Edward P. Richardson

Neuropathological classification of Huntington's disease.

In postmortem brain specimens from 163 clinically diagnosed cases of Huntingtons disease (HD) the striatum exhibited marked variation in the severity of neuropathological involvement. A system for grading this severity was established by macroscopic and microscopic criteria, resulting in five grades (0–4) designated in ascending order of severity. The grade correlates closely with the extent of clinical disability as assessed by a rating scale. In five cases of clinically diagnosed HD there were no discernible neuropathological abnormalities (grade 0), suggesting that the anatomical changes lag behind the development of clinical abnormalities. In eight cases, neuropathological changes could only be recognized microscopically (grade 1). The earliest changes were seen in the medial paraventricular portions of the caudate nucleus (CN), in the tail of the CN, and in the dorsal part of the putamen. Counts of neurons in the CN reveal that 50% are lost in grade 1 and that 95% are lost in grade 4; astrocytes are greatly increased in grades 2–4. These studies indicate that analyses of the CN in grade 4 would reflect mainly its astrocytic composition with a component of remote neurons projecting to the striatum. Because of the relative preservation of the lateral half of the head of the CN in grades 1–2, these regions would reflect early cellular and biochemical changes in HD.

Spinal epidural abscess.

In an editorial describing his clinical experience of spinal epidural abscess, Heusner (1948) reminds us that “… the decisive factor in the outcome of most cases is the celerity with which the first physician suspects the probable nature of the ailment and summons expert aid”. On pathological grounds he recognized three presentations: (1) an acute metastatic presentation which evolves over hours to days and where the epidural abscess cavity contains frankly purulent material; (2) a subacute presentation evolving over days to weeks where the epidural abscess cavity comprises granulation tissue without significant quantities of necrotic material; (3) a chronic presentation, most often associated with osteomyelitis. The last accounted for only 10% of his series and involved a broader differential diagnosis. In more recent series (Hlavin et al. 1990; Nussbaum et al. 1992; Darouiche et al. 1992; Corboy and Price 1993) this classification has been less distinct with the acute variety predominating.Thirty-nine patients with spinal epidural abscess were evaluated at the Massachusetts General Hospital between 1947 and 1974. Twenty had acute symptoms, and purulent epidural collections were present; 19 had prolonged courses, and epidural granulation tissue was observed at operation. Staphylococcus aureus was the most common etiologic agent (57 per cent), followed by streptococci (18 per cent) and gram-negative bacilli (13 per cent). The source of infection was osteomyelitis in 38 per cent of cases and bacteremia in 26 per cent. In 16 per cent epidural abscess was due to postoperative infection. The progression from spinal ache to root pain to weakness followed by paralysis continues to be characteristic of spinal epidural abscess. Although the disease is uncommon, the complications are so serious that prompt diagnosis and treatment are of paramount importance. The combination of back pain with fewer and local tenderness is an indication for cerebrospinal-fluid examination and, depending on the results, immediate performance of myelography.

Morphometric Demonstration of Atrophic Changes in the Cerebral Cortex, White Matter, and Neostriatum in Huntington's Disease

We performed morphometric analysis of five standardized coronal brain slices at anterior frontal (AF), caudate-putamen-accumbens (CAP), globus pallidus (GP), lateral geniculate nucleus (LGN), and parieto-occipital fissure (OCP) levels in 30 patients with Huntingtons disease (HD) and 13 controls. Associated with the 30% mean reduction in brain weight in HDpatients (p<0.001) were significantly smaller overall cross-sectional areas of brain at all five levels studied, with striking losses in cerebral cortex (21-29%), white matter (29-34%), caudate (57%), putamen (64%), and thalamus (28%) (all p<0.005). In addition, the ventricular system was dilated up to 2.5 times normal at CAP, GP, and LGN levels, 9.5 times normal at the OCP level, and 13 times normal at the AFlevel. Higher grades of severity of HDhad greater reductions in the cross-sectional area of the caudate, putamen, thalamus, and cerebral cortex (p<0.005-0.001), and larger ventricles (p=0.08) compared to lower (less severe) grades of HD. The findings confirm and quantitate the severe atrophy of the neostriatum, in addition to demonstrating a severe loss of cerebral cortex and subcortical white matter in HD. The global atrophy of cerebral cortex and white matter observed in all degrees of HD may account for the cognitive and neuropsychiatric impairments which often precede the onset of chorea.

Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease

We have previously found that a biochemically distinct subset of neurons, containing nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-4), is selectively resistant to the degenerative process that affects the striatum in Hunting-tons disease (HD). We report the morphologic and histochemical characteristics of these striatal neurons and their distribution with respect to the histochemical compartments as defined by acetylcholinesterase (AChE) activity. Sections of striatum were stained histochemically for NADPH-d and AChE and immunocytochemically for somatostatin and neuropeptide Y-like immunoreactivity. The diaphorase end-product was contained within medium-sized neurons which corresponded morphologically to a category of aspiny interneurons. Combined techniques showed that NADPH-d, somatostatin, and neuropeptide Y coexisted within the same neurons in controls and patients with HD. The density of these neurons was greater in the ventral putamen and the nucleus accumbens than in the remainder of the striatum. The distinctive AChE pattern of high and low enzyme activity was altered in HD. The AChE-rich matrix zone was markedly reduced in size, while the total area of zones of low enzyme activity was not different from that found in control striatum. The relation between these AChE chemical compartments and the distribution of preserved diaphorase neurons remained intact; NADPH-d neurons were predominantly observed in the matrix zone.

Subacute encephalomyelitis of AIDS and its relation to HTLV‐III infection

Subacute encephalitis, characterized by demyelination, gliosis of the gray and white matter, focal necrosis, microglial nodules, atypical oligodendrocyte nuclei, and multinucleation of cells, was present in 27 of 30 (90%) autopsied patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Subacute encephalitis was mainly distributed in the frontal (58%) and temporal (69%) lobes, basal ganglia (77%), amygdala (80%), and hippocampus (64%). Ten (37%) with moderate or severe subacute encephalitis were demented; 82% with mild subacute encephalitis had no recognized neurologic disorder. Human T-lymphotropic virus type III (HTLV-III) was isolated from neural tissue or CSF in 11 of 13 patients, 10 with subacute encephalitis, and 1 without CNS lesions. We conclude that subacute encephalitis is common in AIDS patients and is most likely caused by CNS infection with HTLV-III.

Gilles de la Tourette's syndrome. A postmortem neuropathological and immunohistochemical study.

Immunocytochemical studies of the human forebrain have shown that enkephalin-like, dynorphin-like and substance-P-like immunoreactivity (respectively ELI, DLI, and SPI) normally present in unique pattern (now termed woolly fibers) in the globus pallidus and substantia nigra, in which their concentration is at its densest. Quantitative determinations moreover indicate that the levels of all 3 peptides are higher in the globus pallidus and substantia nigra than in any other region of the brain. We report here the distribution of immunoreactivity of these 3 peptides in the brain of a patient showing the typical clinical manifestations of Gilles de la Tourettes syndrome (TS); a disease for which no characteristic or consistent neuropathological features have been discerned. In the case described here neuropathological examination by means of the usual histopathological methods showed no abnormalities to which the patients illness could be ascribed. ELI- and SPLI-positive woolly fibers were densely stained and of normal distribution. DLI-staining was, however, considerably less dense throughout the brain than normal. The most striking finding was the total absence of DLI-positive woolly fibers in the dorsal part of the external segment of the globus pallidus; the ventral pallidum showed very faint staining. These observations, which indicate a decrease of dynorphin in striatal fibers projecting to the globus pallidus, are, to our knowledge, the first evidence of a distinct pathological change in the brain in TS.

Gastrointestinal involvement in von Recklinghausen's neurofibromatosis

Thirty-nine cases of von Recklinghausens neurofibromatosis with gastrointestinal involvement, including seven newly reported cases, are reviewed. Ten percent of patients with von Recklinghausens disease at the Massachusetts General Hospital had pathologically proven gastrointestinal neurofibromatosis. Twenty-seven patients had gastrointestinal symptoms prior to discovery of gastrointestinal tumors. The most common sites of involvement were the jejunum (17 cases) and the stomach (16), but multiple tumor sites have been reported. In 30 of the 39 cases the tumors were neurofibromas, and in five they were leiomyomas; in eight the tumor had malignant characteristics. Gastrointestinal tumors should be considered in every patient with von Recklinghausens disease and symptoms of gastrointestinal dysfunction.

Clinical and neuropathologic assessment of severity in Huntington's disease

Clinical records were evaluated for 163 Huntingtons disease patients in whom postmortem brain specimens had been graded for degree of neuropathologic involvement in the striatum. Juvenile/adolescent onset (4 to 19 years of age) was associated with very severe neuropathologic involvement produced by an apparent rapid degenerative process. Cases of early (20 to 34 years) and midlife (35 to 49 years) onset had respectively less severe striatal involvement, suggesting a slower degenerative progression. High correlations among the grade of neuropathologic involvement, cell counts of neurons, and a rating of physical disability suggest that each represents a common underlying degenerative process of the disease. The relationship between the age at onset and the extent of neuropathologic involvement suggests that a single mechanism may determine both onset and rate of degenerative disease progression.

Decreased Neuronal and Increased Oligodendroglial Densities in Huntington's Disease Caudate Nucleus

Decreased density of neurons was found throughout the head of the caudate nucleus in Huntingtons disease (HD), with the most severe neuronal loss early in the disease in the medial region. The density of reactive astrocytes is inversely proportional to the neuronal loss. In cases of mild Huntingtons disease which had no identifiable abnormality on conventional neuropathologic evaluation (grade 0), there is a reduction in neuron density without an accompanying reactive astrocytosis. The pattern for decrease in neurons and accompanying astrocytosis suggests that the earliest changes occur in the most medial portion of the head of the caudate nucleus and subsequently sweep laterally across the caudate nucleus to the internal capsule. An increased density of oligodendrocytes is observed in the head of the caudate nucleus for the lower grades (0, 1 and 2). The decreased neuronal and increased Oligodendroglial densities may be of significance in understanding the pathogenesis of HD. These altered densities, observed in the absence of reactive astrocytosis, suggest that these changes may not represent recent effects of disease, but rather that HD gene expression may influence brain cell densities from early in the life of the gene carrier.

Neuropeptide Y, somatostatin, and reduced nicotinamide adenine dinucleotide phosphate diaphorase in the human striatum: A combined immunocytochemical and enzyme histochemical study

Neuropeptide Y and somatostatin immunoreactive neurons and processes were examined in human striatum using both immunofluorescence and avidin biotin immunoperoxidase methods. Reduced nicotinamide adenine dinucleotide phosphate diaphorase activity was histochemically determined by the reduction of nitro blue tetrazolium. Immunofluorescence using a monoclonal anti-somatostatin antibody and a polyclonal anti-neuropeptide Y antibody, followed by diaphorase histochemistry, showed that these three neurochemical markers are co-localized in a single population of medium-sized aspiny intrinsic neurons. Cells were evenly distributed in clusters throughout the striatum, but fiber density was higher in the nucleus accumbens and ventromedial regions of the caudate and putamen. Double-stained reduced nicotinamide adenine dinucleotide phosphate diaphorase-acetylcholinesterase sections demonstrated that these neurons are located in zones of high acetylcholinesterase activity, often at the interface of these zones with regions of low enzyme activity. These biochemically distinctive neurons are uniquely situated to modulate activity between striatal compartments. Our findings provide new information about the modular organization of the striatum and extend these observations in human brain.