Dikran S. Horoupian

Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders

We investigated the validity and reliability of diagnoses made by eight neuropathologists who used the preliminary NINDS neuropathologic diagnostic criteria for progressive supranuclear palsy (PSP) and related disorders. The specific disorders were typical, atypical, and combined PSP, postencephalitic parkinsonism, corticobasal ganglionic degeneration, and Picks disease. These disorders were chosen because of the difficulties in their neuropathologic differentiation. We assessed validity by measuring sensitivity and positive predictive value. Reliability was evaluated by measuring pairwise and group agreement. From a total of 62 histologic cases, each neuropathologist independently classified 16 to 19 cases for the pairwise analysis and 5 to 6 cases for the group analysis. The neuropathologists were unaware of the study design, unfamiliar with the assigned cases, and initially had no clinical information about the cases. Our results showed that with routine sampling and staining methods, neuropathologic examination alone was not fully adequate for differentiating the disorders. The main difficulties were discriminating the subtypes of PSP and separating postencephalitic parkinsonism from PSP. Corticobasal ganglionic degeneration and Picks disease were less difficult to distinguish from PSP. The addition of minimal clinical information contributed to the accuracy of the diagnosis. On the basis of results obtained, we propose clinicopathologic diagnostic criteria to improve on the NINDS criteria

Diffuse Lewy body disease: neuropathological and biochemical studies of six patients

SummaryPost-mortem pathological and biochemical studies are reported on six patients with progressive dementia. The characteristic pathological finding was neurofilament-containing cytoplasmic inclusions in cortical and subcortical neurons. The clinical and pathological findings were consistent with so-called diffuse Lewy body disease. The patients had variable changes of the Alzheimer type, with five of six patients displaying “plaques only” Alzheimers changes. Biochemical studies showed profound decreases in neocortical choline acetyltransferase (ChAT) activities that correlated with marked neuronal loss in the basal nucleus of Meynert. ChAT activities were normal in the hippocampus in three patients who also had no significant Alzheimer type hippocampal changes. All patients had decreased cortical somatostatin-like immunoreactivity. Our observations suggest that dementia in diffuse Lewy body disease bears biochemical similarities to Alzheimers disease, in that biochemical markers for both intrinsic cortical neurons and ascending cholinergic neurons are affected.

Spinal cord glioneuronal tumor with "rosetted" neuropil islands and meningeal dissemination: a case report.

Abstract Distinctive glioneuronal tumors arising within the cerebrum and displaying neuropil-like islands and tumor cells immunoreactive for neuronal and glial antigens have recently been described. We report a similar tumor in the cervico-thoracic region of the spinal cord in a 44-year-old woman that recurred 1 year later with dissemination to the lumbar dura and cauda equina. The tumor was composed of “rosetted” neuropil islands displaying immunoreactivity for synaptophysin, whereas the intervening tumor cells were more fibrillar and immunoreactive for GFAP. The tumor cell nuclei immediately surrounding these neuropil islands were immunoreactive to the newly characterized neuronal marker, anti-Hu. While several cases of neurocytomas have been described in the spinal cord, to the best of our knowledge, this is the first example of a glioneuronal tumor with “rosetted” neuropil islands to be reported in the spinal cord.

Unusual case of corticobasal degeneration with tau/Gallyas-positive neuronal and glial tangles

A 74-year-old woman with corticobasal degeneration (CBD) had a 9-year history of progressive loss of strength and rigidity of her right hand and then arm, followed by speech difficulties, dyskinesia, rigidity, spasticity and weakness of the ipsilateral lower limb, ultimately also involving the apposite side. She later developed supranuclear gaze palsy. Her memory remained intact during most of the duration of her disease. Laboratory tests and anti-Parkinsonian medications were not helpful. At autopsy, frontal lobe atrophy, discoloration of putamen (Pt) and pallor of substantia nigra (Sn) were observed. Neuronal loss and gliosis were extensive in motor cortex and milder in frontal cortex, abruptly ending at the central sulcus and junction of cingulate gyrus. “Achromatic” neurons were present. Neuronal loss and gliosis were seen in Pt and Sn and corticobasal inclusions in Sn. Numerous Gallyas/tau-positive, Bielschowsky/ubiquitin-negative coil, sickle, or coma-shaped tangles and thread-like processes were found in affected cortex, Pt and Sn. Some of the tangles were in neurons, but most occurred in astroglia, and their processes. The presence of Gallyas/tau-positive glia in CBD may have the same diagnostic significance as in progressive supranuclear palsy, analogous to the argyrophilic ubiquinated inclusions in oligodendroglia in multisystem atrophy. We suggest that in CBD: (1) cytoskeletal protein metabolism in neurons and glia can simultaneously be perturbed in certain neurodegenerative diseases, and (2) the astrocytosis in CBD may not be simply a reactive process but an integral part of the disease.

Epidermal growth factor receptor in meningiomas is expressed predominantly on endothelial cells

The immunohistochemistry of the epidermal growth factor receptor (EGFR) was studied with monoclonal antibodies in 12 meningiomas of various histologic subtypes, nine benign and three malignant. Strong immunoreactivity of EGFR epitopes was found in the endothelia of the tumor vasculature in six cases. A much weaker reaction was detected within tumor cells in six cases, in one of which it was diffuse and five focal. No correlation was established between the presence of EGFR epitopes and the histologic type or biologic behavior of the meningiomas. The results suggest that the EGFR may participate in tumor angiogenesis, but its role in the growth of neoplastic meningioma cells remains elusive.

Spinal cord pathology in pediatric acquired immunodeficiency syndrome

We examined the spinal cords from 15 consecutive autopsies of infants and children with AIDS using a battery of histochemical and immunocytochemical stains, and in four cases, electron microscopy. Corticospinal tract (CST) signs were a notable clinical finding in 14; however, the age of onset, rate of progression, severity of dysfunction, and duration varied among patients. Ten cases had pathologic changes in the CST. In four of the ten cases, the changes were consistent with an “axonopathy” since axons and myelin were both diminished in the CST. These cases may represent CST wallerian degeneration, since they had marked injury to cerebral white matter in the form of chronic inflammation with multinucleated cells, gliosis, and myelin pallor. In five cases, with an average age at death of 31 months, the CST showed poor myelination with relative preservation of axons. These cases may represent delayed myelination or possibly cytokine-mediated injury to newly formed myelin since the CST is one of the last tracts to myelinate in the spinal cord. One child with primary CNS lymphoma had a complicated pattern of spinal injury due to unilateral CST wallerian degeneration possibly superimposed upon delayed myelination, in addition to patchy areas of demyelination associated with perivascular lymphomatous infiltrates. Four children with mild CST signs, ranging in age from 5 to 6 months, had CST myelin pallor that was consistent with the degree of myelination expected for age. We did not find vacuolar myelopathy similar to that seen in adult AIDS, but did note focal vacuolar changes in the thoracic posterior columns in the oldest child.

Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia

We describe the first case of an Epstein-Barr virus (EBV)-associated natural killer-large granular lymphocyte (NK-LGL) leukemia in the United States to the best of our knowledge. A 29-year-old woman of Japanese descent developed EBV infection after a blood transfusion as indicated by a rise in serum antibody titers. Peripheral blood and bone marrow aspirate smears demonstrated increased LGLs. Flow cytometry showed that these cells expressed NK-associated surface antigens. Cytogenetic analysis of the bone marrow aspirate showed two distinct but related clones with multiple copies of a modified 7 marker chromosome. Death followed colonic perforation. Findings at necropsy included bone marrow lymphocytosis and erythrophagocytosis, a mononucleosis-like lymphadenitis, atypical hepatitis with a mixed, predominantly T-cell infiltrate, interstitial pneumonitis, and multiorgan system vasculitis with perforation of the transverse colon. Epstein-Barr virus transcripts were identified in lymphocytes infiltrating liver and peripheral nerve by in situ hybridization. In addition, Southern blot analyses showed monoclonal bands superimposed on oligoclonal ladders of EBV termini in liver and lymph node. The identical episomal form of EBV was found in the bone marrow, lymph node, and liver. No immunoglobulin (Ig), T-cell receptor beta, or T-cell receptor gamma chain gene rearrangements were identified. These studies support the hypothesis that the LGL population was a neoplastic EBV-related clonal proliferation of NK cells.

Corpora amylacea: a marker for mesial temporal sclerosis.

Mesial temporal sclerosis (MTS) is the most frequently encountered abnormality in temporal lobectomies performed for medically intractable seizure disorders. The pathologic diagnosis of MTS relies on the identification of neuronal loss affecting various regions of the hippocampus. However, neuronal loss is often difficult to assess, particularly in lobectomies that are not performed en bloc. Because of this difficulty the presence of hippocampal pathology is often indeterminate. In this report we describe our experience with 73 temporal lobectomies performed for seizure disorders. In 58%, increased numbers of corpora amylacea (CoA) were found in association with MTS. The relationship between CoA and the pathogenetic mechanisms underlying MTS remains speculative. However, the association between MTS and corpora amylacea is important to recognize since the identification of abundant numbers of CoA provides a marker for MTS that can be useful in cases in which neuronal loss and gliosis are difficult to assess. For this purpose, it is strongly recommended that tissues resected from the hippocampus and amygdala for temporal lobe epilepsy be stained with LFB-PAS to highlight CoA

Striatonigral degeneration, olivopontocerebellar atrophy and "atypical" Pick disease.

SummaryA 75-year-old woman with parkinsonism plus was found at autopsy to have striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) and intracytoplasmic neuronal inclusions, mostly confined to the hippocampus and pontine nuclei. These inclusions were intensely argyrophilic, ubiquitinated and expressed variable immunoreactivity for neurofilament but not for tau-1 and Alz 50 proteins. Ultrastructurally, they were formed of skeins of intermediate filaments averaging 11 nm in diameter. They were considered to represent Pick bodies. There was no cortical atrophy, gliosis or sponginess. To our knowledge, SND and OPCA in association with Picks disease has not been previously reported. In addition, intracytoplasmic oligodendroglial inclusions were present in the deeper layers of the cortex, especially the pericentral gyri, the striatum and the white matter of certain regions of the cerebral hemispheres, as well as in the cerebellum. These inclusions which have been previously reported in multisystem atrophy, had to be distinguished from cortical Lewy bodies, Pick bodies, and the nonspecific ubiquitinated bodies in the white matter of the aged brain, mainly by their topographical distribution and immunostaining properties.

Alzheimer's disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration.

Abstract We report here a 70-year-old woman whose initial clinical presentation suggested corticobasal degeneration, but autopsy revealed dementia with Lewy bodies (DLB) with severe Alzheimer’s disease (AD)-type pathology accentuated in the motor cortex, in conjunction with a high burden of both cortical and brain stem LB. Review of the literature disclosed four patients with AD whose peri-Rolandic region was particularly involved by the disease and who exhibited similar clinical and neuropathological findings as in our patient except they lacked LB. It appears that DLB if associated with severe AD-type pathology can, like some unusual cases of AD, mimic corticobasal degeneration.