Comparison between 201Tl-chloride and 99Tc(m)-sestamibi SPET brain imaging for differentiating intracranial lymphoma from non-malignant lesions in AIDS patients.

The aim of this study was to compare 201Tl-chloride and 99Tc(m)-sestamibi (MIBI) SPET brain imaging for differentiating brain lymphoma from other intracranial lesions in AIDS patients. Both studies were performed on the same day in 17 AIDS patients with intracranial enhancing lesions on either CT or MRI. Eleven patients underwent brain biopsy and six patients were followed clinically. We calculated the radiopharmaceutical uptake ratio of the lesion to that on the contralateral side with the guidance of CT or MRI findings. Ratios of 1.5 or more were considered to represent malignant lesions and ratios < 1.5 were considered to represent benign lesions. Biopsy revealed four cases of lymphoma, four cases of toxoplasmosis and two cases of progressive multi-focal leukoencephalopathy; one biopsy yielded necrosis. Both the MIBI and 201Tl studies yielded no false-negative cases of lymphoma (sensitivity 100%). Of the 13 non-lymphoma cases, the 201Tl studies showed seven true-negative cases (specificity 54%) and the MIBI studies showed nine true-negative cases (specificity 69%). The biopsies of the false-positive cases (toxoplasmosis) showed a pattern of healing after medical treatment. We conclude that MIBI is more helpful than 201Tl because of higher specificity and equal sensitivity. The medical treatment of toxoplasmosis is a cause of false-positive 201Tl and MIBI studies.

Cell death and birth in multiple sclerosis brain.

The hallmark of the brain pathology in multiple sclerosis is the white matter plaque, characterized by myelin destruction and oligodendrocyte loss. To examine the role that cell death plays in the development of MS lesions, we used the in situ TUNEL technique, a method that sensitively detects DNA fragmentation associated with death at the single cell level. We found that patchy areas within acute MS lesions have massive numbers of inflammatory and glial cells undergoing cell death. The punched out areas of some long-standing chronic lesions also had labeled glial cells showing that the attack was not a single event. Immunocytochemical identification of the dying cells with glial specific marker co-labeling showed that 14-40% were the myelin-sustaining oligodendroglial cell. Confocal microscopic evaluation of fluorescein-labeled TUNEL positive cells revealed nuclei with morphologic characteristics of apoptosis, and electrophoresed MS brain DNA produced a ladder characteristic of apoptotic DNA cleavage confirming that substantial numbers of labeled cells, but not necessarily all, were dying by apoptotic mechanisms rather than cell necrosis. Companion studies using a marker for cell proliferation on MS lesions revealed that unexpectedly large populations of perivascular inflammatory cells and parenchymal glial cells had entered the cell proliferation cycle. These findings establish that two opposing glial cell responses - relentless cell death and coincident brisk cellular proliferation - are important features of MS pathology. In the end, however, glial cell loss prevails, and we suspect apoptosis may be the critical death mechanism responsible for the depletion of myelin observed in this condition.

Demyelinating disease versus tumor in surgical neuropathology. Clues to a correct pathological diagnosis.

Clinical presentations as well as radiological and histopathological findings in biopsies from patients with multiple sclerosis (MS) or other demyelinating disorders of the central nervous system are sometimes misleading, resulting in an erroneous diagnosis of brain or spinal cord tumor. We report 17 patients who presented with symptoms mimicking those of brain (14 cases) or spinal cord (three cases) tumors. Computerized tomography or magnetic resonance imaging studies or both were interpreted as consistent with a tumor in each case. All patients underwent surgery, and all 17 pathological specimens were eventually diagnosed as showing demyelinating disease, usually consistent with MS. In each case we examined a variety of histological features and immunohistochemical studies and addressed their relative importance in considering the diagnosis of MS. All cases showed perivascular lymphocytic inflammation with variable amounts of macrophage infiltration, necrosis, and edema. The hypercellularity of the lesions and the presence of atypical reactive astrocytes with mitotic figures were the disturbing features that might have led to the erroneous diagnosis of an astrocytic neoplasm. Immunohistochemistry for astrocytic (glial fibrillary acidic protein) and macrophage (HAM-56) markers are helpful in evaluating biopsies. Our results emphasize the need to perform special stains (i.e., for myelin and axons) that demonstrate myelin loss and relative preservation of axons and allow a correct diagnosis.

Neurologic complications of cloacogenic carcinoma.

Cloacogenic carcinoma is a rare tumor, originating from epithelium of the anal transition zone. We report a 63-yr-old man with pathologically proven cloacogenic carcinoma which caused a rapidly progressive paraparesis and changes in mental status. These were related to extramedullary deposits around the spinal cord and cauda equina and intramedullary deposits in the brain. This pattern of neural involvement with anal canal carcinoma has not been reported previously.

Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis revealed by organelle-specific antibodies.

Many studies have established the central involvement of the Golgi apparatus in the transport and processing of plasma membrane, lysosomal, and secreted proteins. The Golgi apparatus of neurons is also involved in the axoplasmic flow of fast-moving macromolecules and in the orthograde, retrograde, and transsynaptic transport of exogenous ligands. Markers of the Golgi apparatus, based on traditional methods of enzyme cytochemistry, are not applicable to human tissues obtained at autopsy. For that reason, the Golgi apparatus of brain cells has not been examined adequately in diseases of the human nervous system. Here we report that an antiserum raised against MG-160, a 160-kDa sialoglycoprotein of medial cisternae of the Golgi apparatus of several rat cells, is a specific and easily reproducible immunocytochemical marker of the Golgi apparatus of human neurons and other cells obtained at autopsy. Application of this probe in amyotrophic lateral sclerosis has shown a fragmentation of the Golgi apparatus in motor neurons similar to that induced by depolymerization of microtubules. We suggest that the fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis has functional implications because significant reductions of secretion of insulin and immunoglobulins have been observed in islet cells and plasma cells, respectively, treated with microtubule-disrupting agents.

Enteroviral-related antigen in circulating immune complexes of amyotrophic lateral sclerosis patients.

Circulating immune complexes were isolated by polyethylene glycol precipitation from the sera of patients with amyotrophic lateral sclerosis. Rabbits immunized with circulating immune complexes from 3 of 5 amyotrophic lateral sclerosis patients induced antisera that specifically reacted with enterovirus-infected cells by immunofluorescence and enzyme-linked immunosorbent assay. These antisera were nonneutralizing and did not react with purified virus. In addition, peripheral lymphocytes of amyotrophic lateral sclerosis patients produced lymphokine in response to extracts from enterovirus (Coxsackie B4) infected cells. These results suggest both a humoral (circulating immune complex) and a cellular immune response in some patients with amyotrophic lateral sclerosis to enterovirus-coded or -induced antigen.

Focal accumulation of phosphorylated neurofilaments within anterior horn cell in familial amyotrophic lateral sclerosis.

Distribution of phosphorylated neurofilament proteins within anterior horn cells in three cases of familial and six cases of sporadic amyotrophic lateral sclerosis (ALS) and ten control cases were investigated by using a monoclonal antibody. Two distinct staining patterns of perikarya were observed; (1) homogeneous pattern; either the entire or a part of the perikaryon was immunostained homogeneously (homogeneously diffuse or partial pattern); (2) focal pattern: perikarya contained very distinct, inclusion-like focal accumulation of immunoreactive products of various morphologies such as round, ring-shaped, cord-like, tube-like and more irregular shapes. The homogeneous pattern was found in all three groups but was most common in sporadic ALS. On the other hand, the focal pattern was seen almost exclusively in familial ALS. The focal accumulation of neurofilaments appears at least in part to be related to the Lewy body-like hyaline inclusion which is known to contain neurofilaments. In addition, cord-like swellings of neurites in familial ALS also showed focal neurofilament accumulation. These observations suggest that the focal accumulation of phosphorylated neurofilaments is characteristic of familial ALS, although it may not be specific to the entity. The pathological process(es) producing the neurofilamentous abnormality may play an important role in anterior horn cell degeneration in familial ALS.

A Golgi study of the large anterior horn cells of the lumbar cords in normal spinal cords and in amyotrophic lateral sclerosis.

The Golgi-Cox method was used to compare transverse sections of the lumbar cords of amyotrophic lateral sclerosis (ALS) patients and controls. Large anterior horn cells of the control cords could be divided into three groups based on arrangement of the dendrites arising from the soma; bipolar, tripolar and multipolar. Axons could be identified by their characteristic morphology; tapering axon hillocks and initial segments, followed by an increase in caliber at the first myelinated segments. Axons usually emanated from somata, but sometimes from dendrites. Only a single abnormal neuron with a plump soma and very thin dendrites, was seen in the controls. Atrophic neurons were rare in the controls. In ALS, various abnormal changes were found in the anterior horn cells. In some, the axon remained thin and did not attain a normal thickness at the point where one might expect the first myelinated segment. The normal morphology of the dendrites was sometimes disturbed resulting in a poor extension of the dendritic trees, and thin dendrites. This communication is the first description of the Golgi method applied to ALS cases.

Immunoregulatory and activated T cells in amyotrophic lateral sclerosis patients.

Circulatory immune complexes are increased in amyotrophic lateral sclerosis (ALS) and an autoimmune mechanism has been inferred. Autoimmune diseases may have changes in the percentages of immunoregulatory T cells and increased activated T cells (Ia+ T) in peripheral blood. The latter are also increased with active viral and bacterial infection and immunization. We found no significant changes of the percentages of immunoregulatory T cells and no relation of the individual values to the clinical state. Ia+ T cells were not increased over the normal range but within that range there was significant negative correlation with the ALS clinical score.

Ganglioside patterns in amyotrophic lateral sclerosis brain regions.

In a search for evidence of biochemical disorders in regions of postmortem brain other than the motor cortex in amyotrophic lateral sclerosis (ALS), ganglioside patterns were also examined in the frontal, temporal, and parahippocampal gyrus cortex. In 21 ALS brains studied (20 sporadic, 1 familial), abnormal patterns were found in the frontal cortex (81%), temporal cortex (75%), motor cortex (70%), and parahippocampal gyrus cortex (71%). Patterns were established by measuring the percentage distribution of 12 ganglioside species. Two abnormal patterns were detected. One was based on low proportions of GD1b, GT1b, and GQ1b associated with high proportions of GM2 and GD3 (GM1, GD1a, GD2, and GT1a values were normal). The second abnormality was the appearance of Gx. Neither abnormality was seen in the 13 non-ALS control brains. The first, and predominant, abnormality was found in the frontal cortex in 14 brains, and the second was observed in 13 brains; 10 brains showed both abnormalities. These findings thus constitute evidence that the disease process in ALS extends beyond the motor cortex and involves neurons in several brain areas.

Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis.

Twenty-two of 32 sporadic cases of amyotrophic lateral sclerosis had argyrophilic spheroids, 20 micrometers or larger, in the anterior horns of the spinal cords. The fine structure of these spherical bodies was characterized by interwoven, small bundles of 10 nm neurofilaments. Scattered mitochondria, vesicles and fragments of smooth endoplasmic reticulum were commonly found among the bundles of neurofilaments. The spheroids were present not only in the myelinated axons, but also in the perikarya of the anterior horn cells. In anterior horn neurons occasional fragments of rough endoplasmic reticulum, lipofuscin and even nuclei were found among the neurofilaments, in addition to the other components. Rarely, some filamentous accumulations contained unusual features such as paracrystalline arrays, polyglucosan bodies and honeycomb-like structures. Linear densities, associated with ribosome-like particles, were found scattered within focal collections of randomly arranged neurofilaments in some perikarya of two cases. Occasional mitochondria with regularly arranged short protrusions on the outer membrane were observed in the myelinated axons in one case.

Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients.

Deposits of IgG and complement were demonstrated by direct immunofluorescent techniques with sections of motor cortex and spinal cord from amyotrophic lateral sclerosis (ALS) patients. Six of 16 ALS patients showed deposits within the spinal cord while 5 of 13 showed similar deposits within the motor cortex. The specificity of this staining was shown by blocking experiments and the use of conjugated F(ab')2. Similar deposits were found in the CNS in disease states associated with possible immune or infectious etiologies and were not found in the CNS of normal controls.

Kinetics of replication of lactate dehydrogenase-elevating virus in age-dependent polioencephalomyelitis.

The kinetics of replication of lactate dehydrogenase-elevating virus (LDV) in age-dependent polioencephalomyelitis was studied in genetically susceptible (C58/J) and resistant (C57BL/6J) mice. The peripheral replication pattern (plasma concentration) for LDV was similar in both strains. However, the concentration of virus within the central nervous system was strikingly different. In nonsusceptible C57BL/6J mice, little or no virus was found within the central nervous system. In the lumbar cord of susceptible C58/J mice, an increase in the concentration of LDV began 5 days postinfection and continued during the preclinical stages of disease. A direct correlation was shown between the concentration of LDV in spinal cord and the appearance of motor neuron disease but not the degree of inflammatory reaction.

Acute myelopathy secondary to spinal venous thrombosis.

A 66-year-old female presented with the acute onset of paraplegia progressing rapidly to quadriplegia and terminating fatally in less than a month. At autopsy extensive hemorrhagic infarction of the spinal cord was noted associated with widespread venous thrombosis. Other similar cases are reviewed and the pathophysiology is discussed.

HLA frequencies in amyotrophic lateral sclerosis.

Our study of the distribution of HLA-A, -B, and -C in patients with amyotrophic lateral sclerosis (ALS) found no statistically significant deviation. We found a trend, however, toward a decrease in HLA-A9, as we had reported previously, and toward an increase in HLA-Bw35 and -Cw4. The worldwide incidence of ALS is uniform except in Guam and on Japan's Kii peninsula, and published reports from many countries, including Guam, show no consistent deviation in HLA frequencies related to ALS.

Immunological profile of amyotrophic lateral sclerosis patients and their cell-mediated immune responses to viral and CNS antigens.

The 'immunological profile' of amyotrophic lateral sclerosis (ALS) patients was established from standard tests for B- and T-cell function. This showed no significant difference from age and sex-matched other neurological (CNS) disease controls and normal subjects. Immune complex (IC) levels in ALS serum differed significantly from normal controls but not from CNS controls. There was no relation between the various indices of immune activity of IC levels and the clinical disability of the ALS patient or progression of the disease. Distribution of complement-fixing antibodies to poliovirus was similar to sera of ALS and control groups. The in vitro cell-mediated immune responses to poliovirus, however, were significantly greater in ALS patients than in CNS controls and were inversely related to the ALS disability score. Poliovirus has not been demonstrated in the CNS or extra-CNS tissues of ALS patients by conventional means but, if latent or defective poliovirus or related virus were present, this could account for sensitization and a possible autoimmune mechanism. ALS patients exhibited in vitro cellular immunity to ALS and normal CNS subfractions. These responses were not related to the ALS disability score or progression of the disease and probably represent epiphenomena.

Virological studies in amyotrophic lateral sclerosis.

Complement-fixing antibody response to eleven different viruses were measured in amyotrophic lateral sclerosis (ALS) patients, contacts of ALS patients, neurological controls, and normal controls. The normal controls showed a decreased response to adeno-associated virus and an increased response to adenovirus when compared to the other groups. Levels of interferon-like substances also were investigated in sera and cerebrospinal fluids of ALS patients and neurological controls. Responses were of a low titer and were not increased in the ALS group. Explant cultures were established from tissues of 24 ALS autopsy cases. Cultures were investigated directly or following fusion to various indicator cell lines for viral-like agents. Techniques such as interference assays, 5-bromodeoxyuridine (BudR) induction, hemadsorption, and fluorescent antibody staining failed to detect virus. By addition of helper adenovirus to primary explant cultures, adeno-associated virus was isolated from 2 of 11 ALS cases.

Neuron specific in vitro cytotoxicity of sera from patients with amyotrophic lateral sclerosis.

Sera from patients with amyotrophic lateral sclerosis (ALS) were assayed for a neuron-specific cytotoxic effect on long-term organized cultures of neonatal mouse anterior horn segments. Blind studies show that ALS sera when incorporated into the culture media have a greater degree of antineuronal toxicity than sera from patients with other neurological diseases or from family members of ALS patients.