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.

Differential brain region-specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey-white matter variation.

INTRODUCTION AND OBJECTIVES: Rett Syndrome (RTT) is a neurodevelopmental disorder caused by Methyl CpG Binding Protein 2 (MECP2) gene mutations. Previous studies of MeCP2 in the human brain showed variable and inconsistent mosaic-pattern immunolabelling, which has been interpreted as a reflection of activation-state variability. We aimed to study post mortem MeCP2 and BDNF (MeCP2 target) degradation and brain region-specific detection in relation to RTT pathophysiology. METHODS: We investigated MeCP2 and BDNF stabilities in non-RTT human brains by immunohistochemical labelling and compared them in three brain regions of RTT and controls. RESULTS: In surgically excised samples of human hippocampus and cerebellum, MeCP2 was universally detected. There was no significantly obvious difference between males and females. However, post mortem delay in autopsy samples had substantial influence on MeCP2 detection. Immunohistochemistry studies in RTT patients showed lower MeCP2 detection in glial cells of the white matter. Glial fibrillary acidic protein (GFAP) expression was also reduced in RTT brain samples without obvious change in myelin basic protein (MBP). Neurons did not show any noticeable decrease in MeCP2 detection. BDNF immunohistochemical detection showed an astroglial/endothelial pattern without noticeable difference between RTT and controls. CONCLUSIONS: Our findings indicate that MeCP2 protein is widely expressed in mature human brain cells at all ages. However, our data points towards a possible white matter abnormality in RTT and highlights the importance of studying human RTT brain tissues in parallel with research on animal and cell models of RTT.

Progressive supranuclear palsy in a family with TDP-43 pathology.

UNLABELLED: A member of a family with an autosomal dominant pattern of frontotemporal dementia (FTD) with a TDP-43 pathological substrate in other members and no mutations in FTD-associated genes developed behavioral variant FTD followed by Progressive Supranuclear Palsy. Autopsy revealed a pure tauopathy of PSP pattern. CONCLUSIONS: The findings raise the possibility of shared pathogenic pathways and a proximal genetic abnormality between PSP and FTLD-43.

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.

Progressive supranuclear palsy: a review of co-existing neurodegeneration.

OBJECTIVES: The neuropathological findings of 32 progressive supranuclear palsy (PSP) cases over a period of 17 years were reviewed. RESULTS: Of the 26 cases with adequate clinical data, 20 patients either presented with cognitive dysfunction or developed a cognitive impairment subsequently during the course of the disease. Co-existing changes of argyrophilic grains and corticobasal degeneration (CBD) were found in 28% and 32% of the cases respectively. Alzheimer-related pathology was found in 69% of cases but only 18.75% of cases fulfilled the consortium to establish a registry for Alzheimer's disease (CERAD) criteria for either definite or probable Alzheimer's disease. Lewy bodies were noted in four cases (12.5%), all in the subcortical regions. Only seven cases of PSP showed no pathological evidence of other co-existing neurodegenerative diseases. The severity of the cerebrovascular pathology in this cohort was insufficient to explain any clinical symptomatology. CONCLUSIONS: As in previous studies, this study has demonstrated the frequent co-existence of pathological changes usually noted in other neurodegenerative diseases in PSP. Whether these co-existing pathological changes contribute to the cognitive impairment in PSP remains uncertain.

Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex.

The pathology of glaucoma has been extensively studied at the level of the retina and optic nerve head. Here the first clinicopathological case of human glaucoma is reported demonstrating degenerative changes in the brain involving the intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Pathological evidence of neural degeneration in this patient is correlated with clinical, optic nerve head, visual field, and neuroradiology findings. Neuropathology in the glaucoma brain is compared to age matched controls. In the presence of advanced human glaucoma with 50% visual field loss, neural damage is evident in multiple vision stations within the brain.

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.

Differential response of sensory and motor axons in nerve allografts after withdrawal of immunosuppressive therapy.

OBJECT: Rejection of nerve allografts and loss of regenerated host axons after withdrawal of immunosuppressive therapy poses an ongoing challenge in peripheral nerve repair. The present report is of a blinded prospective controlled study in which an established rat model of nerve allotransplantation is used to examine the effect of fiber type on survival and degeneration of nerve allografts after discontinuation of immunosuppression. The authors hypothesized that sensory axons will selectively resist a rejection response, whereas motor axons will degenerate. METHODS: Four-centimeter nerve segments from ACI rats were grafted into peroneal and sural (mixed) or saphenous (sensory) nerve gaps in Lewis rats. In some rats, L4-6 dorsal root ganglia were ablated before grafting, creating pure motor sural and peroneal nerves. All rats received 12 weeks of immunosuppressive therapy to support nerve regeneration into allografts. Immunosuppression with cyclosporin was then withdrawn. At planned death (12-18 weeks postsurgery), graft tissue was subjected to histomorphometric analysis for evaluation of axon survival and loss. Graft rejection led to loss of all axons in approximately 60% of the allograft segments. The mixed nerve group was most prone to complete rejection, with significantly lowered axon counts at Weeks 16 and 18 compared with the Week 12 baseline. Axons from the sensory nerve were least likely to degenerate. The pure motor nerve group axons demonstrated intermediate sensitivity, with a selective loss of larger axons at Week 16 and a significant decrease in axon counts from the Week 12 baseline at Week 18. CONCLUSIONS: Whereas the majority of axons are lost after withdrawal of immunosuppressive therapy from nerve allografts, there is a selective survival of axons from cutaneous sensory nerves and smaller-diameter motor fibers. The biological and molecular mechanisms that make some axons impervious to injury remain to be determined.

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.

Epidemiology of diabetes mellitus in Western pacific region: focus on Philippines.

The aim of Diabcare-Asia project was to collect data on diabetes control, management and complication status among patients in 12 Asian countries. Information was extracted from medical records, interviews and laboratory assessment. The majority (96%) of patients were diagnosed with type 2 diabetes mellitus, with mean age (+/-SD) of 59.3+/-12.5 years and mean diabetes duration of 9.4+/-7.0 years. Mean body mass index (BMI) was 24.7+/-4.9 kg/m(2) and the majority (60%) had BMI < or =25 kg/m(2). The majority (70%) of patients were treated with oral antidiabetic drugs (OADs), 15% with insulin, 10% with insulin and OAD combination therapy and 5% with diet control. Among OADs-treated patients, most (44%) received two or more medication. Majority of patients (> or =79%) had satisfactory metabolic control of triglycerides (<2.2 mmol/l), total cholesterol (<6.5 mmol/l) and HDL cholesterol (>0.9 mmol/l). Glucose self-monitoring (either urine or blood) was only practiced by 50% of patients. Glycaemic control (HbA1c) was unsatisfactory as majority of patients had HbA1c>7.4% (73%) and 50% had fasting blood glucose (FBG)>7.8 mmol/l. Cataract (26%), neuropathy (42%) and cerebral stroke (6%) were the most frequently reported complications. Clearly, the level of glycaemic control in majority of patients is below satisfaction. Effective education must be emphasised in the management of diabetes.

Glial intranuclear inclusion bodies in a patient with Alzheimer's disease.

We report a case of dementia in an elderly woman with the pathological findings of Alzheimer's disease and numerous intranuclear inclusions in astrocytes and occasionally in neurons. These inclusions were seen in the cerebral cortex, limbic areas, basal ganglia, thalamus, brain stem and cerebellum. They expressed ubiquitin and were ultrastructurally composed of haphazardly arranged straight filaments. The presence of similar intranuclear inclusions in previous cases of adult-onset dementia without other neuropathological changes suggests an important link between these kind of inclusions and dementia. To our knowledge, this type of intranuclear inclusions has not been previously described in association with Alzheimer pathology.

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.