Posttraumatic premature Alzheimer's disease. Neuropathologic findings and pathogenetic considerations.

Dementia following head trauma is generally attributed to contusional injury or its complications. Dementia pugilistica and rare cases of classic Alzheimer's disease (AD) following head injury suggest that trauma may also play a provocative role in neurofibrillary change. The ages and clinical descriptions, however, allow other interpretations. A 38-year-old man died 16 years after substantial recovery from a single episode of severe head trauma. Pathologic study indicated that the clinical deterioration was due to classic AD. Ultrastructural evaluation demonstrated both paired helical and straight filaments in cortical neurons.

Infantile osteopetrosis and neuronal storage disease.

Infantile osteopetrosis often presents with neurologic symptoms that cannot always be attributed to primary bone disease of the skull. We studied an infant with osteopetrosis and pathologic evidence of neuronal and axonal changes. This is the third case in which primary parenchymal disease of the brain was associated with infantile osteopetrosis and the first in which neuronal cytoplasmic storage was documented by light and electronmicroscopy. The simultaneous occurrence of two rare autosomal-recessive disorders, each possibly caused by an inherited lysosomal enzyme deficiency, may not be fortuitous.

X-linked recessive myotubular myopathy: II. Muscle morphology and human myogenesis.

The classification of centronuclear myotubular myopathies is controversial. Within this group of disorders, congenital X-linked recessive myotubular myopathy (XLMTM), characterized by marked cell hypotrophy and structural resemblance to fetal myotubes, represents a distinct entity. The histologic findings in verified and probable cases of XLMTM are reviewed. In addition, the ultrastructural features of muscle in one case of XLMTM are compared with those of normal fetal muscle at various developmental ages. In XLMTM both muscle and nerve show evidence of immaturity. Proliferation of the sarcotubular organelles in XLMTM, not observed in normal fetal muscle, may be due to impaired innervation.

X-linked recessive myotubular myopathy: I. Clinical and pathologic findings in a family.

Four neonatal deaths in one family were due to X-linked myotubular myopathy. The characteristic alterations in muscle, described in three cases, are marked fiber hypotrophy, size variability, and the presence of internal nuclei or pale areas. The diagnosis can be verified only by obtaining a careful genetic history. Previous occurrence of male neonatal death or stillbirth, or of hypotonia and respiratory insufficiency, is critical in the identification of suspected cases. There is morphologic justification for retaining the name "myotubular myopathy" to distinguish this X-linked disorder from other congenital conditions involving muscle weakness that have similar morphologic features.

Malignant astrocytoma six years after the resection of a cerebral metastatic cardiac myxoma: case report.

We describe a woman who had a total resection of a cardiac myxoma followed 8 months later by a hemorrhage in the right frontal lobe secondary to extravascular metastasis of the myxoma. Six years later, after an asymptomatic follow-up, she developed a recurrence of left-sided seizures and an enhancing mass in the same location as the previous tumor. At operation, a malignant astrocytoma was demonstrated. Cardiac myxoma is a true neoplasm with benign histology, which may be associated with heart failure, systemic illness, or peripheral embolization. The neurological manifestations of embolization may include no symptoms, acute or delayed infarction, and intravascular proliferation with aneurysmal dilatation and potential for hemorrhage. The development of extravascular metastatic tumor deposits has been reported previously in only three histologically verified cases. Once the integrity of the blood vessel wall is destroyed by the tumor, a portal of entry is established for tumor cell proliferation in the brain parenchyma. There is no known association between a metastatic cardiac myxoma and a malignant glioma in the literature. Several possibilities for the occurrence of these two neoplasms are discussed.

Fatal subdural bleeding following superficial temporal-middle cerebral artery anastomosis. Case report.

This report describes a sudden death during convalescence from superficial temporal artery-middle cerebral artery bypass surgery. Artificial arterial anastomosis introduces the danger of a high-pressure subdural hemorrhage in an unnatural location.

Bilateral carotid-cavernous fistulae of mixed types with unusual radiological and neuropathological findings.

This report describes a case of bilateral post-traumatic carotid-carotid-cavernous fistulae (CCF), of both typical and atypical types, with delayed clinical deterioration. Unusual neuropathological lesions, distinctive from those due to direct cerebral trauma, are related to combined arterial ischemia and venous hypertension. Atypical CCF is not necessarily a benign disorder. Radiological monitoring is essential to detect spontaneous progressive intracranial shunting, to predict areas that are at risk from venous hypertension, and to identify remote sites of circulatory vulnerability.

Infantile sialic acid storage disease associated with renal disease.

A child with infantile sialic acid storage disease is reported. Ultrasonography demonstrated fetal ascites. At birth, the infant appeared hydropic and presented with numerous dysmorphic features, including sparse white hair, coarse facies, hypertelorism, epicanthal folds, anteverted nostrils, and a long philtrum. In addition, he had visceromegaly, bilateral inguinal hernias, and a slight gibbus deformity. Lymphocytes were vacuolated and bone marrow contained large numbers of foam cells. There were generalized vacuolations of both reticuloendothelial and parenchymal cells in the examined tissues. Neuropathologic studies revealed wide-spread neuronal storage, myelin loss, axonal spheroids, and gliosis. Neurons, endothelial cells, and Kupffer cells stained with wheat germ agglutinin indicated an accumulation of sialic acid. Free sialic acid was significantly increased in urine and serum, as well as in liver, heart, and brain tissues. The alpha-neuraminidase activity was normal. It is assumed that the basic defect of infantile sialic acid storage disease lies in impaired transport of sialic acid across the lysosomal membrane.

An unusual central nervous system infection in a young immunocompromised host.

A 13-year-old girl with a ten-year history of lymphoblastic leukemia and several central nervous system (CNS) relapses developed a bone marrow relapse and accelerated CNS leukemia. Following treatment with CNS radiation and intravenous chemotherapy, she developed fever, pancytopenia, headache, and vomiting. Her neurological function deteriorated and she died on the 20th hospital day. Multiple CSF examinations failed to disclose either leukemic cells or organisms. Blood cultures obtained from a Broviac catheter yielded Micrococcus species. Postmortem examination showed meningoependymitis with intracellular coccal organisms. The pathology of this infection resembles intracranial Whipple's disease. Intracranial intracellular bacterial infection should be excluded in the infectious complications in the immunocompromised host.

Pheochromocytoma and sudden death as a result of cerebral infarction in Turner's syndrome: report of a case.

Various etiologies for hypertension in Turner's syndrome, a common feature of the disorder, are well recognized. Pheochromocytoma is not among them. A young woman with Turner's syndrome, recently diagnosed with hypertension, died suddenly and unexpectedly. A hemorrhagic cerebral infarct and an adrenal gland pheochromocytoma were found at necropsy. This is the first reported case of pheochromocytoma associated with Turner's syndrome.

Striated muscle cells in the leptomeninges in cerebral dysplasia.

Non-neoplastic foci of skeletal muscle cells are rarely noted within human central nervous system. This report describes two children with developmental anomalies and striated muscle in the leptomeninges. Embryological displacement of notochordal or prechordal mesoderm in certain types of cranio-vertebral-cerebral dysplasia may account for the origin, the restricted sites and the infrequent observation of leptomeningeal striated muscle cells.

Axonal dystrophy presenting as the megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a neonatal intestinal syndrome, characterized by defective peristalsis and bladder dilatation, refractory to pharmacological treatment. Examinations of bowel and bladder have failed to demonstrate a pathological explanation for this syndrome. We describe a 7-month-old female infant with MMIHS who had generalized axonal dystrophy of her central, peripheral, and autonomic nervous systems, which may provide a neuropathological explanation for some cases of MMIHS.

Temporal-lobe abnormalities in thanatophoric dysplasia.

We identified distinctive and characteristic abnormalities in the hippocampal formations of 4 individuals with thanatophoric dysplasia (TD), one of whom was a fetus of 19 weeks gestational age. Primitive medial fissures in this subject could be identified, but development of the dentate gyrus and organization of the pyramidal layer in the hippocampal formation were abnormal. We infer that temporal-lobe dysmorphogenesis in TD begins between 11.5 weeks gestational age, when hippocampal and fimbriodentate fissure formation takes place, and 13.5 weeks gestational age, when differential proliferation and migration of the cells that form the pyramidal layer and the dentate gyrus takes place. Any etiology proposed for TD must not only account for disordered endochondral and endomembranous bone formation but also explain the origins of early temporal-lobe dysplasia.

Morphology and distribution of Alzheimer neuritic (senile) and amyloid plaques in striatum and diencephalon.

Mapping of striatal and diencephalic plaque distribution was conducted in 25 cases of dementia of the Alzheimer type. This analysis was carried out by fluorescence microscopy of paraffin-embedded tissue sections treated with Thioflavine S as fluorochrome. Consistent differences in plaque morphology and density between nuclei and fiber tracts were observed. Striatal and pallidal distribution was uneven, with plaque aggregation near and within certain fiber tracts: capsules, medullary laminae, and radial fasciculi. Diencephalic plaques showed also preferred aggregation near and within fiber tracts and within the intralaminar nuclei. The different subcortical plaque morphologies observed according to the nuclear or fiber tract location of the amyloid plaque, indicates that the peripheral ("halo") portion of the plaque is determined by the neurophil response to the primary event: the amyloid deposit. No correlation was observed between the distribution of plaques and any particular neurotransmitter system. In that respect, plaques were present within the nucleus basalis. Neurofibrillary tangle distribution was also seen to be dissociated from plaque distribution.

Post-traumatic Alzheimer's disease: preponderance of a single plaque type.

The cause of Alzheimer's disease is unknown. Several factors have been proposed including head trauma. At present, the link between head injury and a subsequent neurodegenerative process is largely circumstantial, except in the case of dementia pugilistica (punch drunk syndrome) found in boxers. Recent studies have shown that the brains of boxers with this syndrome contain large numbers of 'diffuse' beta-protein immunoreactive plaques. We supposed that this plaque type might be associated with trauma induced Alzheimer-like degeneration. In order to test this hypothesis we have re-investigated a previously reported case of post-traumatic premature Alzheimer's disease. Immunocytochemistry using antibodies to amyloid beta-protein revealed large numbers of 'diffuse' non-Congophilic plaques with little or no neuritic component. A similar preponderance of this plaque type is present in the brains of boxers with dementia pugilistica. Our observations support the idea of a trauma induced Alzheimer-like degenerative process and indicate that such a condition is associated with a marked preponderance of 'diffuse' plaques.

Sudden and unexpected death in infancy and childhood: neuropathological findings.

This report describes the neuropathological findings in 58 infants and children dying suddenly and unexpectedly. Utilizing historical, clinical, laboratory and pathological findings, two subgroups were distinguished: in one a cause of death was established (CODE); members of the other (more than 50% of the total sample) were victims of sudden infant death syndrome (SIDS). The importance of historical as well as pathological data in excluding SIDS is stressed. In each subgroup, both focal lesions and diffuse glial reactive hypertrophy were identified in 64% of all children below 9 months of age. These changes were not related to age group or maturation and, except for a history of perinatal asphyxia, lesions were not predictably correlated with clinical data. The brains of children dying of established cause (CODE) are not a suitable control group with which to compare those of SIDS.

Fingerprint inclusions in normal fetal muscle.

In muscle disease, fingerprint inclusions are variously described as a diagnostic or non-specific alteration. Fingerprint inclusions identified in human fetal muscle suggest these bodies may be transient structures of developmental significance accounting for their infrequent occurrence in myopathies of diverse pathogenesis and clinical expression.

Dysplasia of the corpus callosum in identical twins with nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is an autosomal recessively inherited disorder of the glycine degradation pathway leading to accumulation of glycine in body fluids and tissues. Identical twins with nonketotic hyperglycinemia and dysplasia of the corpus callosum are described in support of the hypothesis that some patients with NKH have a genetic defect of the glycine degradation pathway resulting in abnormal corpus callosal development. It is important to screen for metabolic defects whenever similar structural defects are present.

Hydrocephalus of intrauterine onset in perinatally lethal osteogenesis imperfecta: clinical, sonographic, and pathologic correlations.

Five neonates with perinatally lethal osteogenesis imperfecta (OI) have come to necropsy at Women & Infants' Hospital of Rhode Island in the past eight years. Four had true hydrocephalus, defined as enlargement of the lateral ventricles with thinning of the cortical mantle. In all 4 hydrocephalus was diagnosed by sonography before birth. All 4 died almost immediately after birth, whereas the neonate without hydrocephalus lived for 22 days. Significant necropsy findings in the 4 with hydrocephalus included healing occipital-bone fractures with stenosis of the foramen magnum, remote and recent cerebral parenchymal and intraventricular hemorrhage, and remote and recent subarachnoid hemorrhage. True hydrocephalus of intrauterine onset has rarely been described in perinatally lethal OI, but its high incidence (80%) in this population suggests that it may be a common phenomenon. Hydrocephalus of intrauterine onset in perinatally lethal OI may indicate relatively more severe disease.

Pattern of mutant p53 expression in human astrocytomas suggests the existence of alternate pathways of tumorigenesis.

BACKGROUND: Clinical observations suggest that malignant astrocytomas may arise from well-differentiated, low-grade tumors that have undergone anaplastic progression or may develop de novo. Mutations that alter the function of the p53 gene product are thought to play a critical role in astrocytoma tumorigenesis. The authors studied the pattern of mutant p53 expression in astrocytomas to define its role in the formation of malignant tumors by these different pathways. METHODS: Tissues from 44 astrocytomas corresponding to Grades I-IV of the World Health Organization (WHO) classification were analyzed for the presence of mutations in exons 5, 7, and 8 of the p53 gene using single strand conformation polymorphism (SSCP) and sequence analysis of DNA amplified by the polymerase chain reaction. Immunostaining for mutant p53 proteins was performed on tissues fixed in formaldehyde solution and embedded in paraffin; the tissues were from these 44 astrocytomas and another 103 astrocytomas obtained from archival material. RESULTS: Tumors with mutant p53 genes were reliably identified by immunostaining for mutant p53 proteins. A higher percentage of astrocytomas of histologic Grades II-IV stained positively for p53 than were identified by mutational analysis. The average ages of patients with Grade III/IV astrocytomas with prominent (> 10%) p53 staining and those with sparse (< 10%) or no p53 staining were 44.5, 64.3, and 67.9 years, respectively (P < 0.0001). CONCLUSIONS: The pattern of mutant p53 expression is consistent with a role in driving the progression of low-grade astrocytomas to more malignant tumors. These results provide a genetic basis for the clinical observation that malignant astrocytomas resulting from anaplastic progression occur in a younger patient population than do malignant astrocytomas arising de novo.