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A previously healthy 48-year-old female presented to the emergency department with a 2-week history of low back pain, progressive lower extremities weakness, and right leg numbness. There were no bowel or bladder dysfunction symptoms. Spine magnetic resonance imaging (MRI) showed an intradural cystic lesion dorsal to the spinal cord at the level of L1 measuring 1.6 × 2.1 × 4.1 cm, which was T1 hypointense and T2 hyperintense, with a small soft tissue component and no gadolinium enhancement (Figure 1). A small lipomatous component was also noted. There were no associated vertebral anomalies. The patient underwent a T12-L2 laminectomy and cyst resection, which was subtotal due to the cyst adherence to the conus medullaris. Histopathology showed characteristic features of a neurenteric cyst, with respiratory-type epithelium in the cyst wall (Figure 2). Eight months later, follow-up MRI showed no evidence of recurrence. The patient reported improved sensation in the lower extremities; however, there was some residual weakness predominantly in the proximal hip flexors bilaterally.

BACKGROUND Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown.METHODS We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide.RESULTS A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; PCONCLUSIONS In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials. gov number, NCT00482677.)

A 37-year-old man presented with a 7-month history of vertigo, nausea, dysphagia, right-sided tinnitus, and hearing loss. He denied headache, paresthesias, change in vision, or problems with cognition. He endorsed a history of progressive fatigue, generalized weakness, and poor libido. His symptoms left him functionally impaired and bedridden.

Under natural conditions and in some experimental models, rabies virus infection of the central nervous system causes relatively mild histopathological changes, without prominent evidence of neuronal death despite its lethality. In this study, the effects of rabies virus infection on the structure of neurons were investigated with experimentally infected transgenic mice expressing yellow fluorescent protein (YFP) in neuronal subpopulations. Six-week-old mice were inoculated in the hind-limb footpad with the CVS strain of fixed virus or were mock infected with vehicle (phosphate-buffered saline). Brain regions were subsequently examined by light, epifluorescent, and electron microscopy. In moribund CVS-infected mice, histopathological changes were minimal in paraffin-embedded tissue sections, although mild inflammatory changes were present. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase-3 immunostaining showed only a few apoptotic cells in the cerebral cortex and hippocampus. Silver staining demonstrated the preservation of cytoskeletal integrity in the cerebral cortex. However, fluorescence microscopy revealed marked beading and fragmentation of the dendrites and axons of layer V pyramidal neurons in the cerebral cortex, cerebellar mossy fibers, and axons in brainstem tracts. At an earlier time point, when mice displayed hind-limb paralysis, beading was observed in a few axons in the cerebellar commissure. Toluidine blue-stained resin-embedded sections from moribund YFP-expressing animals revealed vacuoles within the perikarya and proximal dendrites of pyramidal neurons in the cerebral cortex and hippocampus. These vacuoles corresponded with swollen mitochondria under electron microscopy. Vacuolation was also observed ultrastructurally in axons and in presynaptic nerve endings. We conclude that the observed structural changes are sufficient to explain the severe clinical disease with a fatal outcome in this experimental model of rabies.

Acute gastrointestinal hemorrhage from a gastroaortic fistula in the gastric fundoplication pouch is a rare complication of Nissen fundoplication. The present case reports a gastroaortic fistula secondary to gastric ulceration associated with prior Nissen fundoplication and nonsteroidal anti-inflammatory drug use. A 55-year-old man presented with massive hematemesis and died of exsanguination during emergency laparotomy. Recognition of factors that predispose a patient to gastric ulceration after fundoplication, including nonsteroidal anti-inflammatory drug use, is critical to arouse the high index of suspicion required to diagnose and manage this life-threatening complication.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m(2) once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (

Tumour necrosis factor alpha inhibitors, such as infliximab, and other biologic agents are associated with increased risk of opportunistic infection, including tuberculosis. Tuberculosis infections associated with infliximab tend to present atypically and can be difficult to diagnose, as they are more likely to manifest as extrapulmonary or disseminated disease. The authors report a case involving a 29-year-old male patient who died following 16 days of treatment for undifferentiated sepsis and who was found on autopsy to have widespread disseminated tuberculosis. Prior to the onset of illness, the patient had received infliximab for the treatment of Crohn’s disease. Following discussion of the case, the authors review the definition of adverse events, provide a root cause analysis of the cognitive errors and breakdowns in the health care system that contributed to the reported outcome, and identify opportunities to address these breakdowns and improve patient safety measures for future cases.

There is recent in vitro evidence that human neurons express the innate immune response receptor, Toll-like receptor-3 (TLR-3), and that expression is enhanced in viral infections. The authors examined the immunohistochemical expression of TLR-3 in the cerebellar cortex of postmortem human brains. Purkinje cells were found to express TLR-3 in all cases of rabies (4 of 4) and herpes simplex encephalitis (2 of 2) as well as in cases of amyotrophic lateral sclerosis (1 of 2), stroke (1 of 2), and Alzheimer's disease (3 of 3). In cases of viral infection, direct viral infection was not necessary for enhanced neuronal TLR-3 expression, suggesting that soluble factors likely play an important role in inducing TLR-3 expression. In addition to neurons, occasional Bergmann glia expressed TLR-3 in some cases. This study has provided evidence that human brain neurons can express TLR-3 in vivo and suggests that neurons may play an important role in initiating an inflammatory reaction in a variety of neurological diseases.

It is generally accepted that there are not prominent features of neuronal cell death in rabies encephalitis. However, Hemachudha and coworkers recently reported widespread apoptosis in the central nervous system of several human rabies cases (BMC Infect Dis 5: 104, 2005). In this study we have evaluated morphological features and markers of neuronal apoptosis in postmortem brain tissue from 12 cases of human rabies who died in four different countries. Histopathological analysis, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) staining, and immunostaining for cleaved (activated) caspase-3 were performed on paraffin-embedded tissues from the cerebral cortex, hippocampus, and brainstem, and additional regional areas from one of the cases. We did not find morphological evidence of neuronal apoptosis or TUNEL staining in any of the cases of rabies encephalitis. Similarly, immunostained cleaved caspase-3 was not seen in neurons, but prominent staining was observed in microglial processes. We conclude that neuronal apoptosis does not play an important pathogenetic role in human rabies encephalitis.

Alpha-synuclein protein aggregates are a major component of Lewy bodies, the intracytoplasmic inclusions found in dopaminergic neurons that are a defining characteristic of Parkinson's disease. Other "synucleopathies" include dementia with Lewy bodies and multisystem atrophy. In vitro, the formation of these deposits can be induced by a number of substances, including metal ions. Fish provide a useful model to study the long-term biological effects of metal ion exposure, but to date no studies have been reported concerning such exposures with respect to alpha-synuclein aggregation. Mature white sucker fish (Catostomus commersoni; aged 5-8 years) were sampled from two sites within the Red Lake area of Northwestern Ontario, a region highly contaminated by metal ions due to mining activity. Individual fish were characterized with respect to liver metal ion uptake and metallothionein levels. Central nervous system (CNS) tissues of fish from test sites representing high and low metal ion contamination were examined immunohistochemically using a polyclonal antibody recognising alpha-synuclein protein. We demonstrate here that the CNS of fish exposed to elevated metal ion environments had increased alpha-synuclein-like immunoreactive aggregates, potentially reflecting metal ion exposure leading to CNS toxicity. These findings demonstrate that fish may be an important new model for studying environmental risk factors and the pathology associated with Parkinson's disease.

Minocycline is a tetracycline derivative with antiapoptotic and anti-inflammatory properties, and the drug has been shown to have beneficial effects in a variety of models of neurological disorders. The potentially neuroprotective role of minocycline was assessed in experimental in vitro and in vivo models of rabies virus infection. In this study, 5 nM minocycline did not improve the viability of embryonic mouse cortical and hippocampal neurons infected in vitro with the attenuated SAD-D29 strain of rabies virus, based on assessments using trypan blue exclusion. Two-day-old ICR mice were inoculated in the right hind limb thigh muscle with SAD-D29, and they received daily subcutaneous injections of either 50 mg/kg minocycline or vehicle (phosphate-buffered saline). Infected minocycline-treated mice experienced an earlier onset of neurologic signs and greater mortality (83% versus 50%) than those receiving vehicle (log rank test, P = 0.002 and P = 0.003, respectively). Immunohistochemical analysis of rabies virus antigen distribution was performed at early time points and in moribund mice. There were greater numbers of infected neurons in the regional brain areas of minocycline-treated mice than in vehicle-treated mice, which was significant in the CA1 region of the hippocampus. There was less apoptosis ( P = 0.01) and caspase 3 immunostaining ( P = 0.0008) in the midbrains of mice treated with minocycline than in mice treated with vehicle, consistent with a neuroprotective role of neuronal apoptosis that may have had a mild effect of inhibiting viral spread. Reduced infiltration of CD3 + T cells was observed in the pons/medulla of moribund mice that received minocycline therapy ( P = 0.008), suggesting that the anti-inflammatory actions of minocycline may intensify the neurologic disease. These findings indicate that minocycline has important detrimental effects in the therapy of experimental rabies. Empirical therapy with minocycline should therefore be approached with caution in cases of human rabies and possibly other viral encephalitides until more experimental data become available.

A 28-year-old woman presented with a one day history of high fever and partial seizures with secondary generalization. This was preceded by a three week history of headache, ataxia, and fatigue. An initial computed tomogram head scan showed a low density mass lesion in the right frontal operculum without enhancement. On the next day, a repeat scan showed a new frontopolar, expansile, low density cortical lesion (Figure 1A) suggestive of encephalitis. Cerebrospinal fluid showed a pleocytosis of 311 mononuclear white blood cell count per μL and an elevated protein of 1.57 g/L. She received intravenous acyclovir and antibiotics. She remained febrile and became mute. A magnetic resonance (MR) scan under general anesthesia on her fourth hospital day showed frontal and perisylvian lesions with restricted diffusion (Figure 1B - D and Figure 2). A right frontal brain biopsy showed meningoencephalitis and immunohistochemical staining was positive for herpes simplex virus (HSV) antigen (Figure 3). Subsequently, HSV-1 DNA was demonstrated in both cerebrospinal fluid and brain tissue with polymerase chain amplification. She improved after a course of intravenous therapy with acyclovir with residual frontal lobe signs, including marked executive dysfunction, and her speech became normal.

Cultured rat prostatic adenocarcinoma (AT3) cells infected with the challenge virus standard (CVS) strain of fixed rabies virus showed characteristic morphologic features of apoptosis, evidence of oligonucleosomal DNA fragmentation, and expression of the Bax protein. CVS-infected Bcl-2-transfected AT3 cells did not demonstrate these features. Adult ICR mice inoculated intracerebrally with CVS showed morphologic changes of apoptosis, DNA fragmentation, and increased Bax expression in neurons, with changes most marked in the hippocampus and cerebral cortex. Ultrastructurally, some neurons demonstrated morphologic features more typical of necrosis. These studies provide evidence that apoptosis plays an important role in the pathogenesis of rabies virus infection.