A. Julio Martinez

Intracranial Ependymomas of ChildhoodLong-term Outcome and Prognostic Factors

A detailed outcome analysis was performed on 40 children with intracranial ependymomas treated at our institution between 1975 and 1993 to identify those factors that were predictive of overall and progression-free survival. Three patients (7.5%) who were treated in the first 5 years of the study died within 3 months of surgery and were excluded from further outcome assessments. Eight (22%) of the 37 patients who survived the perioperative period had evidence of leptomeningeal dissemination at presentation, on the basis of either imaging (three children) and/or cytological (six children) results. The 5- and 10-year progression-free survival rates among these 37 patients were 45.1 and 36.1%, respectively; overall survival rates were 57.1 and 45.0%, respectively. The site of progression was local in 17 of 19 patients with progressive disease. Three factors were found to have a significant association (P < or = 0.05) with the outcome on both univariate and multivariate analyses: 1) the extent of the resection, 2) the age of the patient at diagnosis, and 3) the duration of the symptoms before diagnosis. The 5-year progression-free and overall survivals were 8.9 and 22%, respectively, among patients who had evidence of residual disease on postoperative imaging studies, compared with 68 and 80% rates among patients with no apparent residual disease (P = 0.0001 and P < 0.0001, respectively). Patients younger than 3 years fared significantly worse than older children (5-year progression-free and overall survival rates of 12 and 22%, respectively, in the younger children versus 60 and 75% in older children (P = 0.003 and P = 0.01, respectively). In addition, patients with a duration of symptoms before diagnosis of < 1 month had a worse outcome than those with a more protracted course (5-year progression-free and overall survival rates of 33 and 33%, respectively, versus rates of 53 and 64%, respectively (P = 0.02 for both). Neither the finding of evidence for dissemination at presentation nor the detection of anaplastic histological features (e.g., dense cellularity or high numbers of mitoses) were associated with a significantly worse outcome in this series. The combination of variables that had the strongest association with both favorable and unfavorable outcomes was the combination of the age of the patient and the resection extent. Only 2 of 17 patients older than 3 years with gross total resections have died, whereas 13 of 20 children who were either younger than 3 years or had radiologically incomplete resections have died (P < 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Environmental Isolation of Balamuthia mandrillaris Associated with a Case of Amebic Encephalitis

ABSTRACT This report describes the first isolation of the ameba Balamuthia mandrillaris from an environmental soil sample associated with a fatal case of amebic encephalitis in a northern California child. Isolation of the ameba into culture from autopsied brain tissue confirmed the presence of Balamuthia. In trying to locate a possible source of infection, soil and water samples from the childs home and play areas were examined for the presence of Balamuthia. The environmental samples (plated onto nonnutrient agar with Escherichia coli as a food source) contained, in addition to the ameba, a variety of soil organisms, including other amebas, ciliates, fungi, and nematodes, as contaminants. Presumptive Balamuthia amebas were recognized only after cultures had been kept for several weeks, after they had burrowed into the agar. These were transferred through a succession of nonnutrient agar plates to eliminate fungal and other contaminants. In subsequent transfers, axenic Naegleria amebas and, later, tissue cultures (monkey kidney cells) served as the food source. Finally, the amebas were transferred to cell-free axenic medium. In vitro, the Balamuthia isolate is a slow-growing organism with a generation time of ∼30 h and produces populations of ∼2 × 105 amebas per ml. It was confirmed as Balamuthia by indirect immunofluorescence staining with rabbit anti-Balamuthia serum and human anti-Balamuthia antibody-containing serum from the amebic encephalitis patient. The environmental isolate is similar in its antimicrobial sensitivities and identical in its 16S ribosomal DNA sequences to the Balamuthia isolate from the deceased patient.

Chlordecone intoxication in man 1. Clinical observations

Industrial overexposure to chlordecone, an organochlorine insecticide, caused tremor in 76 of 148 exposed workers. Chlordecone was absorbed through oral, respiratory, and dermal routes, the last possibly the most significant. Epidemiology of this incident disclosed low-level, wide spread environmental exposure of man to chlordecone. In 23 workers with chronic chlordecone intoxication, tremor was associated with opsoclonus, pleuritic pain and arthralgia. No seizures were reported. The site of action of chlordecone on the central nervous system is unknown. It concentrates inhuman adipose and hepatic tissue but is not biodegradable, either in humans or elsewhere in nature.

Subacute sclerosing panencephalitis Correlation of clinical, neurophysiologic and neuropathologic findings

Clinical, neurophysiologic and neuropathologic findings were correlated in five cases of subacute sclerosing panencephalitis (SSPE). In the early stages, the disease chiefly affects the occipital areas, then spreads to the anterior portion of the cerebral hemispheres. Subcortical structures, brain stem, and spinal cord are involved later. Involvement of the brain stem by intranuclear inclusion bodies appears to be an almost constant finding. The EEG complexes typical of early SSPE indicate relative preservation of the cortex. Later, when marked cortical damage occurs, these EEG changes disappear. Neuropathologic findings—neuronaI abnormalities, gIial and inflammatory changes, demyelination, and inclusion bodies—most likely are dependent on the clinical stage at the time of brain biopsy or autopsy.

Malignant Gliomas of the Optic Nerve Pathways

We compared the clinical course and histopathologic findings in five patients with malignant gliomas originating from the optic nerve pathways with those in previously reported cases to elucidate further the clinical features of this tumor and facilitate future diagnoses. Patients with malignant optic nerve pathway gliomas had unilateral or bilateral visual dysfunction, which was often accompanied by periorbital discomfort in an otherwise asymptomatic adult. Regardless of origin, the clinical course invariably was bilateral blindness rapidly followed by death. Occasionally, the diagnosis was made preoperatively and was confirmed by surgical exploration and biopsy.

THE NEUROPATHOLOGY OF ORGAN TRANSPLANTATION : COMPARISON AND CONTRAST IN 500 PATIENTS

The main objective of this report is to compare and contrast the type and frequency of neuropathological findings following liver, heart, lung, heart-lung, kidney and bone marrow transplantation and to provide an overview of the major systemic complications in patients that received allografts. This is a retrospective analysis of the complete autopsy records and clinical histories of 500 adults who underwent organ transplantation at the University of Pittsburgh Medical Center during the interval of March, 1981 through July, 1997. This study is based on the neuropathological and systemic findings among 225 liver, 101 heart, 40 lung, 28 heart-lung, 74 kidney and 32 bone marrow transplants. Clinico-pathological correlations were made. All patients received base-line immunosuppressive therapy with one or more of the following drugs: cyclosporine, corticosteroids and azathioprine. Since August, 1989, the primary immunosuppressive agent is FK-506 (Tacrolimus). Some patients received antilymphocyte globulin (OKT3), when acute rejection was imminent. Light microscopic examination of tissue sections, stained with hematoxylin and eosin and in some cases with special stains were made. Ultrastructural evaluation were also performed in selected cases. All of the studies were carried out at the University of Pittsburgh Medical Center, Department of Pathology, Neuropathology Division. Cerebrovascular complications were the most frequent and were seen in 51% of the liver, 59% of the heart, 58% of the lung, 50% of the heart-lung, 49% of the kidney and 44% of the bone marrow allografts. Aspergillus sp. infection was the most common of all CNS infections followed by viral, bacterial and protozoal. Primary Central Nervous System Lymphoma (PCNSL) was seen in 2% of the liver, and 2% of the heart recipients. Post transplant lymphoproliferative disorder (PTLD) involving the brain was seen in 2% of the liver allografts, 3% of the heart, and 7% of the heart-lung recipients. PTLD systemically was seen in 6% of the liver, 7% of the heart, 5% of the lung, 11% of the heart-lung and 4% of the kidney allografts. Graft-versus-host disease was seen only in 41% of the bone marrow recipients. There was no statistically significant difference between the incidence of the total CNS complications among the different organ transplant groups (p value > 0.10), but there was a statistically significant difference in the systemic complications among the organ transplant groups (p value < 0.001). In conclusion that immunocompromised patients with impaired cellular and humoral immunity are at risk for the development of opportunistic infections and hematologic abnormalities. PTLD appears to be different in its pathogenesis from that of PCNSL which occurs anew in the brain of these patients. The neurological complications may be reduced by earlier recognition and better understanding of their etiopathogenesis.

Smith‐Lemli‐Opitz Syndrome: Neuropathological and Ophthalmological Observations

The case of a three‐year‐old boy with the Smith‐Lemli‐Opitz syndrome is reported. In addition to the constellation of skeletal and genital anomalies classically described in this syndrome, this patient had spontaneous opsoclonus‐like eye movements, strabismus, lack of visual following responses and of opticokinetic reflexes. At autopsy the cerebellar vermis was found to be absent. There were retinal hemangiomas. Microscopical examinations showed loss of Purkinje cells and extensive neuronal degeneration within dentate nuclei, associated with patchy demyelination of cerebellar peduncles and central white matter. These findings may contribute to the explanation of the pathophysiology of opsoclonus and some of the neuro‐ophthalmological findings.

Proliferation index as a predictor of prognosis in malignant gliomas of childhood

The prognosis for children with high grade gliomas remains somewhat unpredictable because histologic features alone provide an imperfect assessment of the biologic behavior of a given lesion. Whereas some patients experience prolonged disease control after surgery and adjuvant therapy, others with lesions that appear comparable exhibit rapid disease progression and death.

Beneficial effects of the radioprotectant 21-aminosteroid U-74389G in a radiosurgery rat malignant glioma model

Abstract Purpose: To evaluate the radioprotectant effects of the 21-aminosteroid U-74389G on the rat C6 glioma model after stereotactic radiosurgery. Because radiosurgery causes both tumor cytotoxicity, as well as regional brain edema, we hypothesized that this drug might exhibit advantageous or deleterious effects on healthy and neoplastic tissue. Methods: Rats were implanted with 10 6 C6 glioma cells into the right frontal brain and randomized to a Control Group ( n = 18), radiosurgery on Day 14 (50% isodose=35 Gy) ( n = 15), or radiosurgery preceded by a single 15 mg/kg intravenous dose of 21-aminosteroid ( n = 27). All animals were killed by 90 days and evaluated for survival, tumor size, the presence or absence of regional parenchymal edema, or radiation-induced vasculopathy. Results: After tumor implantation, median survival in the Control Group was 23 days. Significant improvements in median survival were noted after RS alone (median, 31 days; p = 0.02), and RS plus 21-aminosteroid (median, 59 days; p p = 0.002), and after RS plus 21-aminosteroid, 2.9 mm ( p = 0.0002). In the Control Group, the tumor grew as a hypercellular, compact mass. Only 3 of 18 animals had peritumoral edema. In contrast, 7 of 15 animals in the RS group had evidence of edema ( p = 0.006), but rats that received 21-aminosteroid showed no increase compared to controls ( p = 0.38). Similarly, 6 of 15 animals that had radiosurgery alone showed evidence of vasculopathy ( p = 0.005) compared to no animals in the control group and only 2 of 27 aminosteroid-treated animals. Conclusions: The 21-aminosteroid U-74389G exhibits a radioprotectant effect on normal brain tissue, but does not appear to protect the tumor in an in vivo rat radiosurgery model. We believe that the observed beneficial effects on healthy brain led to significant prolongation of animal survival; perhaps, by limiting the adverse effects of high-dose radiosurgery. This radioprotectant should now be evaluated in randomized clinical trials in patients with malignant brain tumors.

Animal Model Balamuthia Mandrillaris CNS Infection: Contrast and Comparison in Immunodeficient and Immunocompetent Mice: A Murine Model of “Granulomatous” Amebic Encephalitis

Balainnlhia mandrillaris and several species of Acanthamoeba are pathogenic “opportunistic” free-living amebas which cause granulomatous encephalitis (GAE) in humans and animals. The granulomatous component is negligible or absent, particularly in immunocompromised individuals. GAE is an “opportunistic” infection, usually seen in debilitated, malnourished individuals, in patients undergoing immunosuppressive therapy for organ transplants, and in Acquired Immunodeficiency Syndrome (AIDS). From around the world 156 cases of GAE have been reported from 1956 through October 1, 1995, 59 (26 in the USA) of them caused by B. mandrillaris, at least seven of them in AIDS patients. The present study was designed to compare and contrast the susceptibility of infection, the rate of infectivity and the histopathological changes within the CNS between the mutant, severe combined immunodeficient mice (SCID) infected with B. mandrillaris and the normal immunocompetent BALB-C mice. The SCID mouse is severely deficient in B and T lymphocytes, therefore lacking immunoglobulin and cell-mediated immunity. This mouse is also prone to develop early T cell lymphomas. One thousand amebic trophozoites and cysts of B. mandrillaris were intranasally and intraperitoneally inoculated in both strains of mice. Seventy percent of the intranasally inoculated SCID mice died due to CNS infection. Amebic trophozoites and cysts were found within CNS parenchyma without inflammatory response. Death occurred from 2 to 4 weeks after inoculation. By contrast only 10 percent of the intranasally inoculated BALB-C mice died with CNS infection showing the characteristic features of GAE. None of the intraperitoneally inoculated mice developed amebic infection. The SCID and BALB-C mice are logical models to study the structural alterations within the CNS of B. mandrillaris infection. This animal model recapitulates with excellent degree of fidelity several aspects of the pathogenesis and histopathological of free-living amebic infection in human beings.