Different pathological processes for acute white matter lesions in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) has variable clinical presentations, prognoses, pathogeneses, and pathological patterns. We conducted a pathological review of acute MS-associated lesions that focused on the degree of axonal injury, myelin loss, and glial reaction to determine whether the observed demyelination was of the primary or secondary type. MATERIALS AND METHODS: After searching the records for a 15-year period at the London Health Sciences Centre Pathology Department, we identified 8 cases of surgical acute lesion biopsies in which clinical MS diagnoses were made before or after the biopsy. RESULTS: The white matter pathologies in these cases could be sorted into 3 morphological patterns. The first pattern, which represents typical demyelinated plaques, was observed in 4 cases and was characterised by nearly complete demyelination accompanied by variable degrees of axon preservation and axonal swelling. The second pattern was observed in 3 cases and was characterised by demyelinating lesions containing variable numbers of myelinated axons mixed with a few demyelinated axons and variable numbers of axonal swellings. The myelinated axons ranged from scattered fibres to bands of variable thickness, and the demyelination was a mixture of primary and secondary demyelination. The third pattern was observed in 1 case and was characterised by well-demarcated areas of reduced myelin staining and numerous apoptotic nuclei. Axonal staining revealed many fragmented axons with reduced myelin staining but no definitely demyelinated axons. CONCLUSIONS: This report shows that the predominant pathology underlying acute MS-related lesions is not limited to demyelination but can include axonal degeneration alone or in combination with primary demyelination which reflect different pathogenesis for these acute lesions.

Neurocytomas: long-term experience of a single institution.

There is a lack of studies reporting on outcomes of control and treatment toxicities for neurocytomas. A 25-year retrospective review of a tertiary center's experience with neurocytomas was completed to report on these outcomes. All cerebral neurocytoma cases (19 patients; median age, 31 years; range, 18-62 years; 18 intraventricular and 1 extraventricular) treated between 1984 and 2009 were analyzed, including central pathology and radiology reviews. Median follow-up was 104.5 months (range, 0.75-261.7 months). Primary treatment was surgery alone (n = 18 patients), followed by surgery and adjuvant radiotherapy (n = 1). The crude local control rate after surgery was 68% for all cases (cerebral neurocytomas) and 74% for central neurocytomas. Salvage therapies included further surgery (n = 4), radiation (n = 3), and chemotherapy (n = 1). Ten-year Kaplan-Meier overall and relapse-free survival rates were 82% and 62% and 81% and 57%, respectively, for all cases and for central neurocytomas only. The median overall survival and relapse-free survival were 104.5 and 79.3 months, respectively, for all cases and for central neurocytomas. Ten patients had grade 3/4 toxicity, and 1 patient had a grade 5 perioperative hemorrhage that resulted in death 23 days after surgery. Late grade 3/4 toxicities occurred in 9 patients. Three patients had permanent grade 2 motor or cognitive deficits. We provide the first report outlining toxicities and survival outcomes in a series of 19 patients. Our experience suggests that initial surgery provides durable local control rates in two-thirds of patients, with low risk for significant permanent deficits. Salvage therapy with surgery and/or radiation provides durable local control in tumors that recur after surgery.

Mefloquine in the treatment of progressive multifocal leukoencephalopathy.

Mefloquine, an antimalarial medication with efficacy against JC virus, was used to treat progressive multifocal leukoencephalopathy. A 54-year-old woman with sarcoidosis presented with a progressive cerebellar syndrome. MRI showed lesions affecting the right cerebellum that progressed over time to the brainstem. JC virus was found in the cerebrospinal fluid (CSF), and brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy. Mefloquine 1000 mg/week was initiated 6 months after symptom onset. Clinical progression stopped immediately, and JC virus became undetectable in the CSF. No clinical or imaging evidence of disease progression has occurred over 20 months of follow-up. This is the first report of successful treatment of progressive multifocal leukoencephalopathy with mefloquine.

MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-ß8.

It has been reported that the miR-106b∼25 cluster, a paralog of the miR-17∼92 cluster, possesses oncogenic activities. However, the precise role of each microRNA (miRNA) in the miR-106b∼25 cluster is not yet known. In this study, we examined the function of miR-93, one of the microRNAs within the miR-106b∼25 cluster, in angiogenesis and tumor formation. We found that miR-93 enhanced cell survival, promoted sphere formation and augmented tumor growth. Most strikingly, when miR-93-overexpressing U87 cells were co-cultured with endothelial cells, they supported endothelial cell spreading, growth, migration and tube formation. In vivo studies revealed that miR-93-expressing cells induced blood vessel formation, allowing blood vessels to extend to tumor tissues in high densities. Angiogenesis promoted by miR-93 in return facilitated cell survival, resulting in enhanced tumor growth. We further showed that integrin-ß8 is a target of miR-93. Higher levels of integrin-ß8 are associated with cell death in tumor mass and in human glioblastoma. Silencing of integrin-ß8 expression using small interfering RNA promoted cell proliferation, whereas ectopic expression of integrin-ß8 decreased cell growth. These findings showed that miR-93 promotes tumor growth and angiogenesis by suppressing, at least in part, integrin-ß8 expression. Our results suggest that inhibition of miR-93 function may be a feasible approach to suppress angiogenesis and tumor growth.

Epithelioid hemangioendothelioma of the spine presenting as cervical myelopathy: case report.

OBJECTIVE AND IMPORTANCE: We report the first case in the literature of cervical myelopathy caused by progressive cord compression as a result of epithelioid hemangioendothelioma of the cervical vertebra. CLINICAL PRESENTATION: A 58-year-old man presented with progressive cervical myelopathy. Imaging revealed a vascular, expansile lesion of contiguous cervical vertebrae causing cord compression. The surgical pathology revealed epithelioid hemangioendothelioma, a rare tumor not previously reported to present in such a fashion. INTERVENTION: Preoperative embolization and a two-stage anterior and posterior surgical decompression and fusion procedure were performed. The high vascularity of this lesion makes surgery a formidable surgical challenge. Adjuvant radiotherapy was administered to the residual tumor because of its potential for low-grade malignancy. CONCLUSION: The diagnosis relied on accurate histopathological assessment. The general principles of achieving cord decompression and tumor control are important. The literature on epithelioid hemangioendothelioma involving the spine is reviewed, and the tumor biology and the role of adjuvant therapy are discussed.

Identification of the motif in versican G3 domain that plays a dominant-negative effect on astrocytoma cell proliferation through inhibiting versican secretion and binding.

This study was designed to investigate the mechanisms by which mutant versican constructs play a dominant-negative effect on astrocytoma cell proliferation. Although a mini-versican or a versican G3 construct promoted growth of U87 astrocytoma cells, a mini-versican lacking epidermal growth factor (EGF) motifs (versicanDeltaEGF) and a G3 mutant (G3DeltaEGF) exerted a dominant-negative effect on cell proliferation. G3DeltaEGF-transfected cells formed smaller colonies, arrested cell cycle at G(1) phase, inhibited expression of cell cycle proteins cdk4 and cyclin D1, and contained multiple nucleoli. In cell surface binding assays, G3 products expressed in COS-7 cells and bacteria bound to U87 cell surface. G3DeltaEGF products exhibited decreased binding activity, but higher levels of G3DeltaEGF products were able to inhibit the binding of G3 to the cell surface. G3DeltaEGF expression inhibited secretion of endogenous versican in astrocytoma cells and also inhibited the secretion of mini-versican in COS-7 cells co-transfected with the mini-versican and G3DeltaEGF constructs. The effect seems to depend on the expression efficiency of G3DeltaEGF, and it occurred via the carbohydrate recognition domain.

Comparison of thermal damage calculated using magnetic resonance thermometry, with magnetic resonance imaging post-treatment and histology, after interstitial microwave thermal therapy of rabbit brain.

Clinical application of high-temperature thermal therapy as a treatment for solid tumours requires an accurate and close to real-time method for assessing tissue damage. Imaging methods that detect structural changes during heating may underestimate the extent of thermal damage. This is due to the occurrence of delayed damage manifested at tissue locations exposed to temperatures lower than those required to cause immediate structural changes. An alternative approach is to measure temperature and then calculate the expected damage based on the temperature history at each tissue location. Magnetic resonance (MR) imaging methods now allow temperature maps of the target and surrounding tissues to be generated in almost real-time. The aim of this work was to evaluate whether thermal damage zones calculated on the basis of MR thermometry maps measured during heating correspond to actual tissue damage as measured after treatment by histological methods and MR imaging. Four male rabbits were treated with high-temperature thermal therapy delivered in the brain by a single microwave antenna operating at 915 MHz. MR scanning was performed before, during and after treatment in a 1.5 T whole-body scanner. Temperature maps were produced using the proton resonance frequency (PRF) shift method of MR thermometry. In addition, conventional T1-weighted and T2-weighted spin-echo images were acquired after treatment. Thermal damage zones corresponding to cell death, microvascular blood flow stasis and protein coagulation were calculated using an Arrhenius analysis of the MR temperature/time course data. The calculated zones were compared with the lesions seen on histopathological examination of the brains which were removed within 6-8 h of treatment. The results showed that calculated damage zones based on MR thermometry agreed well with areas of damage as assessed using histology after heating was completed. The data suggest that real-time calculations of final expected thermal damage based on an Arrhenius analysis of MR temperature data may provide a useful method of real-time monitoring of thermal therapy when combined with conventional T2-weighted images taken after treatment.

Hydroxychloroquine neuromyotoxicity.

Hydroxychloroquine (HCQ) is commonly prescribed for treatment of inflammatory arthritis. The most frequently observed serious side effect is retinal toxicity; however, case reports have described HCQ induced neuromyotoxicity. We describe a case of HCQ neuromyotoxicity and a literature review from 1965 to September 1998 using Medline and Embase. Including our patient, there are 10 reported cases of HCQ neuromyotoxicity. Muscle biopsy consistently reveals curvilinear bodies and muscle fiber atrophy with vacuolar changes. Most cases manifest as insidious onset proximal myopathy that may be associated with peripheral neuropathy and cardiac myotoxicity. Resolution of symptoms is slow after discontinuation of therapy and may be incomplete. Possible predisposing factors include Caucasian race and concomitant renal failure. Patients treated with HCQ who develop a proximal myopathy, cardiomyopathy, or neuropathy, especially in the setting of worsening renal function, should be evaluated for possible HCQ neuromyotoxicity.

Primary spinal epidural mantle cell lymphoma: case report.

OBJECTIVE AND IMPORTANCE: Mantle cell lymphoma is a distinct clinicopathological type of non-Hodgkin's lymphoma that often presents at an advanced stage, with systemic spread. Spinal involvement is uncommon and generally occurs as part of advanced disease or generalized relapses. Primary spinal epidural lymphoma is a rare initial manifestation of non-Hodgkin's lymphoma, and mantle cell lymphoma with initial presentation in the spinal epidural space is extremely rare, having been previously reported in only two cases. CLINICAL PRESENTATION: We report a case of a 71-year-old man who presented with increasing weakness and numbness of the legs. Magnetic resonance imaging revealed a spinal epidural mass in the lumbosacral region. INTERVENTION: The patient underwent a partial L4 and L5-S1 laminectomy, with incomplete resection of the mass for spinal decompression and tissue diagnosis. Mantle cell lymphoma was diagnosed in the pathological examination. CONCLUSION: After radiotherapy, the disease recurred with a soft-tissue mass in the anterior maxillary area of the face. The patient underwent restaging and was treated with chemotherapy, with only a partial response. Mantle cell lymphoma with primary spinal epidural presentation is rare. This diagnosis can be established and other causes of spinal cord compression can be ruled out by obtaining tissue for proper histopathological examinations. Because of its aggressive behavior and poor prognosis, mantle cell lymphoma should be treated using a combined-modality approach.

Long nerve allografts in sheep with Cyclosporin A immunosuppression.

Rodent studies of nerve allografts are limited by a relatively short length of graft segment. The authors attempted to establish an outbred sheep model that would allow the study of longer, more clinically relevant nerve gaps. Using outbred ewes, two 8-cm long radial sensory nerves were grafted into gaps (5 cm) in the median nerve. Sheep received an autograft and an allograft. Four sheep were immunosuppressed with Cyclosporin A (CsA) and four were controls. Blood CsA levels greater than 1000 microg/L were obtained. Systemic immunosuppression resulted in severe opportunistic infections, and the sheep were sacrificed between 35 and 47 days following surgery. Histologically, in the autografts and CsA-treated allografts, evidence of nerve regeneration was seen. Non-immunosuppressed allografts were clearly rejected. While clear differences in the histology of experimental and control grafted nerve tissues were seen, the sheep allograft model presents considerable challenges due to immunosuppression-related infectious complications.

Skeletal muscle infarction in diabetes mellitus.

OBJECTIVE: To analyze the risk factors, clinical features, and methods of diagnosis of diabetic muscle infarction (DMI). METHODS: Three patients with diabetes mellitus (DM) and skeletal muscle infarction were studied, and 49 additional cases reported in the English literature (Medline database search) were reviewed. RESULTS: Review of all 52 patients with DMI revealed a number of typical features: equal sex distribution; mean age 41.5 years (range 19-81 yrs); a number of risk factors [long duration of DM (mean 15.2 yrs), poor control and microvascular diabetic complications (neuropathy, retinopathy, nephropathy) (94%), and insulin dependent type I DM (77%)]; a characteristic clinical presentation with painful diffuse muscle swelling (100%); and sometimes a muscle mass (44%), predilection for quadriceps (62%), hip adductors (13%) and leg muscles (13%), elevated serum creatine phosphokinase (47%), abnormal sonograms (81%), abnormal magnetic resonance image (MRI) findings (100%), typical histopathologic findings of a muscle infarct (100%) (ultrastructural evidence of microangiography in one patient); and a tendency toward spontaneous resolution although recurrences are common (51%). CONCLUSION: Skeletal muscle infarction is a rare complication of long standing, poorly controlled DM associated with multiple end organ microvascular sequelae. Increased clinical awareness is important for early recognition, particularly in a diabetic patient presenting with a painful thigh or leg swelling. MR imaging is the diagnostic study of choice, and in the appropriate clinical setting, may obviate the need for a muscle biopsy.

Overexpression of cyclin A and cyclin B1 proteins in astrocytomas.

BACKGROUND: Cyclins are proteins that are expressed during the progression of a normal cell through the cell cycle. In a number of cancers, overexpression of cyclin A and cyclin B1 proteins has been reported, and in some instances the levels of expression correlated well with the grades of malignancy. The expression of cyclin A and cyclin B1 proteins in astrocytoma may be linked to the histologic grade or proliferative activities. OBJECTIVE: To study the expression of cyclin A and cyclin B1 proteins in astrocytomas and correlate the labeling indices (LIs) of cyclin A and cyclin B1 with histologic grade and Ki-67 LI. DESIGN: The surgical biopsy specimens from 65 adults with astrocytomas were reviewed and divided into grades based on the World Health Organization system. The paraffin sections were immunostained using primary antibodies against Ki-67, cyclin A, and cyclin B1. The LIs of these astrocytomas for the 3 different antibodies were determined by computerized image analysis. RESULTS: The cyclin A LI showed good correlation with astrocytoma grade and Ki-67 LI. Both the nuclear and cytoplasmic cyclin B LIs correlated well with the tumor grade but showed poor correlation with Ki-67 LI. CONCLUSIONS: This study suggests that although both cyclin A and B protein expression are related to the grade of malignancy in astrocytomas, cyclin A levels more generally reflect the proliferative state of these tumors. We also provide indirect evidence that cyclin B1 is associated with the aberrant progression through the G2-M phase checkpoint in astrocytomas.

Versican enhances locomotion of astrocytoma cells and reduces cell adhesion through its G1 domain.

Versican is a large extracellular proteoglycan and is expressed in a variety of tissues including the central nervous system. A malignant astrocytoma cell line U87 with high motility expressed a higher level of versican than another malignant astrocytoma cell line U343 with lower motility. We observed that the U87 cells were less adherent to tissue culture plates than the U343 cells. To investigate the role of versican in astrocytoma cell migration, we generated recombinant products of a mini-versican construct expressed in COS-7 cells. We found that the mini-versican products enhanced astrocytoma cell migration. Furthermore, enhanced migration was promoted by the G1 domain but not the G3 domain of versican. We introduced culture medium containing products of the mini-versican, the G1, and the G3 constructs separately into the astrocytoma cell lines U87 and U343. The mini-versican and the G1 construct, but not the G3 construct, were shown to reduce astrocytoma cell adhesion. The present data suggest that versican exerts its effect on astrocytoma cell migration and adhesion through the G1 domain.

Cytologic diagnosis of a solitary brain metastasis from papillary carcinoma of the thyroid. A case report.

BACKGROUND: Papillary carcinoma of the thyroid metastasizes to the brain in rare instances. In published series and case reports of metastatic papillary thyroid carcinoma, diagnosis of central nervous system (CNS) metastases has been determined by histologic methods. We present a case of papillary carcinoma metastatic to brain diagnosed by cytologic methods. CASE: A 43-year-old female, initially diagnosed at age 12 with papillary carcinoma of the thyroid metastatic to regional lymph nodes and lung, presented with head aches of increasing frequency and severity. A computed tomography scan confirmed a 1-cm nodule in the right inferior frontal lobe of the brain. For clinical reasons, the patient was followed with serial imaging for five years. At age 48 there was significant progression of the CNS disease, and the patient underwent stereotactic biopsy with drainage of cyst fluid. Cytologic examination of the cyst fluid and immunocytochemical studies confirmed the typical features of papillary thyroid carcinoma, including papillary clusters of cells with finely granular chromatin, micronucleoli, nuclear grooves and an associated psammoma body. CONCLUSION: Neurocytology is a useful technique in the examination of cystic lesions of the brain and may be the sole technique for determination of diagnosis.

The hPMS2 exon 5 mutation and malignant glioma. Case report.

Patients with Turcot syndrome (TS) are predisposed to colon tumors and primary brain tumors, typically glioblastomas or medulloblastomas. The authors describe a patient with TS featuring a known germline mutation of exon 5 of the hPMS2 mismatch repair gene who developed two metachronous glioblastomas, both with distinct oligodendroglial features. Molecular genetic analysis revealed allelic loss of chromosome 19q in the patient's second tumor but no allelic loss of chromosome 1p. Prominent microsatellite instability was also found in this tumor, consistent with a germline mismatch repair defect. Because this patient had an unusual underlying condition and his tumor had a unique histological appearance for TS, it was hypothesized that this genetic defect may predispose to malignant gliomas with oligodendroglial features. The authors therefore evaluated whether sporadic glioblastomas and oligodendrogliomas undergo mutations of this region of the hPMS2 gene. However, single-strand conformation polymorphism analysis of hPMS2 exon 5 failed to reveal mutations in 20 sporadic glioblastomas and 16 sporadic oligodendroglial gliomas. Thus, although it is possible that the germline hPMS2 exon 5 mutation may predispose to glioblastomas with an oligodendroglial component, the same genetic defect is not commonly involved in sporadic oligodendrogliomas or glioblastomas.

A study of vestibular schwannomas using positron emission tomography and monoclonal antibody Ki-67.

OBJECTIVE: This study aimed to evaluate the role of positron emission tomography (PET) as an in vivo determinant of tumor aggressiveness and growth. STUDY DESIGN: The study design was a prospective pilot study. SETTING: Positron emission tomography was performed at the Clarke Institute of Psychiatry. All patients were treated at the Sunnybrook Health Science Centre. Both institutions are affiliated with the University of Toronto, Toronto, Canada. PATIENTS: The study consisted of five consecutive patients with vestibular schwannomas with tumor size of 1 cm or larger within the cerebellopontine angle. One was a recurrent tumor and four were primary tumors. INTERVENTIONS: Preoperative PET studies were conducted using 18-fluorodeoxyglucose (FDG) as a radionuclide tracer to measure glucose metabolism within tumors. Tumors were processed and immunostained against Ki-67 nuclear antigen; their proliferative potentials were quantified based on immunoreactivity of tumor cells. MAIN OUTCOME MEASURES: Tumor metabolic activity on PET was compared with that of contralateral cerebellum to arrive at an FDG index. This number was compared with clinical parameters and Ki-67 reactivity. RESULTS: On PET, all tumors showed less metabolic activity than the cerebellum. The FDG uptake varied greatly between tumors independent of clinical parameters. All the tumors had a low proliferative index (<5%) with immunohistochemistry; there were quite a bit of intralesional variations in proliferative activities. CONCLUSION: Large tumor size and recurrent disease did not correlate well with increased FDG uptake on PET. Similarly, they did not show increased cellular activities as expressed by Ki-67 immunostaining.

Hemorrhagic necrotic schwannoma presenting as purulent meningitis.

BACKGROUND: Intracranial schwannoma involving the XIIth cranial nerve is rare. We report an unusual clinical presentation and pathological verification of a schwannoma, which had become haemorrhagic and necrotic, simulating acute purulent meningitis. METHODS: A literature review of intracranial tumors presenting as acute purulent meningitis, with emphasis on schwannomas, was undertaken. RESULTS: Few cases of hypoglossal schwannoma have been reported; the association with purulent meningitis has not been previously documented. CONCLUSION: In patients presenting with sterile purulent meningitis, a necrotic tumor should be considered as a possible etiology.

Isolated intracranial involvement in Rosai-Dorfman disease: a report of two cases and review of the literature.

Rosai-Dorfman disease is an idiopathic histiocytic disorder of lymph nodes and extranodal sites. Central nervous system manifestations of this disease are rare, and to our knowledge only 16 cases of intracranial involvement have been reported previously. Intracranial Rosai-Dorfman disease clinically and radiologically resembles meningioma, and histologic examination is essential for a definitive diagnosis. We report two cases of isolated, intracranial, dural-based Rosai-Dorfman disease, review the literature, and discuss the differential diagnoses of this lesion.

MRI monitoring of interstitial microwave-induced heating and thermal lesions in rabbit brain in vivo.

The purpose of this experiment was to use MRI to monitor microwave heating and thermal damage of brain tissue in vivo. Interstitial microwave antennas were implanted into the cerebral hemispheres of seven anesthetized rabbits. Variable power of 30 to 100 W was applied for periods of 5 to 15 minutes and tissue temperature was monitored continuously. MR images were obtained throughout the procedure at 20-second intervals, using a spoiled gradient-echo sequence, without significant artifact. Magnitude, phase, and complex difference images all demonstrated temperature-related signal changes during heating. The findings were better visualized on the phase and complex difference images. Phase difference image analysis revealed an approximately linear relationship between phase change and temperature. Post-treatment thermal lesions measured up to 2.0 cm in size on pathologic specimens and exhibited a zonal pattern on spin-echo MR images.