies of WNV infected humans have shown multiple organ involvement with a clear neurotropism. We have recently had the opportunity to examine the distribution of Zika virus in autopsies of newborns from infected pregnancies. While both viruses infect multiple organs, Zika appears to cause neurological disease in the fetus through two different mechanisms. Infection during the first trimester showed the potential to infect neural progenitor cells causing severe developmental abnormalities, while infection later in gestation was associated with meningeal infection and destructive ischemic lesions of the brain. Both viruses infect kidney tubules but Zika shares a prominent hepatotropism characteristic of other flaviviruses (e.g., Dengue). Limited transplacental Zika infection would be consistent with restriction to primary maternal infections with high viremia. In the absence of a vaccine, restriction of travel by immunosuppressed and pregnant non‐immune individuals to endemic regions seems prudent.     

Aspergillose cérébrale chez le sujet immunocompétent. À propos de trois cas

Introduction

Cerebral aspergillosis is a severe disease most commonly suspected in immunocompromised patients.

Case report

We report herein three cases of cerebral aspergillosis in immunocompetent adults. Sinus involvement was noted in two cases, but there was no extracerebral involvement in the third case. Mycology samples provided the diagnosis in two cases. In the third case, cerebral imaging visualized a tumor; the patient underwent surgery and the pathology exam of the surgical specimen established the diagnosis. All patients were given antifungal treatment and achieved a good outcome.

Conclusion

Cerebral aspergillosis is highly uncommon in immunocompetent patients. In addition to immunodepression, the notion of pulmonary or ENT involvement may be suggestive. In the brain, aspergillosis mainly involves the basal nuclei and the thalamus.     

Unilateral megalencephaly: hamartoma or neoplasm?

The clinical and pathologic findings in three cases of unilateral megalencephaly, showing a spectrum of mild to severe involvement, are presented. The first case demonstrated an increase in neuronal size and mild gliosis and is contrasted with the second and third cases, which showed a progressive enlargement and bizarre appearance of neurons associated with an increase in number and size of astrocytes. The relationship of these cases to developmental and neoplastic disease in the brain is discussed.     

Neurological complications of swine influenza vaccination

The emphasis upon the remarkably large number of cases of Guillain-Barre syndrome which resulted from the 1976 National Swine Influenza immunization program in the U.S.A. has obscured the fact that other neurological complications, involving the central nervous system also occurred. The anatomical distribution of lesions is almost identical with that seen following other types of vaccination: involvement of the brain, cerebellum, optic nerve, cranial nerves and spinal cord occurred with approximately the same frequency.
5 instances of the very rare subacute or chronic, progressive, post-vaccinal encephalopathy are described, a situation which is identical to the subacute and chronic forms of polyradiculoneuropathy. In a number of cases, in particular the myelopathies, a subclinical involvement of peripheral nerves was demonstrated by means of electrodiagnostic studies, illustrating the often overlooked fact that central nervous system involvement will mask peripheral nerve lesions.
The etiological significance of the swine influenza vaccination was overlooked and completely erroneous diagnoses were established in a surprisingly large number of the 26 new cases reported here.     

Human brain in tissue culture. III. PML-SV40-induced transformation of brain cells and establishment of permanent lines.

Cells from explants and monolayer subcultures of adult human brain obtained from biopsies or autopsies of ten multiple sclerosis (MS) cases, one case each of Jakob-Creutzfeld (JC) and amyotrophic lateral sclerosis (ALS) and three cases with no central nervous system (CNS) involvement were transformed with PML-SV40 virus. Transformation was effected to establish permanent lines of these particular adult brain cells so that sufficient quantities would be available for other research projects. The procedure previously used to transform human fibroblasts (Koprowski et al., '62) was successfully applied to human brain cells. The success of transformation was dependent on the growth condition of the cultures at the time of infection. Events occurring after viral infection and during the pre-transformation and the post-transformation phases are described.     

Neurologic manifestations of the acquired immunodeficiency syndrome

Recognition of the neurological symptoms and signs of the acquired immunodeficiency syndrome (AIDS) since 1982 has demonstrated the involvement of the nervous system in approximately one third of the cases. Certain opportunistic infections or tumors had been previously described in the course of immunodeficiency states of other origins: cerebral toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, atypical mycobacteriosis and cerebral lymphoma. Other disorders such as subacute encephalitis raise specific etiopathogenic questions. Several of these affections can be associated or succeed each other and this is the natural course in AIDS. The detection of those conditions that are curable, among which toxoplasmosis, is of primary importance.     

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.     

Central nervous system fungal infections in tropics

Fungal infections of the central nervous system range from chronic indolent forms to acute fulminant forms causing significant morbidity and mortality. They often show atypical and variable neuroradiologic findings because of the absence of typical inflammatory response. The neuroradiologist must have high degree of suspicion in immunocompromised patients regarding the possibility of central nervous system fungal infections and keep in mind the appearances of various fungi even when immune response is intact. Next is to identify the pattern of involvement whether hematogenous or direct sinonasal and then make a well-informed speculation regarding the type of the pathogen based on the clinical features and imaging appearance.     

Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging

Children with merosin-deficient congenital muscular dystrophy (CMD) have striking white matter changes on T-2 weighted brain magnetic resonance imaging (MRI). There have been occasional cases with structural abnormalities, mainly involving the occipital cortex. We report our brain imaging findings in 14 children with merosin-deficient CMD. Ten cases had a severe reduction or absence of merosin on immunocytochemistry and four cases had partial reduction. All 14 cases had white matter changes, which appeared after the first 6 months of life and persisted with time. The changes were diffuse and the oldest child scanned (14 years) also showed involvement of the U fibres. Five children with total absence of merosin also had structural abnormalities. One child had moderate mental retardation and epilepsy, mainly characterised by complex partial seizures, with atypical absences, which had been difficult to treat. Brain MRI showed marked occipital agyria and pontocerebellar hypoplasia. The gyral pattern of the rest of the brain looked normal. The four other cases, all with normal intelligence, also had cerebellar hypoplasia with variable involvement of the pons. They did not, however, have neuronal migration defects. It is recognised that several forms of congenital muscular dystrophy, namely Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, have structural brain abnormalities and associated severe mental retardation. Our cases demonstrate that a range of structural malformations can also be found in a significant number of children with merosin-deficient CMD.     

Neuropathology and general autopsy findings in AIDS during the last 15 years

A retrospective study of 450 consecutive AIDS autopsy cases (397 males, 53 females; mean age at death 38.4 years) in Vienna, Austria, between 1984 and 1999 compares the central nervous system (CNS) findings in three cohorts: 1984–1992 (190 cases), 1993–1995 (162 cases) and 1996–1999 (98 cases, after introduction of triple antiretroviral therapy) and the relationship of CNS findings to systemic AIDS pathology in the latter two cohorts. In these two groups, following involvement of the lung (85% and 75%, respectively), the brain continued to be the second most frequently involved organ (decrease from 80% to 60%, respectively). Extracerebral protozoal (Pneumocystis carinii, toxoplasmosis), Mycobacterium avium complex, viral [e.g., cytomegalovirus (CMV)], multiple opportunistic organ and CNS infections, and Kaposi sarcoma significantly decreased over time. There was less decrease in fungal infections, while bacterial organ and CNS infections (except for mycobacteriosis), lymphomas, HIV-associated CNS lesions (around 30%), non HIV-associated changes (vascular, metabolic, etc.) and negative CNS findings (10–11%) remained unchanged. Nonspecific CNS changes (e.g., meningeal fibrosis) increased. Extracerebral pathology in subjects with advanced HIV-related CNS lesions showed more frequent but decreasing systemic bacterial and CMV infections than those with negative or nonspecific neuropathology, while other opportunistic and multiple organ infections and lymphomas showed no differences between both groups. In a cohort of drug abusers, HIV encephalitis, progressive multifocal leukoencephalopathy, bacterial infections, hepatic encephalopathy, and negative CNS findings were more frequent than in non-users who showed increased incidence of CMV, toxoplasmosis, or other opportunistic CNS infections, and nonspecific CNS findings; the frequency of lymphomas was similar in both drug abusers and non-users. Similar to a recent autopsy study from San Diego, these data suggest that despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding, while the increased incidence of HIV encephalitis in our small cohort of drug users was less than observed in other recent autopsy studies. Received: 7 March 2000 / Revised, accepted: 24 March 2000