Selective sparing of a class of striatal neurons in Huntington's disease.

A distinct subpopulation of striatal aspiny neurons, containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase, is preserved in the caudate nucleus in Huntington's disease. Biochemical assays confirmed a significant increase in the activity of this enzyme in both the caudate nucleus and putamen in postmortem brain tissue from patients with this disease. The resistance of these neurons suggests that the gene defect in Huntington's disease may be modifiable by the local biochemical environment. This finding may provide insight into the nature of the genetically programmed cell death that is a characteristic of the disease.

The Vascular Access Questionnaire: assessing patient-reported views of vascular access.

BACKGROUND: The use of central venous catheters for vascular access in hemodialysis (HD) patients is associated with an increased risk of complications compared to arteriovenous fistulas (AVF). Despite this, catheter use remains high and patient satisfaction may be an important driver of catheter use. METHODS: We developed the Vascular Access Questionnaire (VAQ) to measure patient-reported views of their vascular access. Chronic HD patients at two centers were asked to rate how bothered they were by 17 access-related problems. VAQ symptom scores were compared between patients using catheters and those using fistulas for vascular access. RESULTS: Two hundred and twenty-two patients were eligible for the study. Symptom score was not different between patients using catheters and those using fistulas (p=0.36). However, patients using fistulas were more likely to be at least moderately bothered by pain, bleeding, bruising, swelling, and the appearance of their access than patients using catheters. Elderly patients reported lower symptom scores with catheters than fistulas. CONCLUSIONS: Patients appear to be primarily concerned with the appearance of their access and cannulation-related complications, particularly the elderly. Better education about the risk of adverse events with catheters and the implementation of measures aimed at reducing cannulation-related complications may help to increase fistula rates and improve patient satisfaction with their vascular access.

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 Huntington's disease (HD) and 13 controls. Associated with the 30% mean reduction in brain weight in HD patients (p less than 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 less than 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 AF level. Higher grades of severity of HD had greater reductions in the cross-sectional area of the caudate, putamen, thalamus, and cerebral cortex (p less than 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.

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 Huntington's 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 Huntington's 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.

An improved approach to prepare human brains for research.

We describe two protocols for preparing human brains collected for research and diagnosis. In both protocols, one half brain is processed for research and the other for neuropathological evaluation. Clinical, neuropathological and tissue mRNA retention data are used for sample categorization. In protocol 1, coronal, whole hemisphere slices cut at standardized landmarks are frozen with a cooling device at -90 degrees C, which yields discrete anatomical structures. In selected instances, small blocks of brain are frozen at -160 degrees C in liquid nitrogen vapor. Cooling device or liquid nitrogen vapor frozen samples are suitable for in situ hybridization, protein blotting or immunohistochemistry. Morphological freezing artifacts are minimal. In protocol 2, one half brain is frozen en bloc on dry ice; this tissue is suitable for regional evaluation of gene expression or neurochemistry. Morphological freezing artifacts are severe. In both protocols, the other half brain is fixed in formalin prior to sectioning and diagnostic evaluation. The standardized selection of paraffin blocks from each brain allows precise diagnoses to be established, including identification of dangerous infectious processes; moreover, it makes it possible to produce a set of uniformly selected blocks and slides for comparative studies. These protocols lead to standardized tissue preparation for research and reduce variables impairing interpretation and comparison of data.

Neuropathological classification of Huntington's disease.

In postmortem brain specimens from 163 clinically diagnosed cases of Huntington's 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.

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-d), is selectively resistant to the degenerative process that affects the striatum in Huntington's 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.

The nosology of Creutzfeldt-Jakob disease and conditions related to the accumulation of PrPCJD in the nervous system.

Although typical cases of Creutzfeldt-Jakob disease are readily recognized pathologically and clinically, variant forms often pose a diagnostic challenge. From the 1920's, when this disease was first characterized, until quite recently diagnosis relied heavily on morphologic changes. New advances in immunoassays and PrP gene analysis now provide important adjuncts in recognizing the spectrum of disorders of PrP metabolism associated with these transmissible encephalopathies.

The development of neuropathology at the Massachusetts General Hospital and Harvard Medical School.

Few institutions have shaped neuropathology as a discipline as profoundly as Massachusetts General Hospital (MGH) and Harvard Medical School. Their fascination over many decades is due to a unique accumulation of excellent, intellectually stimulating neurologists with a sincere interest in the morphologic and pathogenetic basis of nervous system diseases. Their approach was strictly case oriented and clinico-pathological conferences were developed to the highest standard. In this review, the foundations of neuropathology in Boston are recounted.

Clinical, neuropathological and genetic aspects of the tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which patients develop hamartomatous lesions in the nervous system and a host of other organs. While considerable experience has been gained in defining the clinical spectrum of TSC, a number of nosological questions remain. Neuropathological studies have continued to refine our knowledge of the nervous system abnormalities that characterize TSC. Molecular genetic studies have implicated two chromosomal regions in the genesis of TSC, one on chromosome 9q and the other on chromosome 16p. The chromosome 16p gene, designated TSC2, has been cloned, although its function remains speculative. The identification of the TSC1 gene on chromosome 9q, along with functional studies and mutational analyses of both TSC genes, will likely provide fascinating insights into the pathogenesis of TSC.

Septic thrombosis of the dural venous sinuses.

From 1940 to 1984, 19 cases of septic dural-sinus thrombosis have been diagnosed at the Massachusetts General Hospital, and some 136 cases have been reported from other institutions. Septic thrombosis most frequently involves the cavernous sinuses (96 cases). Facial or sphenoid air sinus infection often precede cavernous-sinus disease. In addition to the classical signs of proptosis, chemosis, and oculomotor paralysis, isolated sixth-nerve palsy and hypo- or hyperesthesia of the fifth nerve may be found. The major pathogens associated with cavernous-sinus infection include Staphylococcus aureus, other gram-positive organisms, and anaerobes. Septic lateral-sinus thrombosis (64 cases) is almost exclusively a complication of otitis media and/or mastoid infection. Organisms causing this infection include Proteus species, Escherichia coli, S. aureus, and anaerobes. Septic thrombosis of the superior sagittal sinus (23 cases) most frequently accompanies bacterial meningitis or air sinus infection. Causative organisms include Streptococcus pneumoniae, S. aureus, other streptococci, and Klebsiella species. Because septic dural-sinus thrombosis is rare, this disease is frequently misdiagnosed. Evaluation should include lumbar puncture, air sinus films, and computed tomographic scan with contrast. Other helpful diagnostic tests may include carotid angiography, and dynamic brain scan. Orbital venography is the most definitive study in cases of chronic cavernous-sinus thrombosis. Therapy should include intravenous antibiotics and early surgical drainage of purulent exudate in the air sinuses or mastoid regions. Retrospective analysis suggests that treatment with heparin may reduce mortality in carefully selected cases of septic cavernous-sinus thrombosis. Anticoagulation is not recommended in other forms of septic dural-sinus thrombosis. Mortality in the antibiotic-era remains high, particularly in patients with septic thrombosis of the cavernous (30%) and superior sagittal (78%) sinuses.

A case of adult microcephaly.

A microcephalic woman who walked, spoke a few words, and was capable of some self-care, died at age 20. The brain weighed 260 g--the equivalent of that of an infant of eight months' gestation. The remarkable neuropathological features in our case included very small cerebral hemispheres, normal cerebral cortex, myelinated white matter, and large neuronal heterotopias situated along the ventricular walls and deep in the white matter adjacent to the intact nuclei of the basal ganglia, amygdala, and thalamus. The brainstem and cerebellum were relatively less reduced in size and showed normal structure and no heterotopias. In rats, microcephaly can be induced experimentally by giving carcinogens during sensitive periods of embryogenesis. Here, the microcephaly appears to result from necrosis of the neuroblasts lining the ventricles, and from a concomitant reduction in DNA synthesis. The pathogenesis of the microcephaly in our patient and others remains undefined. Our study shows that a great discrepancy may exist between brain size and level of function.

Subacute necrotizing polioencephalopathy.

A previously healthy 20-year-old woman died of a progressive cerebral disease that involved the brain stem and the cerebral hemispheres successively. The illness ran its course in 80 days. Postmortem examination showed a multifocal necrotizing encephalopathy that chiefly affected gray matter structures and that was mainly located in the brain stem and cerebral cortex. The cause and pathogenesis remain unknown.

Primary lateral sclerosis: a case report.

The syndrome of primary lateral sclerosis (PLS) has been reported clinically on many occasions. Pathologic confirmation in the modern era, however, has generally been lacking. In a recently reported case of PLS, the disorder was complicated by a pontine infarct. We describe a 65-year-old woman whose illness began with spastic dysarthria, which gradually worsened to the point that 18 months later she could barely utter a sound. Meanwhile, dysphagia, brisk reflexes, and a pseudobulbar affect had developed. Three years after onset she had a spastic contractured right-sided hemiplegia and walked with short shuffling steps. The spasticity slowly progressed, and she died of aspiration pneumonia 3.5 years after the onset of dysarthria. Neuropathologic examination showed bilateral atrophy of the precentral gyri, which microscopically showed a paucity of Betz cells. There was loss of myelin throughout the corticospinal system, yet the anterior-horn cells of the spinal cord and hypoglossal nuclei were well preserved. Intracytoplasmic eosinophilic inclusion bodies, of unknown cause and significance, were observed in occasional motor neurons, one in the hypoglossal nucleus and two in spinal cord anterior horns. Clinically and pathologically, this case meets the criteria for PLS.

Cerebral white-matter hypoplasia.

Twelve patients, including three sisters, with lifelong severe intellectual impairment and neurologic defects were found to have generalized hypoplasia of the cerebral white matter, with corresponding enlargement of the ventricular system. Gray-matter structures were remarkably intact. Reactive cellular changes (gliosis, phagocytosis, inflammation) were absent. To our knowledge, this particular syndrome has not previously been delineated in the extensive literature on cerebral palsy. The abnormalities in these cases could result from the effects of a selectively acting tissue-damaging factor, such as has been postulated in perinatal telencephalic leukoencephalopathy, but the factors underlying the disorder are still unknown.

Delayed encephalopathy after strangling.

An 11-year-old boy who had been the victim of a strangling attempt was asymptomatic for one week whereupon involuntary movements involving the trunk and limbs developed, along with repetitive episodes of opisthotonos and autonomic dysfunction. Meanwhile, he remained alert and appeared to be mentally intact. An electroencephalogram was normal. He died 13 weeks after the onset of the neurological disorder. The neuropathological examination showed cavitating lesions in the caudate nucleus, putamen, and globus pallidus bilaterally, with sparing of the white matter. The delayed onset of a progressively evolving neurological disorder has been noted in various forms of hypoxicischemic insult, including previously reported cases of strangling, but its occurrence cannot be predicted from the preceding clinical state or course. In the cases in which abnormal movements have been predominant, the pathological findings have been similar despite diversity in the preceding circumstances. We suggest the underlying metabolic disorder common to these cases may be lactic acidosis, and that they should be studied for evidence of a biochemical defect.

Dermatoleukodystrophy with neuroaxonal spheroids.

A Japanese brother and sister, the progeny of healthy parents, were born with thickened, wrinkled skin and died between the age of 2 and 3 years with a progressive cerebral disease characterized by generalized mental and motor impairment. Postmortem neuropathological studies disclosed a remarkable leukodystrophy in which multiple axonal spheroids were the outstanding feature. Ultrastructurally, the spheroids contained granules resembling ceroid-lipofuscin bodies. Similar granules were found in degenerating oligodendrocytes and in Schwann cells. The skin showed hypercellular and sclerotic features, suggestive of a genodermatosis. This combined neurologic and dermatologic syndrome, which, to our knowledge, has not hitherto been recognized, may well result from a genetically determined metabolic disorder, the nature of which still remains undisclosed.

Hypoxic-ischemic leukoencephalopathy in man.

Three cases of hypoxic-ischemic leukoencephalopathy were studied. In two patients, the neurologic disorder followed drug overdosage; in the third, the apparent precipitating event was a postoperative myocardial infarction complicated by circulatory insufficiency. All patients were deeply unresponsive, with varying reflex patterns. In all three cases, the brain showed extensive symmetrical necrotic lesions of the central white matter, with minimal damage to gray matter structures. The lesions in case 3 showed, in addition, vascular necrosis and ring hemorrhages. Common to all cases was a prolonged period of hypoxemia, hypotension, and elevated venous pressure. Acidosis occurred in two. These observations and analysis of previous reports of similar cases suggest that leukoencephalopathy tends to occur when the hypoxemia is prolonged and is associated with periods of hypotension and metabolic imbalance.

Keyhole aqueduct syndrome.

Communicating syringes confined to the brain stem are extraordinarily rare. Two patients, presenting with signs and symptoms of cerebellar dysfunction, later developed evidence of brain-stem disease with dysarthria, nystagmus, deafness, and internuclear ophthalmoplegia. The condition of both patients had been diagnosed clinically as multiple sclerosis, but at autopsy they had a striking keyhole-shaped syrinx in the midbrain and upper pons, which communicated with the aqueduct and fourth ventricle without associated syringomyelia. In addition, both patients had marked atrophy and gliosis of the cerebellum, one with extension of the syrinx into cerebellar folia. The unique character of these lesions coupled with the similarity of the clinical features of the cases prompted us to name this disorder--"keyhole aqueduct syndrome."

Adrenoleukodystrophy. A clinical and pathological study of 17 cases.

Adrenoleukodystrophy was diagnosed pathologically in 17 male patients. The diagnosis was suggested by clinical and laboratory signs of primary adrenal failure and by neurological signs referable to the degeneration of white matter. Neurological findings usually predominated over clinical stigmata of adrenal failure. Adrenal biopsy has proved to be the most reliable diagnostic test, while brain biopsy has often been misleading. The histological picture of the brain lesion differs substantially from that of the adrenal, but the presence of similar ultrastructural cytoplasmic inclusions suggests a common metabolic disorder. Morphological analysis of the cerebral lesion indicates that the destruction may spread in a caudal-rostral direction. The intense inflammatory cell response occurs within the demyelinated areas, behing the area of active myelin breakdown, and appears to be a secondary feature of white matter degeneration.