Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis.

INTRODUCTION: Infantile neuroaxonal dystrophy (INAD), an autosomal recessive neurodegenerative disorder due to PLA2G6 mutation, is classified both as a PLA2G6-associated neurodegeneration (PLAN) disorder and as one of the neurodegeneration with brain iron accumulation (NBIA) disorders. Age of onset and clinical presentation in INAD is variable. Typically described imaging features of cerebellar atrophy, cerebellar cortex bright FLAIR signal, and globus pallidus iron deposition are variable or late findings. We characterize clinical and neuroimaging phenotypes in nine children with confirmed PLA2G6 mutations and show a useful imaging feature, clava hypertrophy, which may aid in earlier identification of patients. Measurements of the clava confirm actual enlargement, rather than apparent enlargement due to volume loss of the other brain stem structures. METHODS: A retrospective clinical and MRI review was performed. Brain stem measurements were performed and compared with age-matched controls. RESULTS: We identified nine patients, all with novel PLA2G6 gene mutations. MRI, available in eight, showed clava hypertrophy, regardless of age or the absence of other more typically described neuroimaging findings. Brain autopsy in our cohort confirmed prominent spheroid bodies in the clava nuclei. CONCLUSION: Clava hypertrophy is an important early imaging feature which may aid in indentification of children who would benefit from specific testing for PLA2G6 mutations.

Infrared spectroscopic characterisation of multiple sclerosis plaques in the human central nervous system.

Fourier transform infrared spectroscopy has been used for the characterisation of white matter, grey matter and multiple sclerosis plaques from human central nervous system tissue. We demonstrate significant differences in the infrared spectra of the three types of tissue, which show that an infrared spectroscopic discrimination of multiple sclerosis plaques from healthy brain tissue is possible in principle. The spectral changes reveal pronounced lipid loss in plaques, consistent with the demyelinating nature of the disease. The chronic plaques studied here can also be distinguished from other non-myelinated areas of the brain, based on differences in water content.

Beware of connective tissue proteins: assignment and implications of collagen absorptions in infrared spectra of human tissues.

Infrared spectra of human central nervous system tissue and human breast carcinoma are presented. The spectra are discussed in terms of the composition of the tissues. It is shown that differences between spectra of white and grey matter can be rationalised on the basis of differences in lipid content. Spectra of the choroid plexus and arachnoid villus of the meninges show a series of absorptions not observed in other CNS tissue. These absorptions are discussed in terms of the connective tissue content of the samples. We demonstrate that the presence of collagen results in the appearance of a series of characteristic absorptions which may be mis-assigned as DNA phosphate absorptions. The implications of the presence of collagen in tissues for the diagnosis of disease states by IR spectroscopic methods, with particular reference to cancer, is discussed.

Primary rhabdomyosarcoma of the cerebellum--a light, electron microscopic, and immunohistochemical study.

A primary cerebellar rhabdomyosarcoma (RMS) in a six and a half year old boy is reported. Microscopy of the surgical material revealed lobules of closely packed cells with a high mitotic rate, pleomorphic hyperchromatic nuclei and scant cytoplasm. At their periphery, the lobules merged with rounded cells with similar nuclei but more abundant cytoplasm. These areas were surrounded by interlacing fascicles of strap cells, which were occasionally multinucleated and showed cross striations. Electron microscopy (EM) revealed the primitive nature of the closely packed cells; however, occasional intermediate size filaments were present within their cytoplasm and focal basement membrane accumulation was observed. Cells with more abundant cytoplasm had large accumulations of thick and thin filaments while strap cells showed well-developed cross striations. Immunohistochemical studies (peroxidase-antiperoxidase technique) showed vimentin in the primitive cells and desmin, myoglobin and adenosine triphosphatase as the tumor cells appeared more differentiated. Immunoreaction with antibodies against glial fibrillary acidic protein, S-100 protein and neurofilament protein were negative. Electron microscopic and immunohistochemical studies in this case demonstrated that this was an exclusively mesenchymal tumor with rhabdomyoblastic differentiation and that the pattern of differentiation follows that seen in normal myogenesis.

Intermediate filaments in meningiomas.

The presence of intermediate filaments (IF) (diameter 10 nm) is a characteristic electron microscopic finding in the cytoplasm of meningioma cells. To identify these IF, immunohistochemical staining for cytokeratins and vimentin and two-dimensional (2-D) gel electrophoresis followed by immunoblot analysis were applied to a group of 16 meningiomas. Thirteen meningiomas were obtained directly from surgery and three came from an autopsy in which they were found in close proximity as discrete tumor masses. Except for the angioblastic type, all major histological variants were represented (nine transitional, four syncytial, and three fibroblastic). None of the meningiomas stained for epithelial or internal organ cytokeratins. With monoclonal antibodies, each of the meningiomas stained positively for vimentin. Two-D gels revealed vimentin and vimentin breakdown products as the only IF present; these findings were verified by immunoblots. The study concludes that vimentin is the IF present in fibroblastic, syncytial, and transitional meningiomas.

Thymic carcinoma with focal neuroblastoma differentiation.

A small, incidentally found, thymic carcinoma (malignant thymoma) showed an extraordinary mixed-cell composition. The tumor was predominantly made up of poorly differentiated cells with light-microscopic, ultrastructural, and immunohistochemical features of thymic epithelium. However, small distinct groups of cells displaying features of neuroblastoma were scattered throughout the tumor. This unique case further illustrates the multiple capabilities of differentiation of thymic tumors.

Inflammatory myopathy in F1 hybrid mice with acute graft-versus-host reactions.

Polymyositis and myasthenia gravis-like syndromes have been seen in patients with GVH disease following bone marrow transplantation. We therefore investigated the histopathology of muscle in mice with acute graft-versus-host disease in order to determine whether these conditions are caused by injury from the GVH reaction itself or are due to radiation and drugs used to prepare the host for transplantation. GVH reactions were induced by intravenously infusing 50 x 50(6) lymph node and spleen cells from A/J-strain donors into (C57BL/6 x A/J)F1-hybrid recipients. These mice developed an active inflammatory myopathy beginning 15 days after engraftment. The inflammatory infiltrates were focal in distribution, initially around perimysial blood vessels, and later around muscle fibers. The infiltrating cell population was composed of lymphocytes, plasmacytoid cells, and macrophages. Muscle cell necrosis was observed and was temporally related to elevations in serum creatine kinase. Similar histologic changes were present in the myocardium. Our findings support the notion that muscle involvement in patients with GVH disease is caused by the disease itself. Myositis accompanying experimental GVH disease in mice may hold promise as a model of autoimmune inflammatory myopathy.

Casein kinase II is associated with neurofibrillary tangles but is not an intrinsic component of paired helical filaments.

Neurofibrillary tangles (NFT) are pathological cytoskeletal structures composed of paired helical filaments (PHF), and are found in neurons of patients afflicted with many neurodegenerative disorders, including Alzheimer's disease (AD). We previously found that an antiserum against casein kinase II (CK-II) stained NFT intensely in the brain tissue of AD patients. In the current study, we found that the anti-CK-II antiserum stains NFT and neuronal inclusions in many other neurodegenerative diseases as well, including Guam-Parkinson dementia complex, chromosome 18 deletion syndrome, progressive supranuclear palsy, Kufs' disease, and Pick's disease. This antiserum reacted, in crude brain homogenates, with both a doublet of Mr 43,000 and a Mr 27,000 Da protein which could correspond to the alpha, alpha', and beta chains of CK-II. The staining of these bands was adsorbed by preincubating anti-CK-II antiserum with purified CK-II. Preincubation of brain sections with purified CK-II strongly intensified the immunostaining of NFT with anti-CK-II, suggesting that NFT may bind CK-II. In the AD brain homogenates, the particulate CK-II levels are increased whereas the cytosolic levels are decreased without a change in total CK-II levels, consistent with the idea that CK-II binds to the particulate PHF, a major constituent of NFT. In accord with these findings, purified PHF bound CK-II, but purified PHF did not contain CK-II as its component. These results suggest that CK-II might be an extraneously deposited component of NFT. Thus, the altered CK-II compartmentalization might have significant consequences in the pathogenesis of AD.

Hallervorden-Spatz disease: MR and pathologic findings.

PURPOSE: To compare the MR findings of eight cases with clinical diagnosis of Hallervorden-Spatz disease (HSD) with the pathologic findings of two other cases of HSD. MATERIALS AND METHODS: The eight imaged cases were studied with 0.5-T (seven cases) and/or 1.5-T (five cases) units. Six patients also had CT scans. The two other cases with proven HSD had detailed histologic evaluation. RESULTS: The 1.5-T findings showed abnormalities confined to the pallidum, which presented a diffuse low signal intensity in T2-weighted images, and an anteromedial area of high signal intensity (eye-of-the-tiger sign). In 0.5-T studies, low signal intensity was less evident and poorly detectable in spin echo, but gradient-echo images could enhance its demonstration; the area of high signal intensity was always well demonstrated. In three cases (three with 1.5 T, one with 0.5 T) a central spot of low signal intensity was seen in this area. The pathologic cases, in addition to neuroaxonal swellings and iron deposits, exhibited areas of "loose" tissue with vacuolization and lesser amounts of iron in the anteromedial part of the pallidum, in a location corresponding to the area of high signal intensity of the imaged cases. CONCLUSION: Comparison of MR findings with the pathologic studies demonstrates that the low signal intensity in T2-weighted images at 1.5 T corresponds to iron deposits in a dense tissue, and that the high signal intensity of the eye-of-the-tiger sign corresponds to an area of loose tissue with vacuolization. No correlation was found in the two pathologic cases for the central spot of low signal intensity.

Cell-mediated allergy to a cerebral aneurysm clip: case report.

BACKGROUND AND IMPORTANCE: Titanium aneurysm clips have superior imaging characteristics and have been supplanting their stainless steel counterparts. We report the case of a 36-year-old woman with a histologically demonstrated cell-mediated reaction to a cobalt alloy aneurysm clip. CLINICAL PRESENTATION: The patient underwent a craniotomy and clip placement for a ruptured cerebral aneurysm. Both the aneurysm clip and the wires used to fix the craniotomy were made of stainless steel (cobalt and nickel) alloys. Postoperatively, the patient was plagued by intense pruritus. INTERVENTION: Skin patch testing revealed a severe reaction to nickel and cobalt. Surgical removal of the aneurysm clip and wires resulted in the disappearance of the patient's symptoms. A histological analysis of the tissue adjacent to the clip and wires was consistent with Type IV delayed type hypersensitivity. CONCLUSION: Stainless steel surgical implants in the head can cause diffuse, severe pruritus in susceptible individuals. Although the role of the aneurysm clip, as opposed to the more superficial wires, in the genesis of the patient's symptoms is not certain, this case demonstrates that a cobalt alloy aneurysm clip can activate T cells and cause an immunological reaction in the central nervous system.

Thalamic tumors in children. Long-term follow-up and treatment guidelines.

The authors review the cases of 60 children (aged 5 months to 18 years) with thalamic tumors who were seen at The Hospital for Sick Children between 1951 and 1983. The diagnosis of thalamic tumor was based on neuroradiological studies; 33 children were first seen in the pre-computerized tomography (CT) era and 27 since the advent of CT scanning. Histological diagnosis was obtained in 37 patients at the time of operation. A further four tumors were verified histologically at autopsy. Thirty-six patients required cerebrospinal fluid shunt placement. Sixteen patients had no surgery on their tumor, three underwent needle biopsy, 20 underwent open biopsy, and 21 had partial resection. Forty-four patients were irradiated. All 20 patients with malignant tumors died, with a mean survival time of 1.1 years. Of 19 patients with benign tumors, 11 died, with a mean survival time of 5.3 years, and eight are still alive after a mean period of 7.2 years since diagnosis. Based on this series, the authors recommend open biopsy of thalamic tumors (and resection if deemed safe), followed by radiation in selected cases.

Mobile lipid accumulation in necrotic tissue of high grade astrocytomas.

Multiple samples from 42 astrocytomas were investigated ex vivo by 1H MR spectroscopy followed by histological assessment. MR visible lipids were detected in 27 of 32 grade 4 astrocytomas. These lipids were heterogeneously distributed within the tumours. Their amount correlated positively with the amount of histologically detected necrosis. Mobile lipids were also observed in grade 4 astrocytoma samples without necrosis, as well as in one of three grade 3, two of three grade 2 and two of four grade 1 astrocytomas. The clinical significance of MR visible lipids, their cellular location, and their possible biological bases are discussed.

Glial fibrillary acidic protein (GFAP) in oligodendrogliomas: a reflection of transient GFAP expression by immature oligodendroglia.

Fourteen pure oligodendrogliomas were studied by light- and electronmicroscopy and immunohistochemistry to examine glial fibrillary acidic protein (GFAP) positivity in the tumors. To compare the immunohistochemical staining patterns of neoplastic oligodendroglia and immature oligodendroglia, myelination glia in the white matter of eight normal brains from children under 6 months of age were studied. The tumors possessed light microscopic and ultrastructural features characteristic of oligodendrogliomas. Microtubules were found in the cytoplasm of nine tumors on electronmicroscopy. In one, intermediate filaments and microtubules were observed in occasional tumor cells with polygonal crystalline structures in the cytoplasm. Using the peroxidase-antiperoxidase technique, all specimens were stained for GFAP, vimentin, S-100 and neuron-specific enolase (NSE). In nine tumors, variable numbers of cells with an oligodendroglial morphology reacted positively for GFAP. All tumors were positive for S-100 and negative for vimentin and NSE. The myelination glia in the eight normal brains stained positively for GFAP but not for vimentin. Vimentin is expressed by developing, reactive and neoplastic astrocytes. Thus, GFAP positivity combined with vimentin negativity in both neoplastic and immature oligodendroglia suggests that GFAP positivity in oligodendrogliomas may reflect the transient expression of this intermediate filament by immature oligodendroglia.

Single-blind study of dystrophin staining in carriers of Duchenne muscular dystrophy.

A single-blind study of dystrophin staining in skeletal muscle was performed in 13 biopsies from carriers of Duchenne Muscular Dystrophy (DMD) and controls. The results indicate that immunohistochemical analysis of dystrophin staining is a valuable diagnostic test for DMD carriers when DNA for testing is unavailable from critical family members or is uninformative, when creatine kinase (CK) values are conflicting or when CK values must be used in isolation.

Neuropathological changes in chronic adult hydrocephalus: cortical biopsies and autopsy findings.

BACKGROUND: The cortical changes resulting from chronic hydrocephalus in adults are not well defined. METHODS: Retrospective analysis of twenty-one patients (age 64-88 years) with a clinical diagnosis of "normal pressure hydrocephalus" who underwent cortical biopsy at the time of intracranial pressure monitoring or shunt insertion, and eight patients who were biopsied but not shunted. Eleven brains (age 26-92 years), seven from patients who could be considered to have "normal pressure hydrocephalus", were also examined following autopsy. Age- and sex-matched control brains with small ventricles and no history of dementia were compared to the hydrocephalic brains. Senile plaques and neurofibrillary tangles were assessed semiquantitatively and a non-parametric statistical analysis was employed. RESULTS: Five biopsies exhibited both senile plaques and rare neurofibrillary tangles, while two had only neurofibrillary tangles. Neurofibrillary tangles were more prevalent in hydrocephalic brains than in controls. There was no difference in the prevalence of senile plaques between the two groups. Grumose bodies in the substantia nigra were identified in five autopsy brains, a prevalence higher than in control brains. CONCLUSIONS: These pathological features are not specific for hydrocephalus; however, they suggest that long-standing ventriculomegaly is associated with degenerative brain changes in sites beyond the periventricular white matter. The presence of senile plaques in cortical biopsies from hydrocephalic patients does not appear to be a contraindication to shunting; however a prospective study in patients undergoing intracranial pressure monitoring would better address the issue.

Malignant astrocytoma of the optic nerve in a child.

Malignant gliomas of optic nerve and chiasm are rare, rapidly fatal neoplasms of adulthood. This report documents the occurrence of a malignant astrocytoma of the optic nerve in an 11-year-old boy who 9 years previously had a cerebellar medulloblastoma treated with surgery and irradiation. This malignant optic nerve glioma followed the same aggressive clinical course as that seen in adults, with death 9 months after diagnosis despite surgery and chemotherapy. Radiation may have been an important factor in the development of this malignant tumor which is almost never seen in the pediatric age group.

Intermediate filaments in the human pituitary gland: an immunohistochemical study.

Normal pituitaries, pituitaries showing CHC and selected adenomas were assessed for their possible content of intermediate filaments (IF), using immunohistochemical techniques. Normal pituitaries were stained for each of the five known IF (Cytokeratins (CK), glial fibrillary acidic protein (GFAP), desmin, vimentin, and neurofilaments (NF]. Desmin could not be demonstrated, and NF staining was limited to processes in the posterior gland. In serial sections, CK was demonstrated in some corticotrophs, somatotrophs, and lactotrophs. Vimentin was limited to processes in the posterior gland. Folliculo-stellate cells (FSC), demonstrated by staining for S100 protein, exhibited a small subpopulation staining for CK, and another subpopulation staining for GFAP. GFAP was also demonstrated in glial processes in the posterior gland. Cells showing Crooke's hyaline change stained intensely for CK. Null cell adenomas did not stain for CK. Corticotroph adenomas, somatotroph adenomas, with or without fibrous bodies, and lactotroph adenomas contain CK-immunoreactive cells. We conclude that CK is the major IF present in the anterior pituitary gland, within some normal corticotrophs, somatotrophs and lactotrophs, and also in adenomas derived from these cells.

Periodontoid synovial cyst causing cervico-medullary compression.

BACKGROUND: Periodontoid synovial cysts are rare lesions which may produce symptomatic cervico-medullary compression. METHOD: We report such a patient, whose progressive neurological deterioration required surgical treatment by transoral odontoidectomy and decompression. RESULTS: The diagnostic and theraputic interventions are described, including a lumbar puncture which precipitated a transient loss of consciousness and respiratory arrest. Surgery achieved clinical improvement, without complications or need for operative stablization. Detailed neuropathology is presented, as well as a literature review. CONCLUSION: Appropriate neuroradiological assessment is required in patients with suspected cervico-medullary compression, and symptomatic periodontoid synovial cysts may respond well to transoral surgical decompression.

Neural network classification of infrared spectra of control and Alzheimer's diseased tissue.

Artificial neural network classification methods were applied to infrared spectra of histopathologically confirmed Alzheimer's diseased and control brain tissue. Principal component analysis was used as a preprocessing technique for some of these artificial neural networks while others were trained using the original spectra. The leave-one-out method was used for cross-validation and linear discriminant analysis was used as a performance benchmark. In the cases where principal components were used, the artificial neural networks consistently outperformed their linear discriminant counterparts; 100% versus 98% correct classifications, respectively, for the two class problem, and 90% versus 81% for a more complex five class problem. Using the original spectra, only one of the three selected artificial neural network architectures (a variation of the back-propagation algorithm using fuzzy encoding) produced results comparable to the best corresponding principal component cases: 98% and 85% correct classifications for the two and five class problems, respectively.

Metastatic meningioma detected in pleural fluid.

Meningiomas with both malignant cytologic features and clinical behavior are rare. A 39-yr-old man with recurrent meningioma developed a pleural effusion which, on cytologic examination, contained metastatic meningioma. The diagnosis was subsequently confirmed histologically and ultrastructurally. In conclusion, metastatic meningiomas can retain meningotheliomatous cytologic features which may allow a diagnosis to be made of clinically unanticipated tumor spread.