Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis.

The present study analyses autopsy material from five multiple sclerosis patients who received autologous stem cell transplantation. A total of 53 white matter lesions were investigated using routine and immunohistochemical stainings to characterize the demyelinating activity, inflammatory infiltrates, acutely damaged axons and macrophages/microglial cells. We found evidence for ongoing active demyelination in all of the five patients. The inflammatory infiltrate within the lesions showed only very few T cells and CD8+ cytotoxic T cells dominated the T cell population. B cells and plasma cells were completely absent from the lesions. High numbers of acutely damaged axons were found in active lesion areas. Tissue injury was associated with activated macrophages/microglial cells. The present results indicate that ongoing demyelination and axonal degeneration exist despite pronounced immunosuppression. Our data parallel results from some of the clinical phase I/II studies showing continued clinical disease progression in multiple sclerosis patients with high expanded disability system scores despite autologous stem cell transplantation.

Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred.

Myosin storage myopathy (OMIM 608358), a congenital myopathy characterised by subsarcolemmal, hyaline-like accumulations of myosin in Type I muscle fibres, was first described by Cancilla and Colleagues in 1971 [Neurology 1971;21:579-585] in two siblings as 'familial myopathy with probable lysis of myofibrils in type I muscle fibres'. Two mutations in the slow skeletal myosin heavy chain gene (MYH7) have recently been associated with the disease in other families. We have identified a novel heterozygous Leu1793Pro mutation in MYH7 in DNA from paraffin sections of one of the original siblings. This historical molecular analysis confirms the original cases had myosin storage myopathy.

Enterogenous cysts of the spinal canal and cerebellopontine angle.

Enterogenous cysts are rare, benign lesions involving the spinal canal or the cerebellopontine angle. Typically they present with compression of the spinal cord or cranial nerves. They are usually 1 cm or less in size and are typically lined by columnar mucin-producing epithelium resembling enteric epithelium or columnar ciliated epithelium resembling respiratory epithelium. The case records of the Division of Neuropathology at Indiana University were reviewed for cystic lesions of the spinal canal and cranial cavity for a 26-year period. Seven surgically resected enterogenous cysts were identified. The original slides were studied. Additional sections were stained with mucicarmine, and immunohistochemical stains including thyroid transcription factor 1, epithelial membrane antigen, and cytokeratin 5/6 (CK5/6) were performed. Electron microscopy was performed in 1 case. The cysts ranged in size from 4 to 10 mm. One had stratified cuboidal epithelium, 1 had ciliated columnar and stratified squamous epithelium, 1 had columnar mucinous epithelium, and 4 had ciliated columnar epithelium. Epithelial membrane antigen and CK5/6 positivity were observed in all cases. Strong CK5/6 positivity was seen in the basal cells, with little or no immunoreactivity in the ciliated cells. Mucicarmine positivity was observed in 4 cases, and thyroid transcription factor 1 positivity was observed in 2 cases. Electron microscopy demonstrated well-developed stereocilia, distinct basal cells, and a thin basement membrane. The histopathologic, ultrastructural, and immunologic findings in these lesions are similar to those present in the bronchial epithelium, supporting the hypothesis of endodermal origin for these lesions.

Immunolocalization of the oligodendrocyte transcription factor 1 (Olig1) in brain tumors.

Recent in situ hybridization studies showed that mRNA levels of OLIG1 and OLIG2 transcription factors are elevated in oligodendrogliomas. We raised polyclonal antibodies against a synthetic peptide homologous to the human transcription factor Olig1 and studied by immunohistochemistry the expression of Olig1 in 84 brain tumors and in non-neoplastic brain tissues. All oligodendrogliomas, oligoastrocytomas, and dysembryoplastic neuroepithelial tumors showed moderate to strong intranuclear immunoreactivity in cells morphologically identified as oligodendrocytes. In addition, some astrocytomas showed a slight to moderate intranuclear immunoreactivity. None of the other neuroepithelial and non-neuroepithelial tumors showed nuclear immunoreactivity. Double immunostaining of oligodendrogliomas, oligoastrocytomas, and glioblastoma multiforme (GBM) using antibodies against Olig1 and GFAP showed the presence of 3 different cell populations: 1) immunopositive for Olig1 and immunonegative for GFAP, histologically identified as oligodendrocytes; 2) immunopositive only for GFAP, histologically identified as astrocytes; and 3) immunonegative for both antibodies ("null cells"), histologically observed as a population of cells usually with round nuclei and a small amount of cytoplasm. The use of double immunostaining facilitated the distinction among these 3 different tumors. In summary, the use of immunohistochemistry using Olig1 antibodies alone or in combination with anti-GFAP antibody, which can be performed in the routine diagnostic setting, may help in the diagnosis of neuroepithelial tumors.

DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration.

Acute, subchronic, or chronic exposures to particulate matter (PM) and pollutant gases affect people in urban areas and those exposed to fires, disasters, and wars. Respiratory tract inflammation, production of mediators of inflammation capable of reaching the brain, systemic circulation of PM, and disruption of the nasal respiratory and olfactory barriers are likely in these populations. DNA damage is crucial in aging and in age-associated diseases such as Alzheimer's disease. We evaluated apurinic/apyrimidinic (AP) sites in nasal and brain genomic DNA, and explored by immunohistochemistry the expression of nuclear factor NFkappaB p65, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX2), metallothionein I and II, apolipoprotein E, amyloid precursor protein (APP), and beta-amyloid(1-42) in healthy dogs naturally exposed to urban pollution in Mexico City. Nickel (Ni) and vanadium (V) were measured by inductively coupled plasma mass spectrometry (ICP-MS). Forty mongrel dogs, ages 7 days-10 years were studied (14 controls from Tlaxcala and 26 exposed to urban pollution in South West Metropolitan Mexico City (SWMMC)). Nasal respiratory and olfactory epithelium were found to be early pollutant targets. Olfactory bulb and hippocampal AP sites were significantly higher in exposed than in control age matched animals. Ni and V were present in a gradient from olfactory mucosa > olfactory bulb > frontal cortex. Exposed dogs had (a) nuclear neuronal NFkappaB p65, (b) endothelial, glial and neuronal iNOS, (c) endothelial and glial COX2, (d) ApoE in neuronal, glial and vascular cells, and (e) APP and beta amyloid(1-42) in neurons, diffuse plaques (the earliest at age 11 months), and in subarachnoid blood vessels. Increased AP sites and the inflammatory and stress protein brain responses were early and significant in dogs exposed to urban pollution. Oil combustion PM-associated metals Ni and V were detected in the brain. There was an acceleration of Alzheimer's-type pathology in dogs chronically exposed to air pollutants. Respiratory tract inflammation and deteriorating olfactory and respiratory barriers may play a role in the observed neuropathology. These data suggest that Alzheimer's disease may be the sequela of air pollutant exposures and the resulting systemic inflammation.

Malignant transformation of a chiasmatic pilocytic astrocytoma in a patient with diencephalic syndrome.

Chiasmatic gliomas with metastatic spread are rare in children and are usually associated with diencephalic syndrome. They are mostly pilocytic astrocytomas and their transformation to high-grade astrocytomas has never previously been reported in the pediatric population. We report leptomeningeal spread of a chiasmatic pilocytic astrocytoma in a child presenting with diencephalic syndrome. He was treated with chemotherapy and radiation. The tumor recurred with transformation into a high-grade astrocytoma. Radiation therapy may have played a role in transformation of the tumor, but more research is needed to further clarify the biological behavior of this tumor.

Air pollution and brain damage.

Exposure to complex mixtures of air pollutants produces inflammation in the upper and lower respiratory tract. Because the nasal cavity is a common portal of entry, respiratory and olfactory epithelia are vulnerable targets for toxicological damage. This study has evaluated, by light and electron microscopy and immunohistochemical expression of nuclear factor-kappa beta (NF-kappaB) and inducible nitric oxide synthase (iNOS), the olfactory and respiratory nasal mucosae, olfactory bulb, and cortical and subcortical structures from 32 healthy mongrel canine residents in Southwest Metropolitan Mexico City (SWMMC), a highly polluted urban region. Findings were compared to those in 8 dogs from Tlaxcala, a less polluted, control city. In SWMMC dogs, expression of nuclear neuronal NF-kappaB and iNOS in cortical endothelial cells occurred at ages 2 and 4 weeks; subsequent damage included alterations of the blood-brain barrier (BBB), degenerating cortical neurons, apoptotic glial white matter cells, deposition of apolipoprotein E (apoE)-positive lipid droplets in smooth muscle cells and pericytes, nonneuritic plaques, and neurofibrillary tangles. Persistent pulmonary inflammation and deteriorating olfactory and respiratory barriers may play a role in the neuropathology observed in the brains of these highly exposed canines. Neurodegenerative disorders such as Alzheimer's may begin early in life with air pollutants playing a crucial role.

Acromegaly caused by a growth hormone-releasing hormone-secreting carcinoid tumor: case report.

OBJECTIVE AND IMPORTANCE: We describe a patient with acromegaly and pituitary hyperplasia secondary to a growth hormone-releasing hormone-secreting gastrointestinal carcinoid tumor. This case report illustrates the importance of including this rare clinical syndrome in the differential diagnosis of acromegaly for patients with suspected or known neuroendocrine tumors. CLINICAL PRESENTATION: A 19-year-old, Asian-American, male patient with a 2-year history of a nonresectable, metastatic, intestinal carcinoid tumor presented with complaints of headaches, arthralgias, sweats, and changing features. The examination revealed a young subject with acromegalic features, without visual field deficits. Magnetic resonance imaging revealed a diffuse sellar mass that extended suprasellarly to compress the optic chiasm. Endocrinological studies demonstrated a growth hormone level of more than 100 ng/ml and an inappropriately elevated growth hormone-releasing hormone level. INTERVENTION: The patient underwent transsphenoidal resection of the pituitary mass for diagnostic and decompressive purposes. The pathological examination revealed pituitary hyperplasia, without evidence of an adenoma. Therapy with long-acting repeatable octreotide (Sandostatin LAR; Novartis AG, Basel, Switzerland) was initiated postoperatively, to further control the acromegaly and carcinoid tumor. The soft-tissue swelling resolved, and the patient remained free of headaches, arthralgias, and sweats at the 6-month follow-up examination. CONCLUSION: Ectopic acromegaly is a rare syndrome that must be recognized by neurosurgeons because its treatment differs from that of classic pituitary acromegaly. We describe a patient for whom this syndrome was documented with magnetic resonance imaging, endocrinological testing, and pathological examinations.

The neurological masquerade of intravascular lymphomatosis.

BACKGROUND: Intravascular lymphomatosis (IVL) is an uncommon systemic disease characterized by occlusion of small vessels by malignant lymphomatous cells. Central nervous system involvement usually presents as subacute encephalopathy, dementia, seizures, or multifocal cerebrovascular events. OBJECTIVE: To increase awareness about IVL, an uncommon cause of neurological disease. DESIGN: This is a retrospective case series of 8 pathologically proved cases of IVL with neurological disease. Patients were part of a pathological series collected between April 1962 and October 1998 at Indiana University School of Medicine and the Armed Forces Institute of Pathology, Washington, DC. SETTING: Neurological and neuropathological examinations were performed at tertiary referral hospitals. PATIENTS: Eleven patients were diagnosed pathologically as having IVL, but 3 were not included in this evaluation because of a lack of appropriate clinical information. Of the final sample (n = 8), there were 4 men and 4 women (mean +/- SD age, 62.9 +/- 9.9 years). RESULTS: All 8 patients had focal neurological deficits, 7 had encephalopathy or dementia, 5 had epileptic seizures, and 2 had myelopathy. Death occurred at a mean of 7.7 months (range, 1-24 months) after the onset of symptoms. All patients had elevated cerebrospinal fluid protein levels, 4 had pleocytosis, and 2 had an elevated IgG level in their cerebrospinal fluid. Of the 4 patients who underwent a brain biopsy, 1 was diagnosed as having IVL before death. CONCLUSIONS: Intravascular lymphomatosis is an uncommon disease with a myriad of potential neurological manifestations. Diagnosis requires a high index of suspicion and a pathological examination. If diagnosed early, aggressive chemotherapy is potentially curative, although the overall prognosis remains dismal.