Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study.

Fludarabine phosphate (NSC 312878), an adenosine deaminase resistant analogue of 9-beta-D-arabinofuranosyladenine, has entered clinical trials. Eleven patients with acute leukemia in relapse received 14 courses of fludarabine phosphate as a 5-day continuous infusion administered at doses of 40 to 100 mg/m2/day. Toxicity was characterized by uniform myelosuppression, as well as occasional nausea, vomiting, and hepatotoxicity. Three episodes of metabolic acidosis and lactic acidemia were noted. In addition, three patients suffered neurotoxicity. Two of these three patients had a severe neurotoxicity syndrome characterized by blindness, encephalopathy, and coma. Neither patient recovered neurological function. Neuropathological findings at autopsy were characterized by a diffuse, necrotizing leukoencephalopathy which was most severe in the occipital lobes. The medullary pyramids and posterior columns were also severely affected. This sporadic fatal neurotoxicity was observed only at doses greater than 40 mg/m2/day. The maximum tolerated dose for a 5-day infusion of fludarabine phosphate is thus 40 mg/m2/day.

Central nervous system malformations in trisomy 9.

Trisomy 21, 18 and 13 are the most common varieties of autosomal trisomy recognized at birth; most of the others lead to spontaneous abortions in the first trimester. Trisomy 9, a rare trisomy, is compatible with life, but, unlike trisomy 21, 18 and 13, the range of manifestations has not been well catalogued. Central nervous system abnormalities have been reported in the majority of cases, usually including a dilated fourth ventricle and malformed cerebellum. The posterior fossa malformation closely resembles the descriptions of the Dandy-Walker malformation leading some to suggest this designation, while others have suggested that the features are unique to trisomy 9. Two cases of trisomy 9 are presented in this report which extend the range of neuropathologic manifestations in this cytogenetic disorder. The first infant had cortical migration abnormalities, anomalous hippocampal formation, simplified inferior olivary nuclei, germinal matrix cysts, mild ventriculomegaly, syringomyelia, and a large myelomeningocele without a Chiari type II malformation. The fourth ventricle was normal in size and the cerebellum unremarkable. The second infant had a cystically dilated fourth ventricle and widely separated cerebellar hemispheres with an intact cerebellar vermis, the features of which we felt were compatible with the Dandy-Walker malformation. In addition, agenesis of the corpus callosum, anomalous hippocampal formation, subpial glial nodules and mild ventriculomegaly were present. These cases extend the range of malformations that may be associated with trisomy 9, and raise the differential diagnosis of trisomy 9 when these malformations are identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous pallido-nigral accumulation of iron pigment and spheroid-like structures in macaque monkeys.

Common incidental pathologic findings in Old World monkeys are spheroid-like structures and iron pigment in the substantia nigra and globus pallidus. The occurrence of each finding correlates with the number of years monkeys have spent in captivity. The spheroids are eosinophilic and argyrophilic, but are generally PAS, iron, and luxol fast blue negative. Ultrastructurally, they consist of aggregations of dense globules and granules interspersed with membranes; normal organelles are absent. One classic spheroid with a thin myelin sheath and accumulated fibrillar material was observed. The material in spheroids is ultrastructurally distinguishable from iron pigment, which is present in glial cells, and from neuronal lipofuscin. Accumulation of spheroids and iron pigmentation may be age-related phenomena involving portions of the brain with shared anatomical and biochemical characteristics. The study of these changes may shed light on the pathogenesis of such spheroid degenerations as Hallervorden-Spatz disease.

Human cerebral malaria: a pathological study.

The following report using light and electron microscopic and immunological techniques is based on a series of 19 Burmese patients who died of cerebral malaria. The principal change was blockage of cerebral capillaries by Plasmodium falciparum-infected erythrocytes. Ring hemorrhages and segmental necrosis of cerebral capillaries were common. Cerebral edema was variable in these cases. Electron-dense knobs, 40 X 80 nm in size, which protruded from the membrane of infected erythrocytes, formed focal junctions between endothelial cells and erythrocytes. These junctions resulted in the entrapment of erythrocytes and caused blockage in the capillary lumen. Immunoperoxidase study revealed that P. falciparum antigens and IgG deposits in the capillary basement membrane. This implies that damage to the cerebral capillary could be related to immune mechanisms.

Malignant tumors in the pituitary gland.

Malignant tumors of the pituitary gland may mimic pituitary adenomas both in clinical presentation and in imaging, and often present with neurologic findings including visual field loss and extraocular movement palsies. We describe a 58-year-old woman without known malignancy who presented with extraocular movement weakness, loss of facial sensation, and a sellar plasmacytoma; a 49-year-old woman with oculomotor palsy, no known malignancy, and rapidly failing vision who had metastatic lung carcinoma; and a 70-year-old woman with metastatic breast carcinoma who presented with rapidly failing vision and a metastasis to the anterior lobe of the pituitary. These cases illustrate several important features of malignancy in the pituitary fossa: that it can mimic a "nonfunctioning" pituitary adenoma in clinical presentation and imaging; that rapidly progressive visual loss, extraocular movement palsies, or facial sensory loss may help to distinguish it from a benign adenoma; and that when the pathologist evaluates an alleged "nonsecretory" or "nonfunctional" adenoma, metastases should be included in the differential diagnosis.

Transmissible spongiform encephalopathy (Creutzfeldt-Jakob disease). Atypical clinical and pathological findings.

A middle-aged neurosurgeon had an 18-month illness characterized by abnormal sleep patterns, paresthesias, and necrotizing cutaneous lesions with vasculitis and signs of cerebral, brainstem, vestibulocerebellar, and progressive spinal cord involvement. Biopsy specimens of nerve and skin showed an acute vasculitis with endovascular cellular proliferation in the pattern of a Köhlmeier-Degos lesion and focal epidermal necrosis. Mental changes and cranial-nerve signs developed. Myoclonus occurred occasionally during sleep. Akinetic mutism ensued. At autopsy, major abnormalities were limited to the nervous system and skin. Spongiform encephalopathy typical of Creutzfeldt-Jakob disease was found with amyloid kuru plaques. A cribriform change distinct from the spongiform change was seen focally in the white matter. Scarred skin lesions and a healed, partially obliterative arteritis were noted. Inoculation of brain and lung into nonhuman primates resulted in a spongiform encephalopathy.

Clinical features of subcortical arteriosclerotic encephalopathy (Binswanger disease).

Subcortical arteriosclerotic encephalopathy, a chronic vascular dementia with hydrocephalus, was characterized pathologically in five patients by severe thickening of small vessels and by diffuse regions of white matter loss with gliosis. Lacunar infarcts were also present. The clinical picture in 11 patients was characterized by: (1) persistent hypertension and systemic vascular disease; (2) acute strokes; (3) subacute accumulation of focal neurologic symptoms and signs over weeks to months; (4) long plateau periods; (5) lengthy clinical course; (6) dementia; (7) prominent motor signs and pseudobulbar palsy and; (8) hydrocephalus. The pathogenesis of subcortical arteriosclerotic encephalopathy is unknown; possible mechanisms include diffuse ischemia and fluid transudation with subsequent gliosis related to subacute hypertensive encephalopathy.

Aphasia following infarction of the left supplementary motor area: a clinicopathologic study.

The speech disturbance of a patient with a single embolic infarct of the left supplementary motor area was characterized by initial mutism, rapid recovery to fluent speech marked by short sentences with normal grammar, persistent severe impairment of writing, and frustration and anxiety related to language tasks.

Spinal subarachnoid hematomas: clue to a source of bleeding in traumatic lumbar puncture.

Although damage to the veins of Batson's epidural plexus is usually considered the origin of bleeding in traumatic lumbar puncture, a lesion of these veins would not explain the cases in which postmortem examination shows blood confined to the subdural and subarachnoid spaces. In two patients who had lumbar punctures a few days before death, there was subarachnoid hematoma of the cauda equina at autopsy. In one of these cases, the radicular vessels were shown to be the source of bleeding. Spinal subarachnoid and subdural hemorrhages after lumbar puncture may be due to laceration of radicular vessels by the spinal needle.

Clinical patterns of failure following stereotactic interstitial irradiation for malignant gliomas.

The vast majority of patients treated for malignant gliomas with surgery, conventional radiation therapy, and systemic chemotherapy recur within 2 cm of their original disease site as documented by CT scanning. We have analyzed the clinical patterns of failure in patients treated with stereotactic interstitial irradiation (brachytherapy) for malignant gliomas in order to determine if this modality has altered the recurrence pattern in this disease. Between December 1985 and December 1989, 53 patients with malignant glioma were treated with stereotactic interstitial irradiation using temporary high activity iodine-125. Thirty-three patients were treated as part of a primary treatment protocol that included 5940 cGy external beam prior to implantation. Twenty patients were treated at time of recurrence. The median dose of radiation given at implantation was 5040 cGy for the primary lesions and 5450 cGy for the recurrent lesions. Twenty-two patients have suffered relapse as documented by clinical and radiographic studies. The predominant patterns of failure in these 22 patients were in the margins of the implant volume (8) and distant sites (10) within the CNS (distant ipsilateral or contralateral hemisphere, spinal axis) or extraneural. Thus, marginal and distant recurrences accounted for 82% of the relapses in our patients. We conclude stereotactic interstitial irradiation has changed the recurrence pattern in patients with malignant glioma with true local recurrence no longer being the predominant pattern of failure as is seen with conventional therapy.

Suprachiasmatic region of the human hypothalamus: homolog to the primate circadian pacemaker?

The suprachiasmatic nuclei (SCN) of the hypothalamus in mammals, including nonhuman primates, contain a key pacemaker of the circadian timing system. Examination of the histology of the anterior hypothalamus in human fetal, child, and adult brains indicates that there is a cluster of neurons which may be homologous to SCN. These neurons are more diffusely organized and laterally placed in human brains than is the SCN of nonhuman primates.

Human brain contains vasopressin and vasoactive intestinal polypeptide neuronal subpopulations in the suprachiasmatic region.

The suprachiasmatic nuclei (SCN) and retinohypothalamic tract ( RHT ) in the anterior hypothalamus have been postulated to play an important role in the timing of daily biological rhythms in mammals. Although physiological studies have described circadian rhythms in man, the presence of an RHT or SCN has not been conclusively demonstrated in the human brain. Immunocytochemical identification of distinct ventral vasoactive intestinal polypeptide (VIP) containing and dorsal vasopressin containing neuronal subpopulations in the human suprachiasmatic region provides correlative evidence of neuronal clusters which are homologous to discrete cell groups in the SCN of other mammalian species. Manipulation of the circadian system has been used to treat some affective illnesses and other physiological timing disorders. Characterization of the neural substrates underlying human circadian rhythms could be useful in the development of future treatment modalities and is essential for understanding normal human circadian organization.

Central nervous system changes after radiation therapy and/or chemotherapy: correlation of CT and autopsy findings.

This is a restrospective correlative study of cranial computed tomography (CT) and autopsy findings in 50 patients after central nervous system radiation therapy and/or chemotherapy. Most patients had more than one posttherapy CT scan and all cases were autopsied. Twenty-six cases (52%) showed no posttherapy CT changes. In 18 cases (36%) enlargement of intracranial subarachnoid spaces and/or ventricles was seen on CT, but only two of these cases showed gross atrophy on postmortem examination; even in these, the cortex was histologically normal, suggesting that these CT changes may be reversible. In six cases a decrease in white-matter density was seen on CT. Two of these cases were histologically normal, two cases showed some white-matter rarefaction, one case contained multiple foci of white-matter and vessel well necrosis, and one case had progressive multifocal leukoencephalopathy.

Controlled studies on the effects of alcohol ingestion on peripheral nerves of macaque monkeys.

In two different studies, monkeys were fed diets with 50% and 30% of calories replaced with alcohol for 5 and 3 years, respectively. Nerves were studied with electrophysiological and quantitative histological methods, but no deleterious effect of alcohol was identified.

Malignant transformation in benign cerebellar astrocytoma. Case report.

The authors give follow-up information on Case 59 of Cushing's 1931 series of cerebellar astrocytomas. The patient died with a malignant cerebellar astrocytoma 48 years after partial removal of a previously benign astrocytoma at the same site. Including the present one, there have been only five reported cases in which this has occurred. Ordinarily, juvenile pilocytic astrocytomas are of extremely genign character, and it is well established that even with incomplete resections patients have survived for years without progression of the tumor. Not all of the cases so reported can be wholly accepted as respresenting malignant transformation of the tumor, but may instead be instances of recurrence of an inherently benign glioma since the presence of features such as endothelial hyperplasia or nuclear atypicality in a juvenile pilocytic astrocytoma does not warrant is being classified as malignant. Features truly suggestive of malignancy are hypercellularity, frequent mitoses, necrosis, and, in some instances, a diffusely infiltrative growth pattern; all of these features were found in the present case.

Fetal cerebellar tissue associated with a primitive neuro-epithelial tumor in an ovarian teratoma.

This is a single case report of an ovarian teratoma. It is a unique case of a primitive neuroepithelial tumor with many similarities to a medullo-blastoma arising in a ovarian teratoma, and the second report of fetal cerebellum occurring in a teratoma of the ovary.

Quantitative changes in astrocytes after portacaval shunting in chimpanzees and in man with normal liver parenchyma.

Chimpanzees without liver cell damage, but subjected to portacaval anastomosis, showed behavioral changes that were accompanied by "Alzheimer II" astrocyte hyperplasia and nuclear enlargement. These findings were similar to those in a human patient with encephalopathy, secondary to a portacaval shunt, whose liver was normal. Controlled quantitative study of astrocytic hyperplasia in different anatomic regions showed the hyperplasia to involve the gray matter with only moderate topographic variation. Individual degrees of hyperplasia somewhat paralleled the severity of clinical symptoms and ammonia levels; no clear-cut relationship with time after shunting could be established. Portacaval shunt encephalopathy in chimpanzees greatly resembles that in man and, thus, lends itself to more detailed experimental analysis.

New syndrome: brain malformation, growth retardation, hypokinesia and polyhydramnios in two brothers.

We report two brothers who were born after pregnancies characterized by polyhydramnios and hypokinesia. Both had brain malformation (absence of corpus callosum in one; arhinencephaly in the other), telecanthus and narrow palpebral fissures. This family and several similar phenotypes reported only in affected brothers could reflect X-linked inheritance.