Joseph F. Megyesi

Acute management of acquired brain injury part II: An evidence-based review of pharmacological interventions

Primary objective: To review the literature on non-pharmacological interventions used in acute settings to manage elevated intracranial pressure (ICP) and minimize cerebral damage in patients with acquired brain injury (ABI). Main outcomes: A literature search of multiple databases (CINAHL, EMBASE, MEDLINE and PSYCHINFO) and hand-searched articles covering the years 1980–2008 was performed. Peer reviewed articles were assessed for methodological quality using the PEDro scoring system for randomized controlled trials (RCTs) and the Downs and Black tool for RCTs and non-randomized trials. Levels of evidence were assigned and recommendations made. Results: Five non-invasive interventions for acute ABI management were assessed: adjusting head posture, body rotation (continuous rotational therapy and prone positioning), hyperventilation, hypothermia and hyperbaric oxygen. Two invasive interventions were also reviewed: cerebrospinal fluid (CSF) drainage and decompressive craniectomy (DC). Conclusions: There is a paucity of information regarding non-pharmacological acute management of patients with ABI. Strong levels of evidence were found for only four of the seven interventions (decompressive craniectomy, cerebrospinal fluid drainage, hypothermia and hyperbaric oxygen) and only for specific components of their use. Further research into all interventions is warranted.

Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity

BackgroundThe pathogenesis of HIV-1 glycoprotein 120 (gp120) associated neuroglial toxicity remains unresolved, but oxidative injury has been widely implicated as a contributing factor. In previous studies, exposure of primary human central nervous system tissue cultures to gp120 led to a simplification of neuronal dendritic elements as well as astrocytic hypertrophy and hyperplasia; neuropathological features of HIV-1-associated dementia. Gp120 and proinflammatory cytokines upregulate inducible nitric oxide synthase (iNOS), an important source of nitric oxide (NO) and nitrosative stress. Because ascorbate scavenges reactive nitrogen and oxygen species, we studied the effect of ascorbate supplementation on iNOS expression as well as the neuronal and glial structural changes associated with gp120 exposure.MethodsHuman CNS cultures were derived from 16–18 week gestation post-mortem fetal brain. Cultures were incubated with 400 μM ascorbate-2-O-phosphate (Asc-p) or vehicle for 18 hours then exposed to 1 nM gp120 for 24 hours. The expression of iNOS and neuronal (MAP2) and astrocytic (GFAP) structural proteins was examined by immunohistochemistry and immunofluorescence using confocal scanning laser microscopy (CSLM).ResultsFollowing gp120 exposure iNOS was markedly upregulated from undetectable levels at baseline. Double label CSLM studies revealed astrocytes to be the prime source of iNOS with rare neurons expressing iNOS. This upregulation was attenuated by the preincubation with Asc-p, which raised the intracellular concentration of ascorbate. Astrocytic hypertrophy and neuronal injury caused by gp120 were also prevented by preincubation with ascorbate.ConclusionsAscorbate supplementation prevents the deleterious upregulation of iNOS and associated neuronal and astrocytic protein expression and structural changes caused by gp120 in human brain cell cultures.

Desmoplastic Fibroma of the Cranium: Case Report and Review of the Literature

OBJECTIVE AND IMPORTANCEDesmoplastic fibroma is a benign bone tumor that can be locally aggressive. It usually occurs in the long bones and mandible. We report on a patient with a desmoplastic fibroma arising in the temporal bone and review previously published cases of desmoplastic fibroma originating within the cranium. CLINICAL PRESENTATIONA 43-year-old woman presented with a 12-year history of progressively worsening head asymmetry. Magnetic resonance imaging and computed tomography demonstrated a mass originating from the bone and involving the adjacent soft tissues. INTERVENTIONA temporal parietal craniectomy was performed with excision of a large tumor involving the bone. An acrylic cranioplasty was used to replace the bone. Pathological examination of the lesion identified desmoplastic fibroma of the cranium. After surgery, the patient’s cranial asymmetry was corrected. CONCLUSIONDesmoplastic fibroma of the cranium is rare. Surgical resection is the treatment of choice.

Intraparenchymal supratentorial neurenteric cyst.

BACKGROUND Neurenteric cysts are congenital cysts of the central nervous system that are believed to be of endodermal origin. In this report we present the unique case of a supratentorial neurenteric cyst that is contained entirely within the brain parenchyma. METHODS A patient presented with an intraparenchymal cystic lesion that was subsequently identified as a neurenteric cyst. This lesion is reviewed in light of the available literature. CASE REPORT A 35-year-old female presented with a one year history of progressive headaches and seizure-like episodes. Her examination revealed no deficits. Magnetic resonance imaging showed a 4 cm x 4 cm x 4 cm cystic lesion within the parenchyma of the right frontal lobe. A right frontal craniotomy and complete excision of the cystic lesion was performed. Pathologic examination confirmed that it was a neurenteric cyst. Postoperatively the patients symptoms improved. CONCLUSION Review of the literature revealed this to be the first case of a surgically excised, pathologically confirmed supratentorial neurenteric cyst, contained entirely within the brain parenchyma.

Acute management of acquired brain injury Part III: an evidence-based review of interventions used to promote arousal from coma.

Primary objective: To review the literature regarding techniques used to promote arousal from coma following an acquired brain injury. Main outcomes: A literature search of multiple databases (CINAHL, EMBASE, MEDLINE and PsycINFO) and hand searched articles covering the years 1980–2008 was performed. Peer reviewed articles were assessed for methodological quality using the PEDro scoring system for randomized controlled trials and the Downs and Black tool for RCTs and non-randomized trials. Levels of evidence were assigned and recommendations were made. Results: Research into coma arousal has generally focused on the stimulation of neural pathways responsible for arousal. These pathways have been targeted using pharmacological and non-pharmacological techniques. This review reports the evidence surrounding agents targeting dopamine pathways (amantadine, bromocriptine and levodopa), sensory stimulation, music therapy and median nerve electrical stimulation. Each of these interventions has shown some degree of benefit in improving consciousness, but further research is necessary. Conclusions: Despite numerous studies, strong evidence was only found for one intervention (Amantadine use in children) and this was based on a single study. However, each of the interventions showed promise in some aspect of arousal and warrant further study. More methodologically rigorous study is needed before any definitive conclusions can be drawn.

Suturing technique and the integrity of dural closures: an in vitro study.

OBJECTIVE:The watertight closure of the dura mater is fundamental to intracranial procedures in neurosurgery. Nevertheless, for any given operator and type of suture, it is still not certain which suturing technique affords the most watertight dural closure. We have developed a laboratory model that allows us to compare the pressures at which dural closures leak when different suturing techniques are used. METHODS:Human cadaveric dura was secured to a glass cylinder filled with colored saline. By application of force to a bag of saline attached to the cylinder, the pressure at which sutured dural incisions leak can be recorded. Using this method, we have compared the closure of 2-cm dural incisions with 3-0 silk using the following techniques (10 per group): 1) interrupted simple, 2) running simple, 3) running locked, and 4) interrupted vertical mattress. We have also compared the closure of 1- × 3-cm dural windows with cadaveric dura and 3-0 silk using the same suturing techniques (10 per group). RESULTS:The pressure at which 2-cm linear dural incisions leaked was significantly higher when they were closed with the interrupted simple suturing technique (P < 0.05). There was no significant difference among the different suturing techniques when they were used to close a 1- × 3-cm dural window with a duraplasty. Overall, the pressures at which sutured linear dural incisions leaked were higher than the pressures at which sutured dural windows closed with duraplasties leaked. CONCLUSION:In the experimental model described, an interrupted simple suturing technique affords the most watertight dural closure for linear incisions, whereas no suturing technique proved advantageous for the closure of a duraplasty.

Do epileptic seizures predict outcome in patients with oligodendroglioma

BACKGROUND Many patients with an oligodendroglioma (OD) experience seizures, some of which become refractory to anti-epileptic drugs (AEDs). This study aims (1) to quantify the rate of seizures and medically refractory epilepsy in patients with ODs; and (2) to determine if there is any association between short-term and long-term survival, and the presence and drug-responsiveness of seizures. METHODS A retrospective review was conducted of the medical records of patients who had been pathologically identified as having an OD at the London Health Sciences Centre or the London Regional Cancer Program in London, Ontario from January 1996 to July 2008. Deaths were ascertained by reviewing all hospital records. Survival analysis was performed. RESULTS One-hundred sixty-six patients met inclusion criteria. Epileptic seizures were the presenting feature or occurred as part of the initial manifestation of the OD in 75.3% of patients, with 90.4% (n=150) experiencing at least one seizure and 76.5% developing epilepsy over the course of observation. Of the 150 patients with seizures, 23 experienced a single seizure (13.9% of the 166), whereas 127 patients experienced multiple seizures (76.5%). In those with multiple seizures, the epilepsy was refractory to drug treatment slightly more than half the time (54.3%). Survival analysis demonstrated consistently superior survival among those with a single seizure. Those without seizures had the worst survival rates over the first few years post-diagnosis; but then no further deaths occurred. Survival among those with refractory seizures tended to be better than among those whose seizures were drug responsive, over the first 10 years post-diagnosis. CONCLUSIONS Seizures are common and may influence survival in patients with oligodendogliomas. Those who experience just one seizure appear to do best.

Castleman's disease and spinal cord compression: case report.

OBJECTIVE AND IMPORTANCE Castleman’s disease is a rare lymphoproliferative disorder most often found in the mediastinum. Localized forms are usually benign, whereas multicentric forms may be aggressive . We report a patient with Castleman’s disease who presented with spinal cord compression, and we review previously published cases of Castleman’s disease involving the central nervous system. To our knowledge, this is only the second case of Castleman’s disease presenting as a spinal epidural mass with cord compression. CLINICAL PRESENTATION A 44-year-old otherwise healthy woman presented acutely with difficulty walking. Examination revealed mild myelopathy in her legs. Magnetic resonance imaging revealed a posterior epidural mass compressing the thoracic spinal cord at T3–T5. INTERVENTION Thoracic laminectomy and gross total resection of the lesion were performed. Pathological examination of the lesion identified the hyaline-vascular type of Castleman’s disease. The patient’s symptoms resolved postoperatively. CONCLUSION Castleman’s disease presenting as a spinal epidural mass lesion with cord compression is rare. Surgical treatment can result in an excellent outcome.

Metastatic PEComa to the brain

Neoplasms of perivascular epithelioid cells (PEComas) have in common the co-expression of melanocytic and muscle immunohistochemical markers. While most reported PEComas have behaved in a benign fashion, malignant PEComas have occasionally been documented [3–5]. We present a case of malignant PEComa, which was Wrst diagnosed as a brain metastasis; this represents the Wrst documentation of brain involvement by PEComa. A 53-year-old woman presented with malaise. Computerized tomography (CT) of the chest and abdomen revealed multiple lung lesions bilaterally, as well as a solitary mass in the left adrenal gland. The largest lung lesion was located in the right upper lobe and measured 5.4 £ 3.5 £ 3.4 cm, while the adrenal mass measured 4.8 £ 3.2 £ 2.9 cm. Fine needle aspiration of one of the lung lesions was interpreted as indeterminate for malignancy. The liver, pancreas, spleen and kidneys were normal by abdominal imaging. Several months later, she presented with headache, nausea and vomiting. She had diYculty with naming. A CT scan of her head revealed a mass in the left posterior temporal lobe, which was mostly solid with cystic components (Fig. 1). The patient underwent a temporal craniotomy and resection of the brain tumor. Postoperatively, neuroimaging showed no evidence of residual tumor. The patient’s headache improved and she was discharged home. Pathologic examination of resected tumor tissue showed cells arranged in sheets and nests, invested with a prominent capillary vasculature (Fig. 2a). The interface between tumor and uninvolved brain was sharp and several foci of necrosis were present. The neoplastic cells were epithelioid, with abundant cytoplasm that varied from eosinophilic and granular to clear (Fig. 2b). The nuclei were round with moderate pleomorphism and they often contained conspicuous nucleoli; mitoses were rare. Periodic acid–SchiV (PAS) staining, with and without diastase digestion, demonstrated intracytoplasmic glycogen (Fig. 2c). The biopsied lung lesion was morphologically similar to the brain tumor, although there was greater nuclear pleomorphism and more prominent nucleoli in the latter. Immunohistochemistry showed strong positivity within tumor cells for HMB45, Melan-A and caldesmon, while desmin was focally positive (Fig. 3a, b). The neoplastic cells failed to stain with antibodies against S100, tyrosinase, epithelial membrane antigen (EMA), vimentin, cytokeratin (AE1/AE3, 8/18, 7/20, 34BE12), inhibin, actin (smooth muscle and muscle speciWc), smooth muscle myosin, neuron speciWc enolase (NSE), synaptophysin, chromogranin, neuroWlament, glial Wbrillary acidic protein (GFAP), CD10, CD99, CD117, CD34, carcinoma embryonic antigen (mono and polyclonal), calretinin, heppar1 and placental alkaline phosphatase. Ultrastructural examination of glutaraldehyde-Wxed tissue revealed intracytoplasmic glycogen and lipid. Premelanosomes and desmosomes were absent. The WHO has recently oVered formal recognition to a group of neoplasms with perivascular epithelioid cell diVerentiation. This group of tumors have in common the presence of epithelioid to spindle cells with J. R. ParWtt (&) · J. L. Keith · J. F. Megyesi · L. C. Ang Department of Pathology, London Health Sciences Centre, University of Western Ontario, 339 Windermere Road, London, ON, Canada N6A 5A5, e-mail: jrparWt@uwo.ca

Investigation of an inhibitor of lipid peroxidation U74006F on tumor growth and protein extravasation in the C6 astrocytoma spheroid implantation glioma model

SummaryThe role played by lipid peroxidation in cerebral tumor growth and protein extravasation has not been defined. A potent in vitro inhibitor of lipid peroxidation (21-[4-2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16a-methylpregna-1,4,9(11)-triene-3,20-dione monomethane sulfonate (U74006F), has been used to assess its influence on both tumor growth and protein extravasation in a rat C6 astrocytoma implantation model.Following spheroid implantation, rats were treated with one of these U74006F regimens: 12 mg/kg/day for 13 days post-implantation, 3.6 mg/kg/day for 13 days post-implantation or 12 mg/kg/day commencing seven days post-implantation until 13 days post-implantation. Tumor wet weights, dry weights and protein flux as measured by Evans blue dye extravasation were assessed. Neither wet weights nor dry weights of any of the three treatment groups was significantly lower when compared to control tumor wet weights and dry weights. Protein extravasation was not significantly reduced by any of the treatments. It is concluded that U74006F did not significantly decrease tumor growth or permeability in the C6 astrocytoma spheroid implantation model.