'Full dose' reirradiation of human cervical spinal cord.

With the progress of modern multimodality cancer treatment, retreatment of late recurrences or second tumors became more commonly encountered in management of patients with cancer. Spinal cord retreatment with radiation is a common problem in this regard. Because radiation myelopathy may result in functional deficits, many oncologists are concerned about radiation-induced myelopathy when retreating tumors located within or immediately adjacent to the previous radiation portal. The treatment decision is complicated because it requires a pertinent assessment of prognostic factors with and without reirradiation, radiobiologic estimation of recovery of occult spinal cord damage from the previous treatment, as well as interactions because of multimodality treatment. Recent studies regarding reirradiation of spinal cord in animals using limb paralysis as an endpoint have shown substantial and almost complete recovery of spinal cord injury after a sufficient time after the initial radiotherapy. We report a case of "full" dose reirradiation of the entire cervical spinal cord in a patient who has not developed clinically detectable radiation-induced myelopathy on long-term follow-up of 17 years after the first radiotherapy and 5 years after the second radiotherapy.

Central diabetes insipidus due to herpes simplex in a patient immunosuppressed by Cushing's syndrome.

OBJECTIVE: To describe a patient immunocompromised by Cushing's syndrome in whom central diabetes insipidus developed as a complication of herpes simplex involvement of the hypothalamus. METHODS: We present a case, including results of laboratory and histopathologic studies, in which herpes simplex was established as the causative agent for central diabetes insipidus. RESULTS: A woman with ectopic corticotropin-dependent Cushing's syndrome, diabetes mellitus, carcinoid tumor, and a history of thyroid cancer had the precipitous onset of seizure and fever, and hypotonic polyuria and progressive hypernatremia developed. Central diabetes insipidus was diagnosed and successfully treated with desmopressin. Nevertheless, the patient's condition deteriorated and she died. Autopsy revealed herpes simplex encephalitis involving the magnicellular neurons of the hypothalamus. CONCLUSION: Central diabetes insipidus caused by viral infections has been reported in immunosuppressed patients, such as those with acquired immunodeficiency syndrome (AIDS). To our knowledge, this is the first report of a herpes infection causing diabetes insipidus in a patient immunosuppressed by Cushing's syndrome. This case demonstrates that, in patients with Cushing's syndrome, diabetes insipidus may develop as a result of herpes simplex infection of the hypothalamus.

Preservation of synapses on principal cells of the central nucleus of the inferior colliculus with aging in the CBA mouse.

The light and electron microscopic features of principal neurons of the central nucleus of the inferior colliculus were quantitated in the CBA mouse. Three age groups of mice were examined, including young (3 months), middle-aged (8 months) and old (25 months). No changes were noted in the size of the principal neurons over the age range examined. At the ultrastructural level, synapses on the somata of the principal neurons showed no change in the number or type of synapses, the length of synaptic apposition nor the size of synaptic terminal area. These results are in contrast with the moderately severe synapse loss which we previously reported in the C57BL/6 mouse strain, a strain which has a genetic deficit producing progressive sensorineural hearing loss starting in young adulthood (Kazee et al., 1995). In contrast, hearing is quite well-preserved across the lifespan in the CBA mouse strain, making this a useful animal to study the intrinsic effects of aging in the auditory system versus the effects of sensorineural hearing loss. The preservation of synapses on principal neurons in this strain suggests that synaptic loss is not an inevitable event in aging, but may be related to the preservation of peripheral auditory function and input to the neurons.

Primary solitary amyloidosis of the spine: a case report and review of the literature.

BACKGROUND: Amyloidosis is a term that encompasses a group of disorders that have as their common feature the intercellular deposition of the amyloid protein by several different pathogenetic mechanisms. Primary solitary amyloidosis, or amyloidoma, is a rare subset of amyloidosis in which the amyloid deposition is focal and not secondary to a systemic process or plasma cell dyscrasia. We present the second reported case of a cervical spine amyloidoma and discuss its presentation and management. METHODS: This 58-year-old man presented with a 1-year history of intermittent chest pain that would radiate into both legs precipitated by valsalva maneuvers. A magnetic resonance imaging (MRI) of the cervical spine revealed a homogenously enhancing lesion focally involving the C-7 vertebral level with significant spinal cord compression. He underwent combined anterior and posterior decompressive procedures with instrumentation for spinal stabilization. Histopathology revealed amyloid deposits and a systemic work-up was negative for amyloidosis. RESULTS: The patients is free of any tumor recurrence at 24 months and has a stable spine construct. CONCLUSIONS: Primary solitary amyloidosis is a rare subtype of amyloidosis which, unlike other forms of amyloidosis, has an excellent prognosis with local resection. Diagnosis requires special stains and therefore a degree of suspicion for the disease. Management of vertebral amyloidoma involves aggressive local resection of the tumor when feasible and stabilization of the spine as mandated by the degree of tumor involvement. Complete evaluation for the diagnosis of systemic amyloidosis is essential for the management and prognostication of each case.

Gap-43 message levels in anterior cerebellum in Alzheimer's disease.

We have previously reported that decreased growth-associated protein (GAP-43) message in frontal association cortex (area 9) of Alzheimer's disease (AD) patients is associated with increased density of neurons containing neurofibrillary tangles (NFTs) [9]. This finding leads to the hypothesis that decreased GAP-43 message in AD may be related to NFTs, rather than to some other aspect of AD pathology. Therefore, we predicted that in areas of brain unaffected by NFTs in AD the GAP-43 message levels should be similar to those of controls. The cerebellum is known to have a number of pathologies of AD, including diffuse plaques (DPs), microglial activation and reactive astrocytes. NFTs, however, are not typically found in the cerebellum. mRNA was extracted from anterior cerebellum of AD and control cases, Northern- and slot-blotted and hybridized against a GAP-43 probe. Poly(dT) and glucose-3-phosphate dehydrogenase probes were used for normalization. The average relative GAP-43 message level was 0.582 in the AD cases and 0.448 in control cases. This 23% difference failed to reach statistical significance. Regression analysis within the AD group demonstrated that GAP-43 message level in cerebellar cortex was not significantly correlated with diffuse plaque density in cerebellar cortex. GAP-43 message levels in cerebellar cortex were also not correlated with summed density of neuritic plaques or summed density of NFTs in cortical regions-here used as an index of severity of disease. The data reported here also emphasize that the (NFT-dependent) reduction in GAP-43 mRNA levels previously reported in frontal association cortex in Alzheimer's disease [9] appears to be region specific and not a general brain phenomenon. The preservation of normal GAP-43 message levels in the cerebellum in AD is consistent with the hypothesis that events related to NFT formation have a major impact on the expression of GAP-43 in Alzheimer's disease.

Putaminal Iron Depositionin HIV Infection.

PURPOSE: T2 shortening (hypointensity) in magnetic resonance (MR) images of the putamen, which may be associated with iron deposition, only occurs in normal subjects over the age of 60 years. Increased or premature putaminal iron deposition may be related to brain injury. We sought to determine the correlation between MR putaminal hypointensity in HIV-infected patients and brain iron deposition. METHODS: Eleven T2-weighted axial MR scans were retrospectively rated for the extent of putaminal hypointensity from patients who also had neuropathological examination for the extent of putaminal iron disposition. Correlations between MR putaminal hypointensity and brain iron were obtained. RESULTS: Neuropathological examination in 9 of 10 patients with putaminal hypointensity demonstrated putaminal iron deposition, predominantly in a perivascular pattern. CONCLUSIONS: Premature putaminal iron deposition occurs in patients with HIV infection and may be detected by MR imaging.

Incorrect diagnosis of Alzheimer's disease. A clinicopathologic study.

OBJECTIVES: To examine the accuracy of clinical diagnoses of Alzheimer's disease (AD) in subjects enrolled in the Rochester Alzheimer's Disease Project (RADP) who were examined at autopsy, and to present a list of clinical "red flags." DESIGN: Autopsy examination of both prospective and retrospective subjects consecutively enrolled in this clinicopathologic study of the RADP. SETTING: University hospital and research center, using a multidisciplinary geriatric neurology clinic, satellite clinics, nursing home visits, and home visits. PATIENTS: One hundred seventy subjects clinically diagnosed as having AD who were enrolled in the RADP between 1983 and 1993 underwent neuropathologic examination. Of these, 93 had been enrolled prospectively and 77 retrospectively. MAIN OUTCOME MEASURES: Agreement between clinical and pathologic diagnoses. RESULTS: One hundred forty-nine subjects of 170 clinically diagnosed as having AD fulfilled the pathologic criteria for AD, yielding an accuracy rate of 88%. Of 93 subjects enrolled prospectively and diagnosed as having AD, 83 (90%) met the histologic criteria for AD. Of the 77 subjects enrolled retrospectively, neuropathologic examination indicated definite AD in 66 (86%). CONCLUSIONS: There was a high correlation between clinicians' diagnoses and final pathologic diagnoses. The most common clinical errors involved the misdiagnosis of dementias due to Parkinson's disease and cerebrovascular disease. There was no significant difference in the accuracy rates of subjects enrolled prospectively and retrospectively.

Synaptic loss in the central nucleus of the inferior colliculus correlates with sensorineural hearing loss in the C57BL/6 mouse model of presbycusis.

Between 3 and 25 months of age, light and electron microscopic features of principal neurons in the central nucleus of the inferior colliculus of the C57BL/6 mouse were quantitated. This mouse strain has a genetic defect producing progressive sensorineural hearing loss which starts during young adulthood (2 months of age) with high-frequency sounds. During the second year of life, hearing is severely impaired, progressively involving all frequencies. The hearing loss was documented in the present study by auditory brainstem recordings of the mice at various ages. The cochleas from many of the same animals showed massive loss of both inner and outer hair cells beginning at the base (high-frequency region) and progressing with age along the entire length to the apex (low-frequency region). In the inferior colliculi, there was a significant decrease in the size of principal neurons in the central nucleus. There was a dramatic decrease in the number of synapses of all morphologic types on principal neuronal somas. The percentage of somatic membrane covered by synapses decreased by 67%. A ventral (high frequency) to dorsal (low frequency) gradient of synaptic loss could not be identified within the central nucleus. These synaptic changes may be related to the equally dramatic physiologic changes which have been noted in the central nucleus of the inferior colliculus, in which response properties of neurons normally sensitive to high-frequency sounds become more sensitive to low-frequency sounds. The synaptic loss noted in this study may be due to more than the loss of primary afferent pathways. It may represent alterations of the complex synaptic circuitry related to the central deficits of presbycusis.

Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy.

The pathogenesis of human immunodeficiency virus type 1 (HIV-1) associated dementia in adults involves neuronal loss from discrete areas of the neocortex and subcortical regions, but the mechanism for neuronal death is poorly understood. Gene-directed cell death resulting in apoptosis is thought to be a normal feature of neuronal development, but little is known about neuronal apoptosis in disease states. We investigated whether HIV-1 infection of the central nervous system is spatially associated with apoptosis of neurons. Using an in situ technique to identify newly cleaved 3'-OH ends of DNA as a marker for apoptosis, we demonstrate the presence of apoptotic neurons in cerebral cortex and basal ganglia of children that had HIV-1 encephalitis with progressive encephalopathy. Furthermore, an association was observed between the localization of apoptotic neurons and perivascular inflammatory cell infiltrates containing HIV-1 infected macrophages and multinucleated giant cells. Apoptotic neurons and p24-positive macrophages were observed infrequently in cerebral cortex and basal ganglia in children with HIV-1 infection without encephalitis or clinical encephalopathy. In nine control (HIV-1 negative) brains, ranging from the first post-natal month of life to 16.5 years of age, infrequent neuronal apoptosis was observed in three cases. These findings suggest that neuronal apoptosis is unlikely to be associated with post-natal development except in early post-natal germinal matrix, and that it may instead represent the end result of specific pathological processes, such as HIV-1 encephalitis.

Cortical Lewy bodies in Alzheimer's disease.

Forty-eight cases of pathologically verified Alzheimer's disease were examined for the presence of ubiquitin-positive cortical Lewy bodies (CLBs). Thirty-four (71%) of 48 cases of Alzheimer's disease had CLBs compared with 4 (44%) of nine patients with idiopathic Parkinson's disease, and 2 (20%) of 10 patients with multi-infarct dementia. None of the 18 cognitively intact elderly controls we examined had CLBs. Among Alzheimer's disease patients, there was a strong correlation between CLBs and degenerative changes in the substantia nigra. We also found an association between the presence of CLBs and extrapyramidal symptoms. Among Alzheimer's disease patients, there was no association of CLBs with either senile plaques or neurons containing neurofibrillary tangles in hippocampus, neocortex, or ventral striatum. The incidence of CLBs among pathologically verified Alzheimer's disease cases is high when a careful search for these inclusions is performed with a sensitive method such as anti-ubiquitin immunocytochemistry.

Glucocorticoid receptor mRNA in Alzheimer's diseased hippocampus.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a common finding in Alzheimer's dementia. Since there is a loss of hippocampal corticosteroid receptors in animal models of aging, and since hippocampal cell loss occurs in Alzheimer's disease (AD), it has been suggested that a loss of hippocampal glucocorticoid receptors (GR) may underlie some aspects of HPA axis dysfunction in patients with AD. Levels of corticosteroid receptor protein are not reliably determined in postmortem human brain due to rapid lability. In contrast, levels of mRNA coding for GR are stable in postmortem tissue. We report here initial observations from in situ hybridization experiments which indicate that regional levels of glucocorticoid receptor mRNA in hippocampus, as determined by film autoradiography, are significantly higher in AD hippocampus than in controls. While neuronal levels of GR mRNA in AD, revealed by emulsion autoradiography, were equal in control and AD tissue. Taken together these results suggest that adrenal dysfunction in AD may relate to defects in receptor function rather than corticosteroid receptor loss in the hippocampus.

Substantia nigra lesions in Alzheimer disease and normal aging.

Clinical and pathological overlap between Alzheimer disease (AD) and Parkinson's disease (PD) has been well described; however, the mechanisms of overlap between these two disorders remain unknown. We retrospectively examined clinical and neuropathological features from 66 individuals participating in the Rochester Alzheimer Disease Center to determine the association of AD with substantia nigra (SN) pathology. SN pathology, identified by a loss of pigmented neurons and the presence of gliosis, pigment-laden macrophages, and Lewy bodies, was blindly scored in 48 AD cases and 18 normal elderly controls. We found moderate or severe pathology in the SN in 2 control brains (11%) and 29 AD brains (60%). The numbers of neocortical and hippocampal neurofibrillary tangles (NFTs) and senile plaques (SPs) were not associated with nigral pathology. There was also no significant association of SN pathology with NFTs or SPs in the striatum, the site to which these neurons project. There was no significant association of increasing SN pathology with aging among AD patients, nor with increasing severity and duration of AD. The signs and symptoms of an extrapyramidal movement disorder were, however, associated with increasing SN pathology. We confirm that pathological lesions in the SN are a common feature of AD and an uncommon feature in normal aging. AD is a significant risk factor for SN lesions and PD, but the pathologic severity of AD, as measured by NFTs and SPs, was not associated with SN lesions.

Osteoma of the frontoethmoidal sinus with secondary brain abscess and intracranial mucocele: case report.

The authors report the case of a 17-year-old patient with an osteoma of the frontoethmoidal sinus who had a secondary abscess of the frontal lobe and an intracranial mucocele. Clinical, radiological, and surgical correlates of this triad are presented.

Dementia of adult polyglucosan body disease. Evidence of cortical and subcortical dysfunction.

OBJECTIVES: To characterize the dementia associated with adult polyglucosan body disease (APBD) and to correlate the cognitive deficits with abnormalities found on magnetic resonance imaging (MRI). METHODS: Quantitative neuropsychological testing and MRI in one man with APBD and a review of the literature. RESULTS: The dementia of APBD affects cortical and subcortical functions. The cognitive deficits correlate with MRI findings of cortical atrophy and white-matter abnormalities. CONCLUSION: Neuropsychological testing and MRI are helpful in the evaluation of patients with APBD.

Intranuclear rods in severe congenital nemaline myopathy.

We compared the muscle pathology and clinical course in eight patients with congenital nemaline myopathy. An abundance of large intranuclear rods was present in the muscle fibers of one patient with a rapid, fatal course. Intranuclear rods were not present in the muscles of seven patients with a benign course. The large intranuclear rods and the smaller sarcoplasmic rods were similar ultrastructurally and exhibited positive immunoperoxidase staining with anti-alpha-actinin antibodies. The accumulation of alpha-actinin within myonuclei may reflect a severe disturbance of normal intracellular processes regulating myofibrillar synthesis. Since two previously reported infants with intranuclear nemaline rods also had a fatal outcome, the presence of intranuclear rods may represent a marker for a severe form of congenital nemaline myopathy.

Clinicopathologic correlates in Alzheimer disease: assessment of clinical and pathologic diagnostic criteria.

The neuropathologic findings from a group of 123 patients who have come to autopsy from the Rochester Alzheimer Disease Project (RADP) are presented. Among these 123 cases, there were 94 demented subjects who met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) clinical criteria for the diagnosis of "probable Alzheimer disease," and 29 normal elderly controls. Autopsy confirmation of Alzheimer disease (AD) was based on the age-graded National Institutes of Health (NIH) consensus conference pathologic criteria. Using the NINCDS-ADRDA clinical criteria and the NIH pathologic criteria, the diagnostic accuracy was 88%, the sensitivity was 98%, and the specificity was 69%. Additional strict clinical and pathologic criteria developed by the RADP were applied in the final review of these cases to exclude all confounding causes of dementia, including cerebral infarcts. After applying these additional criteria, a subset of 62 cases of "pure" AD and "pure" control subjects was identified for a more detailed examination of neuritic plaques (NP) and neurons containing neurofibrillary tangles (NFT). The NP and NFT were counted in three subfields of hippocampus and two areas of association neocortex. The density of diffuse plaques (plaques lacking dystrophic neurites) was estimated on a semiquantitative basis. Results show that the AD patients and control groups could be distinguished from each other easily on the basis of mean NP and NFT counts, but there was sufficient overlap in the counts to present difficulty in diagnosing any individual case. Abundant diffuse plaque involvement and NFT in the neocortex were, however, seen only in AD cases.

Reduced GAP-43 message levels are associated with increased neurofibrillary tangle density in the frontal association cortex (area 9) in Alzheimer's disease.

We previously suggested the hypothesis that defective neuronal plasticity is a major neurobiological deficit causing the dementia of Alzheimer's disease (AD). We used message levels of the growth-associated protein, GAP-43, as a marker of axonal plasticity to examine the hypothesis of defective neuronal plasticity in AD. When all AD cases are combined, the average level of GAP-43 message in area 9 of the AD frontal association cortex was not significantly different from the level in the comparably aged control cortex. Differentiation of AD cases on the basis of neurofibrillary tangle (NFT) density revealed that in AD cases with high tangle density average GAP-43 message level was reduced fivefold relative to levels in AD cases with low NFT density. AD cases with low neurofibrillary tangle density had levels of GAP-43 message that were not significantly different from the levels of normal controls. Differentiation of AD cases on the basis of neuritic plaque density did not indicate as strong a relationship to GAP-43 message level. The association between neurofibrillary tangle density and GAP-43 message level suggests the hypothesis that neurofibrillary tangles may reduce GAP-43 expression. Data of others show a relationship between high NFT density and reduced levels of synaptophysin-like immunoreactivity and reduced cerebral glucose metabolism. These data combine to suggest a set of AD cases with high NFT density, reduced axonal plasticity, reduced synaptic density, and reduced cerebral glucose metabolism--all variables that may be directly related to the functioning of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffuse axonal injury by simple fall.

Diffuse axonal injury (DAI) is the second most common lethal head trauma after subdural hematoma and probably the most frequent cause of traumatic coma in the absence of an expanding intracranial mass lesion. Though it occurs most often in traffic accidents, it may occasionally result from falls from a height. Previously, it has not been associated with a simple fall or a fall of a distance not more than the victim's own height. We report herein a case of DAI from a simple fall.

In situ hybridization of calcium/calmodulin dependent protein kinase II and tau mRNAs; species differences and relative preservation in Alzheimer's disease.

Abnormal phosphorylation of the microtubule associated protein tau component of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) may result from alterations in protein kinase expression. Calcium/calmodulin dependent protein kinase II (CaM kinase II) has been shown to phosphorylate tau in vitro in such a way to decrease its electrophoretic mobility. A68, apparently a modified form of tau in AD brain, also shows abnormal phosphorylation and slower mobility than tau. To further examine the role of CaM kinase II in AD, in situ hybridization studies were performed on tissues from rat, monkey and human to examine and compare the patterns of CaM kinase II mRNA expression in different brain regions. The most notable differences among the three species were observed in dendrites in layer I of isocortex, in the molecular layer of the dentate gyrus and stratum radiatum and stratum lacunosum-moleculare in hippocampus, where hybridization was detected in rat, but not in monkey or human brain. In addition, comparisons between tau and CaM kinase II mRNA expression were made in tissue from normal aged adults and AD patients, especially in areas prone to NFT formation. CaM kinase II and tau mRNAs were co-expressed in many neuronal populations, both those which are prone to NFT formation as well as those which are rarely affected by AD changes. No major differences in the relative abundance of either CaM kinase II or tau mRNA within particular neuronal populations was noted between normal aged and AD brain. Diminished hybridization was associated with serve neuronal pathology and cell loss.