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The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis as well as transcriptome data across 763 primary tumors. Characterization of CD271+ and CD271- cells by RNA sequencing revealed that these two subpopulations are molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling is upregulated in the CD271+ population and inhibiting this pathway reduced CD271 levels, stem/progenitor cell proliferation and cell survival as well as cell migration in vitro. Importantly, the MEK inhibitor selumetinib extends survival and reduces CD271 levels in vivo. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.
We describe the evolution of neuropathology in Canada, beginning with William Osler who began working in Montréal in 1874 and finishing with the major period of expansion in the 1970s. Organized services began in the 1930s, in Montréal with the neurosurgeons Wilder Penfield and William Cone, and in Toronto with Eric Linell and Mary Tom, who both began their careers as neuroanatomists. Jerzy Olszewski and Gordon Mathieson, who trained in Montréal and Toronto, drove the creation of the CanadianAssociation of Neuropathologists in 1960. Training guided by the Royal College of Physicians and Surgeons of Canada was formalized in 1965, with the first certifying examination in 1968 and the subsequent creation of formal structured training programs. The number of neuropathologists in Canada increased rapidly through the 1960s and 1970s, with individuals coming from both clinical neuroscience and anatomic pathology backgrounds, a pattern that persists to the present day.
The neonatal cat model of kaolin-induced hydrocephalus is associated with progressive and severe ventriculomegaly. In this experiment we studied the evolution of the histopathological changes in hydrocephalic (n = 23) cats from 5–168 days after the induction of hydrocephalus along with age-matched controls (n = 10). In the periventricular white matter, extracellular edema and axonal damage were present within days of the onset of hydrocephalus. This was followed by reactive gliosis, white matter atrophy, and in some animals gross cavitation of the white matter. Even in the chronic, apparently compensated state there was ongoing glial cell death. Six cats were shunted an average of 23.6 ± 6.5 days after the induction of hydrocephalus because they were no longer able to feed independently. In spite of clinical improvement the white matter changes persisted. Overt cortical changes were minimal except where areas of white matter destruction encroached upon the deep layers. The white matter changes are very similar to those seen in periventricular leukomalacia and suggest that ischemia plays a role in neonatal brain injury caused by hydrocephalus.
The cost of care for hydrocephalic patients is not well established.
This retrospective study for the years 1990-1996 analyzed the cost of surgical intervention and hospitalization of hydrocephalic patients in the community-based setting of Manitoba, Canada, with a stable population of 1.138 million.
The number of discharges with a primary diagnosis of hydrocephalus was greater than 200 annually. The mean duration of hospital stay was 12.4 to 21.9 days, depending on the etiology of hydrocephalus. Approximately 80 shunt procedures were performed annually. The total annual cost of care, excluding outpatient costs and chronic non-hospital based costs which could not be determined accurately, was estimated to be CDN$ 3.5 million in this community.
Hydrocephalus is a chronic condition which puts substantial monetary demands on society and therefore deserves greater attention.
A 41-year-old woman with a history of birth injury to the brachial plexus suffered several delayed episodes of neurological deterioration. Magnetic resonance imaging studies revealed a syrinx extending from the conus medullaris into the brainstem and rostrally into both internal capsules. She died of an acute exacerbation of chronic respiratory failure. Autopsy demonstrated syringomyelia and syringobulbia with cavity extension bilaterally along the corticospinal tracts into the internal capsules. Islands of glial tissue in the subarachnoid space around the medulla caused obstruction of the subarachnoid space at the foramen magnum. These were probably the result of birth injury to the cerebellum. A detailed clinico-pathological correlation is provided to explain her neurological deficits. The pathogenesis of syrinx formation is discussed in terms of a late manifestation of birth trauma.
The cortical changes resulting from chronic hydrocephalus in adults are not well defined.
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.
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.
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.
The expansion of neurosurgery and neurology in Montreal and Toronto in the early 20th century was the stimulus for the development of neuropathology in Canada. Rooted in the disciplines of the neurosciences and laboratory medicine, neuropathology evolved into an independent discipline with the founding of the Canadian Association of Neuropathologists in 1960, and the recognition as a specialty by the Royal College of Physicians and Surgeons in Canada in 1965, fostering the development of several successful training programs. Nonetheless, a paucity of data remains concerning the background of training, scopes of practice, and career paths.
We conducted a survey of all physicians in Canada who have either practiced neuropathology or undergone relevant training.
In 2009, 53 physicians were engaged in the practice of neuropathology, either exclusively or a substantial proportion of their time. Most work in tertiary hospitals, but a few service non-academic medical centers. Three routes of training were identified: direct from medical school (often with relevant research training), indirect from another clinical neuroscience specialty, and following or in conjunction with certification in one of the other pathology specialties. Practice profiles differ slightly, and some of the neuropathologists entering from pathology have mixed anatomical pathology/neuropathology responsibilities. Many of those with prior exposure in the neurosciences are more productive with regard to research and publications.
Existing multiple options for neuropathology training have facilitated recruitment and allowed development of a mosaic of specialists able to fulfill the diversity of needs in Canadian medical and scientific communities.
The onset of progressive cerebellar ataxia in early childhood is considered a key feature of ataxiatelangiectasia (A-T), accompanied by ocular apraxia, telangiectasias, immunodeficiency, cancer susceptibility and hypersensitivity to ionizing radiation.
We describe the clinical features and course of three Mennonite children who were diagnosed with A-T following the completion of therapy for lymphoid malignancies.
Prior to cancer therapy, all had non-progressive atypical neurological abnormalities, with onset by age 30 months, including dysarthria, dyskinesia, hypotonia and/or dystonia, without telangiectasias. Cerebellar ataxia was noted in only one of the children and was mild until his death at age eight years. None had severe infections. All three children were “cured” of their lymphoid malignancies, but experienced severe adverse effects from the treatments administered. The two children who received cranial irradiation developed supratentorial primitive neuroectodermal tumors of the brain, an association not previously described, with fatal outcomes.
The range of neurological presentations of A-T is broad. Ataxia and telangiectasias may be minimal or absent and the course seemingly non-progressive. The diagnosis of A-T should be considered in all children with neuromotor dysfunction or peripheral neuropathy, particularly those who develop lymphoid malignancies. The consequences of missing the diagnosis may be dire. Radiation therapy and radiomimetic drugs should be avoided in individuals with A-T.
This chapter focuses on aspects of hydrocephalus that are common to all ages with a particular emphasis on the aging brain and the so called normal pressure hydrocephalus (NPH) syndrome, which is a chronic disease that likely evolved over a period of years. It has been clear for decades that the rate of ventricular dilatation and the state of brain maturation have a significant impact on the pathology, and possibly the pathogenesis of brain damage. Idiopathic NPH has been distinguished from chronic adult hydrocephalus associated with prior meningitis, brain trauma, or subarachnoid hemorrhage. The initial displacement may be at the expense of the subarachnoid compartment, the venous compartment, and the extracellular compartment with negligible damage to brain cells. Blood flow hypoperfusion leads to hypoxic-ischemic changes in the white matter, physical stretching compromises axon integrity, and retarded turnover of the cerebrospinal fluid (CSF) alters the extracellular microenvironment.
Osaama H. Khan, Department of Pathology (Neuropathology) University of Manitoba D212 – 770 Bannatyne Avenue Winnipeg MB R3E 0W3 Canada,
Marc R. Del Bigio, Department of Pathology (Neuropathology) University of Manitoba D212 – 770 Bannatyne Avenue Winnipeg MB R3E 0W3 Canada
Hydrocephalus is a common neurological condition characterized by impairment of cerebrospinal fluid (CSF) flow with subsequent enlargement of CSF-containing ventricular cavities in the brain. CSF absorption occurs through arachnoid villi into venous sinuses and along cranial and spinal nerves into lymphatics. Enlarging ventricles damage the surrounding brain tissue. In children, hydrocephalus is associated with mental retardation, physical disability, and impaired growth. The pathogenesis of brain dysfunction includes alterations in the chemical environment of brain, chronic ischemia in white matter, and physical damage to axons with ultimate disconnection of neurons. Hydrocephalus is the second most frequent congenital malformation (after spina bifida) of the nervous system, occurring in 5–6 per 10 000 live births. It also develops in 80% of patients with spina bifida, and 15% of premature (< 30 weeks) infants following intraventricular hemorrhage. Hydrocephalus can develop later in childhood or adulthood as a consequence of brain tumors, meningitis, brain injury, or subarachnoid hemorrhage.
For detailed discussions of the pathology of hydrocephalus see previous reviews (references 2 and 3). Briefly summarized, the ependyma lining the ventricles is damaged. In the subependymal layer, reactive gliosis is almost always observed and mitotic activity occurs among subependymal cells. Hydrocephalus can cause reduction in cerebral blood flow and alterations in oxidative metabolism in subcortical regions where white-matter axons and myelin are the main target of damage in hydrocephalus. Imaging studies indicate that the brain is edematous in the periventricular region.
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