Oncogenic response of rats with x-ray-induced microcephaly to transplacental ethylnitrosourea.

The relation of congenital malformations to tumor development was examined. Pregnant Sprague-Dawley rats were given 200 rads of X-rays on the 15th or 16th day of gestation and injections of 10 mg ethylnitrosourea (ENU)/kg 1-4 days later, or they were irradiated or injected only. Surviving weanlings that had been irradiated had micrencephaly and other malformations. Offspring exposed to ENU only had no external deformities. By 15 months of age 16.7% of the offspring exposed to X-rays and ENU prenatally had developed neurogenic tumors, whereas 62.2% of those exposed to ENU alone had developed tumors. Those only irradiated had no tumors. Both of the former groups developed oligodendrogliomas, mixed gliomas, ependymomas, and schwannomas, but the first manifestations of tumors occurred later in the group receiving the combined treatment. This delay persisted furing the subsequent period of the study.

Excess chromosome no. 4 in ethylnitrosourea-induced neurogenic tumor lines of the rat.

The chromosomes in 15 cell lines derived from separate tumors induced in rats by ethylnitrosourea (ENU) are described. Thirteen lines were neural (glioma or schwannoma) in origin and type. In 12 of these lines, excess chromosome no. 4 could be demonstrated by Giemsa banding. One to three extra no. 4 chromosomes were seen as numerical or structural abnormalities. Also noted were other changes that were not consistent among lines. The 12 lines produced tumors in newborn rats. The 13th neurogenic line lacked excess chromosome no. 4 and did not produce tumors. The remaining 2 lines were nonneurogenic and lacked excess chromosome no. 4 but produced tumors. Control studies included chromosome analyses of bone marrow preparations from ENU-treated rats with tumors, cell lines from brains of normal rat embryos, and 2 established nonneurogenic rat tumor lines. No excess chromosome no. 4 was seen. These results suggest that nondisjunction and/or rearrangement of chromosome no. 4 is associated with the oncogenic process in neurogenic tumors induced.

Dose-related reduction by prenatal x-irradiation of the transplacental neurocarcinogenicity of ethylnitrosourea in rats.

Pregnant Sprague-Dawley rats were X-irradiated on the 16th day of gestation with 5 to 250 rads and given i.p. injections 4 days later with 10 mg ethylnitrosourea per kg. The offspring were observed over their life span for the appearance of neurogenic tumors. The frequency of animals surviving beyond 4 weeks of age that developed tumors was inversely related to X-ray dose. About 15% developed tumors after exposure to the largest doses, 39 to 46% after the intermediate doses, and 58 to 65% after the smallest doses; 69% tumors occurred after treatment with ethylnitrosourea alone. The reductions in tumor frequency were not due to the increased mortality rate of tumor-prone animals, either before or after the onset of tumor appearance. Mean offspring weight at 4 weeks and 4 months of age was inversely related to X-ray dose but was not significantly different in those animals later developing tumors from that in animals remaining tumor free. Mean time of tumor appearance and mean number of tumors per affected animal were unrelated to tumor frequency. It does not seem that the destruction of target cells is by itself sufficient to explain the results.

Enhanced development of mammary tumors in rats following transplacental and neonatal exposure to ethylnitrosourea.

Transplacental and neonatal induction of mammary tumors (MT's) with ethylnitrosourea (ENU) was studied in Sprague-Dawley rats. A low transplacental ENU dose (10 mg/kg) did not increase the number of MT's or shorten their latency period. High ENU doses (30 mg/kg neonatal, 60 mg/kg transplacental, or 120 mg/kg transplacental) when corrected for differences in life span caused a significant shortening of the tumor induction period and an overall increase in the tumor incidence. With high ENU doses, the MT's were frequently multiple in the same animal and were more often malignant. Tumors developed mostly in females; only a few were observed in males. It is concluded that with a sufficient dose of the carcinogen in susceptible animals, transplacental and neonatal ENU mammary carcinogenesis takes place. The experiment was originally designed to evaluate ENU-induced neurogenic tumors; the results on MT's were obtained incidentally.

Cerebral amyloid angiopathy: the vascular pathology and complications.

Twenty-five cases with cerebral amyloid angiopathy (CAA) were studied. Senile plaques (SP) were present in all cases. In only eight cases which also displayed either SP (two cases), or both SP and Alzheimer's neurofibrillary tangles (NFT) (six cases), was there a history of dementia. In five cases, SP and NFT were observed without a history of dementia. Seven cases had significant cerebral hemorrhage, single or multiple, which could be related to CAA. Ten cases had cerebral infarcts, but only in seven of these cases could the infarcts be related to CAA. In five cases, with moderate to severe CAA and no history of dementia other distinctive vascular changes were also noted in the brain. These CAA-associated vasculopathies (CAA-AV) consisted of: clusters of multiple arteriolar lumina, the so-called "glomerular" formations, with various degrees of amyloid infiltration; aneurysmal vessels with amyloid infiltration; obliterative intimal changes; "double barreling", chronic inflammatory perivascular or transmural infiltrates; hyaline (nonamyloid) arteriolar degeneration, with or without aneurysmal dilatation; and fibrinoid necrotizing vascular change. In all five cases with CAA-AV, there were cerebral infarcts or hemorrhages which were considered to be direct complications of amyloid angiopathy, or of the vasculopathies developing secondary to the amyloid infiltration of vessel walls. It is possible that the associated vasculopathies represented secondary vascular changes that followed amyloid deposition in the blood vessel walls.

Neurofibrillary changes following childhood lead encephalopathy.

This report details the findings in a patient who survived severe lead encephalopathy at age 2 1/4 years, to die 42 years later in a state of severe mental deterioration. The brain revealed diffuse cortical atrophy, most severe in the temporal lobes, followed by hippocampi, amygdaloid nuclei and frontal cortex. Numerous pyramidal cells of the forebrain grisea contained Alzheimer's neurofibrillary tangles. The remaining pyramidal cells of the hippocampi exhibited granulo-vacuolar degeneration. Many senile plaques were present predominantly in the atrophic temporal cortex. Electron microscopic examination revealed many 800 A twisted tubules in the tangles. Atomic absorption spectrophotometry disclosed a tenfold increase of lead in frontal and temporal cortices as compared to suitable controls. The possibility that toxic levels of lead in any form could result in the formation of Alzheimer's fibrillary tangles is discussed.

Fatal massive intracerebral hemorrhage complicating cerebral amyloid angiopathy.

A 58-year-old normotensive woman died 24 hours after a stroke. Two months earlier, she had a transient neurological episode consistent with cerebrovascular insufficiency. Necropsy demonstrated a massive recent hemorrhage in the right occipital lobe associated with severe cerebral amyloid angiopathy (CAA). The cerebral cortex showed interstitial and perivascular neuritic plaques but no Alzheimer's tangles. There was no family history of CAA. A review of the literature indicated that only ten cases of such hemorrhage caused by nonfamilial CAA have been reported. Massive intracerebral hemorrhage seems to be more common in patients with familial Icelandic forms of CAA.

Cerebral vasculitis in rheumatoid arthritis.

A 63-year-old man with severe, untreated rheumatoid arthritis and pleuritis developed an unusual neurological syndrome similar to Gerstman syndrome, followed by dementia and blindness, six weeks before his death. An autopsy showed extensive necrotizing vasculitis, resembling polyarteritis nodosa, involving the brain and resulting in numerous infarcts. The disease was most severe in the posterior portion of the cerebral hemispheres. Other organs were only slightly involved. Severe amyloidosis of cerebral arterioles and senile plaques were noted in the areas of brain with most severe vasculitis. Review of literature indicated only six cases of cerebral vasculitis in rheumatoid disease, five of which were treated with corticosteroids.

Cerebral amyloid angiopathy: possible relationship to rheumatoid vasculitis.

In three cases of cerebral amyloid angiopathy there was also a chronic cerebral vasculitis characterized by segmental fibrinoid necrosis, chronic adventitial inflammatory infiltrates, obliterative "endarteritis" and hyaline arteriolar change, resembling rheumatoid vasculitis. Two of these cases had rheumatoid arthritis, and one had unspecified "arthritis" at the onset of dementia. Both vasculitis and amyloidosis involved the leptomeningeal and cerebral cortical vessels. In the two autopsy-verified cases, the vascular disease was limited to the brain. In the third case, only a brain biopsy was available. Amyloid-containing neuritic plaques were present in the cerebral cortex in all three cases, but they were abundant only in one, which also showed numerous Alzheimer tangles.

The incidence of cerebral amyloid angiopathy in Alzheimer's disease.

The incidence and forms of cerebral amyloid angiopathy were studied in 15 cases of Alzheimer's disease using Congo red staining and polarization. Thirteen cases showed slight to severe involvement; two contained no amyloid vascular degeneration. There was a correlation between the presence of amyloid-rich plaques and cerebral amyloid angiopathy (especially the plaque-like angiopathy) but no correlation with "amyloid-poor" senile plaques or Alzheimer's neurofibrillary degeneration.

Intracranial hemorrhage caused by metastatic tumors.

Fifteen cases of metastatic brain tumors associated with massive subarachnoid, intracerebral, or intraventricular hemorrhage or a combination thereof are reported. Four patients had multiple bleeding cerebral metastasis. In 10 patients, stroke was the first manifestation of the neoplastic disease. It is concluded that metastases of choriocarcinoma, melanoma, and bronchogenic carcinoma are most prone to massive bleeding. The average survival from the beginning of neurologic symptoms was 65 days, but in seven patients, it was 11 days or less. Surgery seems to be beneficial in selected patients. Massive hemorrhage was a complication in 14 percent of our patients with metastases to brain versus 0.8 percent of those with gliomas.

Astrocytes and the plaques of Alzheimer's disease.

We demonstrated senile plaques with glial fibrillary acidic protein (GFAP) stain in prefrontal and parietal cortex and in hippocampus of 3 cases of Alzheimer's disease. A plaque seen with GFAP appeared as a nearly round, spot-like brown blush consisting of numerous fine astrocytic processes, usually surrounded by single or, more often, several astrocytic cell bodies and their thick processes. Some plaques were virtually wrapped by these processes which also penetrated to the core, often directly touching the amyloid deposit. We never saw the plaque-type astrocytic grouping and spot-like blushes in the cortex of younger nondemented controls who were plaque negative. Our observations stress the importance of the astrocyte in plaque formation, either as primary or early secondary reactions. The focal glial reaction, without the neuritic component, possibly may precede neuritic change and relate to subminimal amyloid deposits or to some other undefined change.

Atypical Gerstmann-Straüssler syndrome or familial spinocerebellar ataxia and Alzheimer's disease?

We report a neuropathologic study of a case with features of Gerstmann-Straüssler syndrome (GSS) that is remarkable for the large number of neurofibrillary tangles (NFTs) throughout the neuraxis. The patient had a family history of spinocerebellar ataxia, but without dementia in other affected members. Our case meets the cardinal features of GSS as a rare familial degenerative disease characterized by clinically, spinocerebellar ataxia accompanied by progressive dementia, and pathologically, multiple system atrophy combined with widespread amyloid plaque deposition in the cerebral and cerebellar cortex. However, most pathologic studies stress the absence of NFTs in GSS. The nosology of this case is difficult to resolve because of profuse NFTs and morphologic differences between our and comparison Alzheimer's disease (AD) cases, the most prominent being spongiform changes. This case is remarkable because it combines features of a number of CNS degenerative diseases, including multiple system atrophy, AD, spongiform encephalopathies, and cerebrovascular amyloidosis.

Spinal cord degeneration in AIDS.

Ten months before his death, a 36-year-old homosexual man with AIDS developed progressive symmetric paraparesis with muscle wasting, paresthesias, reflex-uninhibited bladder function, and bowel incontinence. Neuropathologic postmortem examination revealed a symmetric degeneration of the lateral and anterior pyramidal tracts as well as the posterior columns. Scattered microglial nodules were present in the brain and spinal cord. The cause of this spinal cord complication remains uncertain. Possible etiologies of the demyelinating process include infectious, parainfectious, nutritional, paraneoplastic, and toxic causes.

Alzheimer's tangles in sudanophilic leukodystrophy.

We present a case of infantile leukodystrophy with some sudanophilic features. A normally developed male infant did well until age 15 months. Then he had episodes of myoclonus, reversal of intellectual development, rigidity with decerebrate posturing and epilepsy, which became severe. He died at age 7 years, 10 months. On autopsy, the brain was normally developed, but there was severe demyelination and gliosis throughout the white matter; the cerebellar cortex showed atrophy. The striking, unexpected finding was the presence of numerous Alzheimer's tangles containing paired helical filaments in electronmicroscopic examination, not only in the cerebral cortex but also in the brainstem, basal ganglia, and hypothalamus including the nucleus basalis of Meynert. Other unusual findings were hyperostosis of the skull and the appearance of macrophages containing PAS-positive granules in the reticuloendothelial system in many organs.

Hyalinizing plasmacytic granulomatosis of the falx.

Computed tomography scan in a 43-year-old woman revealed a fusiform mass involving the falx. Pathological tissue removed at craniotomy revealed a hyalinizing plasmacytic granulomatosis composed of masses of lymphocytes, plasmacytes, and various sized islands of hyalinized fibers arranged in parallel and surrounded by multinucleated giant cells. Ultrastructurally, the hyalinized fibers consisted of electron-dense, amorphous deposits. After partial removal, irradiation, and steroid therapy, the lesion decreased considerably in size.

Sclerosing peritubular nodules: a hereditary renal abnormality in von Recklinghausen's disease.

A previously unrecognized type of renal lesion characterized by the formation of multiple hamartomatous sclerosing peritubular nodules in the cortex is described. These lesions were hereditary, appearing in three members of a family, which included the mother and her two sons, in association with familial central von Recklinghausen's disease (bilateral acoustic schwannomas). The nodules originated as concentric peritubular proliferations of collagen producing spindle cells, which ultrastructurally showed myofibroblastic differentiation. Four stages of nodule development leading to progressive sclerosis and tubular destruction are described. In spite of widespread involvement of the cortex with numerous nodules, in none of the three patients was there any clinical manifestation of renal dysfunction or hypertension.

Neural, pituitary, and mammary tumors in Sprague-Dawley rats treated with X irradiation to the head and N-Ethyl-N-nitrosourea (ENU) during the early postnatal period: a statistical study of tumor incidence and survival.

To study the late effects of early postnatal treatment with N-ethyl-N-nitrosourea (ENU) preceded by X irradiation to the head, 226 neonatal CD rats were divided into six groups which received the following treatment: (1) 500-rad X irradiation to the head on the third postnatal day (pnd); (2) injection ip with 30 mg/kg ENU on the fourth pnd; (3) injection ip with 30 mg/kg ENU on the seventh pnd; (4) a combination of 500-rad X irradiation to the head on the third pnd, followed by ip 30 mg/kg ENU on the fourth pnd; (5) a combination of 500-rad X irradiation to the head on the third pnd, followed by ip 30 mg/kg ENU on the seventh pnd; and (6) untreated controls. The results indicate that (1) X irradiation to the head alone significantly extended the life span of females compared to that of control females, and did not affect survival of males; (2) X irradiation did not influence the latent period or mortality from neurogenic tumors when ENU was given 1 or 3 days afterward; (3) ENU itself was a factor in shortening latent periods for mammary tumors; (4) X irradiation alone did not increase the incidence of mammary tumors, and revealed no protective effect on the ENU-induced mammary carcinogenesis; (5) X irradiation increased the prevalence of pituitary tumors in the females; (6) no enhancement of pituitary tumors by ENU was observed: and (7) there was a statistically significant association of pituitary and mammary tumors in females.

Case-control study of clinical outcome after aneurysmal subarachnoid hemorrhage.

The clinical and neuropathological features of 84 nonsurvivors of aneurysmal subarachnoid hemorrhage (consecutive autopsy series) were compared with those of 51 survivors (consecutive clinical series). The groups differed significantly in the type of bleeding: 58% of the nonsurvivors had massive subarachnoid hemorrhage (MSAH) compared to 10% of the survivors (P less than 0.00001); 54% of the nonsurvivors had intraventricular hemorrhage (IVH) compared to 29% of the survivors (P less than 0.008); 45% of the nonsurvivors had intracerebral hematoma (ICH) compared to 8% of the survivors (P less than 0.00001). Only 1 of the 19 patients with both MSAH and ICH survived. The incidence of cerebral infarction was similar in nonsurvivors (31%) and survivors (29%). In the absence of associated MSAH, IVH, or ICH, cerebral infarction was uncommon (11%). Documented in-hospital rebleeding was uncommon in nonsurvivors (13%) and survivors (2%). Admission neurological status did not predict outcome independent of the extent of the initial bleeding. Comparison of the two groups suggests that the type and extent of initial bleeding are the most important determinants of mortality in aneurysmal subarachnoid hemorrhage.

Oligodendroglial proliferative abnormality associated with arteriovenous malformation: report of three cases with review of the literature.

A peculiar nonneoplastic oligodendroglial proliferative abnormality associated with cerebral arteriovenous malformations (AVMs) was present in three patients. Histological examination of biopsy material revealed dense oligodendroglial tissue reminiscent of oligodendroglioma in the white matter adjoining the AVMs. Careful consideration of clinical and pathological features suggested that the evidence was insufficient to qualify the lesion as truly neoplastic (oligodendroglioma); rather, a tissue collapse or a hamartomatous proliferation could be considered to be its cause. The literature contains 14 instances of various vascular malformations associated with primary brain tumors, 5 of which were diagnosed as oligodendrogliomas. It is possible, however, that some of the cases reported in the literature constitute oligodendroglial abnormality similar to that observed in our cases rather than genuine oligodendrogliomas. Attention is drawn to this interesting and prognostically important phenomenon.