AANS2000AANS2000Internet Outline of

Neurosurgery

E. R. Flotte MD, 2009

 

Please send comments and corrections to admin@flotte2.com

www.outlineofneurosurgery.com

 

 

 

Neurosurgical Research

Tumors

      Genetics

      Migration

      Invasion

      Growth Factors

      Signaling Pathways

      Angiogenesis

      Immunotherapy

      Tumor Cell Lines

      Tumor Modeling

      Delivery

      Stem Cells

      Miscellaneous

 

Neuroprosthetics

 

 

 

Research: General Principles

 

 

·         “Biomedical Publication for Neurosurgery Residents”, Berger MS N9/00

·         Nationwide Inpatient Sample (NIS): www.ahcpr.gov/data/hcup/nisintro.htm

·         Clinical Trials: N2/04.

 

 

·         “2001: Things to come” Apuzzo MLJ N10/01

 

 

Tumors

 

Genetics

(-) = tumor suppressor; (+) = oncogene

Cell cycle proteins

P53: chr17, G1 police (-); LGA > GBM. Gain of function mutations lead to stable protein, prevents apoptosis

MDM2: inhibits p53(+)

P21: p53 induces to cause arrest(-)

P27/kip1: G1 inhibition(-)

P16/p15: inhibit CDK4/6(-)(genes CDKN2A/B)

CDK4/CDK6: phosphorylate RB(+)

RB: phopsphorylation releases E2F allows G1>S (+)

P14ARF: alternative reading of CDKN2A; RB independent arrest(-)

Growth Factors and Receptors

EDGFR: amplified or overexpressed in primary GBM

PDGFR

DCC: lost in progression

PTEN(MMAC1): (-)

 

 


 

 

 


Migration

“Go or Grow” hypothesis: cells postmitotic before migration.

4 medulloblastoma cells lines divided while migrating (N7/03).

Factor potency: SF/HGF > TGFα > FGF1.

 

Scatter Factor (SF)/ Hepatocyte Growth Factor (HGF)

·         Receptor is MET (c-Met oncogene product)

·         Potent migratory factor

Ephrins

·         Cell-surface bound

·         Bind Eph receptor TKs

·         Regulate axon guidance, neural crest migration

 

 

Invasion

Matrix metalloproteinase inhibitors: Marimastat, prinomastat


 

Growth Factors

·         Gliomas produce PDGF (A & B), EGF, TGFα, IGF-1.

·         Receptors are tyrosine kinases

 

PDGF

·         PDGF-A,B,C,D homodimers (AA, BB, CC, DD) or heterodimer (-AB)

·         Receptors: PDGFRα (binds AA,BB,CC,AB), PDGFRß (binds BB,DD)

·         Overexpression in LGA w/ p53 loss. Expressed in almost all oligodendrogliomas.

·         Simian sarcoma virus is viral homologue of c-sis/PDGFB

·         Involved in angiogenesis

 

EGF

·         EGFR in ErbB family; also binds TGFά

o    Transmembrane glycoprotein, intracellular TyK domain

·         Neurotrophic, development, angiogenesis

·         EGFRvIII: mutation in extracellular domain leads to constituitive activation

·         May be due gene amplification, overexpression, autocrine/paracrine ligand stimulation, or constitutive activation

·         EGFR in gliomas

o    50% GBMs overexpressed/amplified (de novo GBM). 50% of these cases have mutations

o    EGFR mutation can occur without overexpression of wt-EGFR

o    EGFRvIII: most common mutant in GBM. Constitutive autophosphorylation. Oncogenic transformation in absence of ligand

·         EGFR Antagonists: N6/04

 

 

FGF

·         Acidic FGF (aFGF), basic FGF (bFGF), and FGF-3 to -23

·         4 receptors, 1-4

·         Involved in angiogenesis, neurotrophic

TGF-ß

·         Family: BMPs, Mullerian inhibiting substance

·         Receptors: I & II. Serine/Threonine kinases.

·         Released by glioma cells in vivo & in vitro.

·         Inflammation, wound healing, angiogenesis

TNFα

·         Inflammation, angiogenesis

·         Produced by monocytes/macrophages

 

Signaling Pathways

Receptor Tyrosine Kinases

·         600 protein kinases, 130 protein phosphatases. Kinases are commonly in oncogenic pathways

·         Frequent Alterations in Cancer:

         Genomic rearrangements (e.g. Bcr-Abl, EGFR)

         Mutation (e.g. Flt-3, c-Kit, c-Met)

         Overexpression (e.g. EGFR, VEGFR, c-Met)

·         Composed of: Extracellular ligand-binding domain, membranous domain, intracellular domain with intrinsic tyrosine kinase activity

·         Ras > Raf > Mek > MAPK

o    Most RTKs. Needs assistance of scaffolding proteins.

o    Ras inactiviating gene neurofibromin mutated in NF1;

·         PI-3 Kinase (PIP2 > PIP3) > PDK1/2 > Akt

o    Used by EGFR

o    PTEN inhibits PI3K

o    Akt inhibits apoptosis, stimulates cell growth & proliferation

·         PLC-γ (PIP2 > IP3 & DAG)

o    Used by EGFR

·         STATs

o    EGFR activates STAT1,3, & 5

o    STAT1 proapoptotic, antimitotic; STAT3 antiapoptotic, promitotic

·         Mitogen-activated protein kinase

·         Cause DNA synthesis and cell division

·         RTK inhibitors:

o    Herceptin, HER-2 antibody (to extracellular domain). Approved for breast cancer – 15% response rate.

Hesselager N903

 

·         Inhibitors of tyrosine kinase activity: Iressa, Tarceva – EGFR; Gleevec – PDGFR (in clinical trials for GBM)

 

        

Cell Cycle

·         INK4A-ARF locus codes for p16 & p14 suppressors. Deleted/ inactivated in 60% of GBM.

·         p53: on Chr17

·         Rb: inhibited by SV40 T antigen T121.

·         MYC: transcription factor leading to cell proliferation, Amplified in some medulloblastomas.

 

Ubiquitin-Proteosome Pathway

Proteosome inhibitor PS-341

 

Apoptosis

 

Telomerase

Ribonucleoprotein enzyme that replicates telomeric DNA. Reactivated in some cancers, including GBM.

hTERT: human telomerase reverse transcriptase. May predict prognosis.

 

 

 

Sonic Hedgehog

Receptor: Patched (PTCH)

Gli – downstream effectors

Mutated in minority of gliomas


 

Angiogenesis

·          Reviews: ”Angiogenesis in  Nervous System Disorders” Zadeh G N12/03, “Angiogenesis and GliomasJouanneau E N1/08

·         Vasculogenesis: new blood vessel formation (embryonic).

Angiogenesis: New branches formed off existing vessels (tumors, etc)

·         Glioma angiogenesis: VEGF (primary), SF/HGF, bFGF most important

·         Edema: VEGF & angiopoietins

 

VEGF

·         endothelium specific angiogenic factors.

·         5 homologues (B,C,D,E, and placenta growth factor PlGF).

·         Receptors: VEGFR-1, VEGFR-2, neuropilin-1 (Nrp-1)

·         Promotes NO synthesis, vascular permeability, proteases. May be responsible for edema.

·         VEGF in gliomas:

o    VEGF is expressed in human high-grade glioma but not in normal brain

o    VEGF receptors are expressed only on endothelial cells

o    Increased expression of VEGF, and VEGF receptors correlates with tumor vascularity and malignancy grade in human gliomas

o    Upregulation of VEGF is associated with areas of necrosis

o    High proliferation rate of malignant glioma may lead to areas of necrosis and hypoxia and result in increased expression of VEGF

 

Angiopoietins

·         Ang-1 to 4. Ligands for Tie-2, endothelium specific tyrosine kinase receptor.

 

Endostatin/angiostatin: Inhibit angiogenesis

Also thrombospondin 1 & 2, platelet factor-4

 

Therapy: VEGF antisense, Thalidomide: inhibits endothelial cell proliferation, Fumagillin, angiostatin, endostatin, COX2 inhibitors (Celecoxib), Topotecan (VEGF antagonist)

 

Angiogenesis N12/03


 

Immunotherapy

Tumor Associated Antigens

·         Gliomas have been shown to express several tumor associated antigens (TAAs): EGFRIII, glycoprotein 240, tenascin, survivin, squamous cell carcinoma–associated reactive antigen for cytotoxic T cells 1, α-2 chain of interleukin-13 receptor, and melanoma-associated antigens, such as tyrosinase, tyrosinase-related protein 1 and 2, glycoprotein 100, melanoma antigen-1, and melanoma antigen-3.

·         Identification of a universally expressed glioma TAA has not been identified. Tumor cell clones that do not express the particular, targeted TAA (anymore) escape from the immune rejection and, thus, have an important proliferation advantage.

 

Types of Immunotherapy:

Cellular

·         Antigen Presenting Cells (APCs) present antigens to T-cells via MHC

·         MHC not detected in CNS

Cytokines

·         TNFά, IL-2, IL-4, INF-άßγ.

·         No clear survival improvement when administered to GBM patients. IL-2 & INFά showed significant toxicity.

Adoptive

·         Intratumoral injection of peripherally harvested lymphocytes or TILs (tumor infiltrating lymphocytes), stimulated ex vivo with IL-2

·         No definite survival benefit

·         Human, non-MHC restricted, cytotoxic T-cell leukemic cell lines (TALL-104) – cytotoxic against tumors, spares normal tissue

·         Stimulation of autologous lymphocytes with patient’s tumor cells

Passive

·         Intratumoral administration of antibodies leading to cytotoxicity, or conjugated to toxin or radioisotope

  • Antigens: tenascin, EGFR, EGFRvIII (Mab806), IL-4, transferrin receptor (no glioma specific antigens identified yet)
  • Toxins: Pseudomonas, Diptheria
  • Radioisotopes: I131

·         Ex: I131 conjugated anti-tenascin, in Phase II trials

·         IL-4 conjugated to pseudomonas exotoxin, delivered by convection-enhanced delivery in Phase I trials.

·         IL-13 also used.

The types of vaccines listed below represent various methods investigators have devised for presenting cancer antigens to the body's immune system. This list is not meant to be comprehensive.

Antigen/adjuvant vaccines
Antigen vaccines were some of the first cancer vaccines investigated. Antigen vaccines commonly use specific protein fragments, or peptides, to stimulate the immune system to fight tumor cells. One or more cancer cell antigens are combined with a substance that causes an immune response, known as an adjuvant. A cancer patient is vaccinated with this mixture. It is expected that the immune system, in responding to the antigen-carrying adjuvant, will also respond to tumor cells that express that antigen.

Whole cell tumor vaccines
Taken either from the patient's own tumor (autologous) or tumor cells from one or more other patients (allogeneic), these whole cell vaccine preparations contain cancer antigens that are used to stimulate an immune response.

Dendritic cell (DC) vaccines
Specialized white blood cells, known as dendritic cells (DCs), are taken from a patient's blood through a process called leukapheresis. In the laboratory, the DCs are stimulated with the patient's own cancer antigens, grown in petri dishes, and re-injected into the patient. Once injected, DC vaccines activate the immune system's T cells. Activation by DCs is expected to cause T cells to multiply and attack tumor cells that express that antigen.

·         DCVax®-Brain (Northwest Biotherapeutics) is a personalized dendritic cell vaccine for treatment of newly diagnosed Glioblastoma multiforme, which is entering a large Phase II clinical trial

o    Clinical trial data to date in brain cancer patients have shown that DCVax(R)-Brain delays disease recurrence by nearly 3-fold, from 6.9 months to 18.1 months for newly diagnosed patients. DCVax(R)-Brain also extends these patients' survival from 14.6 months to more than 33 months (and continuing -- median not yet reached). In parallel with making DCVax(R)-Brain commercially available to patients at selected medical centers in Switzerland, NWBT is also conducting a Phase II pivotal trial in 141 patients in the US. The trial began enrolling patients in 2006, and is anticipated to conclude around the end of 2008. The Company plans to seek product approval in both the US and EU in early 2009, based upon the results of the Phase II pivotal trial. – Company Press Release  7/8/07

Viral vectors and DNA vaccines
Viral vectors and DNA vaccines use the nucleic acid sequence of the tumor antigen to produce the cancer antigen proteins. The DNA containing the gene for a specific cancer antigen is manipulated in the laboratory so that it will be taken up and processed by immune cells called antigen-presenting cells (APCs). The APC cells then display part of the antigen together with another molecule on the cell surface. The hope is that when these antigen-expressing APC cells are injected into a person, the immune system will respond by attacking not only the APC cells, but also tumor cells containing the same antigen. Vector-based and DNA vaccines are attractive because they are easier to manufacture than some other vaccines.

Idiotype vaccines
Because antibodies contain proteins and carbohydrates, they can themselves act as antigens and induce an antibody response. Antibodies produced by certain cancer cells (i.e., B-cell lymphomas and myelomas), called idiotype antibodies, are unique to each patient and can be used to trigger an immune response in a manner similar to antigen vaccines.

 

·         Dendritic Cell Vaccination: See deVleeschouwer N11/06

·         As opposed to the other antigen-presenting cells, DCs are able to present antigens in both MHC Class II and I molecules. In this way, they can prime both CD4- T helper cells and CD8- cytotoxic T-cells

 

·         The glycosphingolipid GD2, a disialoganglioside normally on the cell membranes of neurons, is expressed on the surfaces of a wide range of tumor cells including neuroblastoma, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas

 


 

Tumor Cell Lines

·         Glioma cells in culture lose GFAP, acquire fibronectin, become fibroblast-like (spindle-shaped)

·         9 of 68 GBM and 1 of 19 Grade 1-2 astrocytomas GFAP (+)

·         Formalin-fixed, parafin-embedded sections suboptimal for staining most tumor antigens

·         Better to use fresh cells  through flourescence-activated cell sorter (or staining freshly frozen samples) (Linskey 1997)

·         Animal serum does not reflect true environment, better to use astro-CM

 

 

Tumor Modeling

Transplantation

·         Cultured human (xenograft) or rodent (allograft) tumor cells implanted into immunodeficient mice

·         Reproducible, but not infiltrative, cultured cells genetically altered

 

Chemical mutagenesis

 

Transgenic Mice

·         Gain-of-function (transgenic mice) or loss-of-function (targeted deletions)

·         Germ-line mutations: Requires cross-breeding. Expensive

·         Conditional models: Somatic cell gene transfer with retroviral vectors

o    MMLV: replication competent, infects proliferating cells

o    Tv-a-RCAS:

§  RCAS: avian-leukosis virus based vector, contains oncogene. ALV is a replication deficient retrovirus

§  tv-a: The RCAS receptor, which is inserted after a specific promoter (eg nestin, GFAP) in transgenic mice.

§  Allows for tissue or cell-specific transfection. The RCAS vector is injected into transgenic mouse and transfects cells targeted by the promoter (i.e. GFAP+) and leads to protein production in only those cells.

§  Can only produce proteins, not delete them (but can produce inhibitors – i.e. SV40 T121 & Rb).

§  N-tv-a mice crossbred with Ef-luc mice to create fluorescent mouse tumor models (N1/05)

·         Knockout rats (N8/03)

 

Signal Transduction Pathways

·         Transduction of  PDGF-B by a replication-competent vector (MMLV) causes formation of variety of tumor types, including GBM

·         Transduction of PDGF-B by replication-incompetent vector (ALV) into nestin (+) CNS progenitors causes formation of oligodendrogliomas.  Transduction into astrocytes forms mixed gliomas.

·         Transgenic mice expressing v-erbB (EFRR homologue) from S-100B promoter (astrocytes & glial precursors) form oligodendrogliomas.

·         In RCAS-TVA system, transfer of EGFR does not form gliomas unless combined with cell cycle disruption.

·         Overexpression of RAS from GFAP promoter induces GBM

·         Overexpression of v-Src from GFAP promoter induces astrocytomas

·         Germline RAS or v-Src overexpression has normal development, develop gliomas by secondary mutation

·         Combined activation of K-RAS and AKT pathways sufficient for GBM formation in nestin (+) progenitors

·         Either alone is insufficient

·         RAS+AKT in differentiated astrocytes does not form gliomas

·         Mutation in cell cycle genes did not increase gliomagenesis

Cell cycle disruption

·         INK4A-ARF -/- mice do not develop gliomas

·         Requires RAS+AKT mutation

·         p53 -/- mice rarely give rise to gliomas (most die of lymphomas or sarcomas early)

·         p53+Nf1 deletion induces GBM

·         NF1 inactivates RAS

·         Deletion of p53 or Rb in GFAP (+) cells do not develop gliomas

·         Disruption of either cell cycle pathway itself weak oncogenic factor, insufficient for gliomagenesis

·         Mutations in cell cycle pathways do appear to be sufficient for tumor progression

·         Increased malignancy and shortened survival seen in Ink4a-Arf -/- mice compared to normal in S100B-v-erbB and PDGF models

Cooperation between cell cycle and signal transduction pathways

·         RAS+AKT in INK4A-ARF -/- mice forms gliomas

·         p53 + NF1 mutations

 


Delivery

 

Convection Enhanced Delivery (CED, Clysis)

·         Therapeutic agents are delivered through catheters driven by pumps. The agents diffuse through the surrounding brain.

·         Multiple agents, icluding liposomes, viral vectors, radioactive ligands, and toxic ligands are under investigation for use with CED.

·         Cintredekin besudotox (IL13-PE38QQR) (NeoPharm Inc.) is IL-13 fused to Pseudomonas exotoxin which binds selectively to interleukin-13R2) receptors overexpressed by malignant gliomas. Delivered via CED.  Vogelbaum MA N11/07

·         Two randomized trials (Precise and TransMID) failed to show a benefit of CED over standard therapy.

 

 

Bioreactors

·         20-800μm

·         Capsule: Alginate

·         Cells: primary postmitotic, immortalized pheochromocytoma P-12, fibroblasts (baby hamster kidney)

·         Immunoprivledged

·         Used to deliver endostatin in rat & mouse glioma models (Joki 2001); disappointing Phase I results

 

 

Tumor Staining

·         Fluorescein Sodium – IV, with or without microscope fluorescent filter

·         5-aminolevulinic acid – metabolized to protoporphyrin IX by tumor enzymes – requires fluorescent filter

 

 

BBB Disruption

·         Mannitol, RMP-7

·         Blood-Brain Barrier: N1/04.

 

 

Bioinformatics

·         The National Cancer Institute's Molecular Targets Development Program (MTDP) to identify and evaluate molecular targets that may be candidates for drug development

 

 

Monoclonal Antibodies

 

 

RNAi

 

 

Miscellaneous

·          Annexin VII: Chr 10q21. Stronger predictor of GBM survival than any other variable (JN11/03)

·         Proteomics: see Jagannathan J N1/09

 

Gene Therapy Primer Chiocca EA N8/03

Advanced Cancer Genetics N11/03

Induction Neurogenesis: N1/04.

Cell cycle: N3/04

RTK N5/04 (N9)

 

Gene Therapy:

mAbs, immunotoxin conjugates, antisense oligonucleotides, ribozymes

 

12 genes amplified in GBM: EGFR, cyclin-dependent kinase 4, murine double minute 2, sarcoma-associated sequence.

Molecular Genetic Imaging

·         Brahma-related gene-1 (Brg-1) negative mutants resulted in the development of embryos with smaller brains containing neurons but virtually no glial cells. When they isolated neural stem cells, placed them into cell culture and then removed Brg1, the cells in the culture turned into neurons but failed to differentiate into glia. (Larry Sherman Developmental Biology)

Meningiomas

See Neurologist 10:3 5/04.

 

Medulloblastoma

·         Developmentally Regulated Genes in Medulloblastoma (Yokoto 04): Unc33 Like Protein (ULIP), SOX4, OTX2, Neurnatin

·         Medulloblastomas mutated at 17p distal to TP53 – unknown gene.

 

 

 


Neuroregeneration and Stem Cells

 

Stem Cells

 

·         Glial Derived Neurotrophic Factor (GDNF) infused by clysis into putamen in Parkinsons pts 39% improvement in UPDRS (N8/03)

 

Reviews:

·         Barami K N9/00.

·         Tator C N11/06.

·         Farin A N1/09 – Foundations and Landmarks in Stem Cell Biology

 

Human Marrow Stromal Cells (hMSCs).

·         Secrete growth factors. Used in TBI, CVA.

 

Human SVZ

·         Thin ribbon multipotiential astrocytes, no RMS, no migratory neuroblasts (Sanai, Nature 427:740, N4/04)

 

Stem Cell plasticity: N8/03

 

\

 

 

Cancer Stem Cell Pathways

·          Bmi-1: The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphomaand later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells. The pathway appears to be active in cancer stem cells of pediatric brain tumors

·         Notch: The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including haematopoietic, neural and mammary stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors.

·         Sonic hedgehog and Wnt: These developmental pathways are also strongly implicated as stem cell regulators. Both Sonic hedgehog(SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand. This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt

 

 

Other Spinal Cord Injury Research

·         Biodegradable Polymer Grafts – act as conduit and for release of therapeutic agents. Friedman JA N9/02

·         Oscillating Field Stimulation Shapiro S JNS1/05

 

 

Parkinson’s Disease Transplantation Research

·         Carotid Body Cell Aggregate Transplantation (Arjone V N8/03)

 

 

RNA Interference

 

·         

 

Neurotechnology

 

Neuroprosthetics

·         Also known as brain-machine interface, brain-computer interface, or neurorobotics

·         Motor neuroprosthetics are machines that recognize electrophysiological alterations in the brain representing motor intention and translate these neural signals into extant activity to control an external device.

·         The most successful neuroprosthetic to date has been the cochlear implant, used now by over 100,000 patients.

·         Receiving devices, in order of spatial and temporal resolution include EEG, electrocorticography, or single-unit electrodes.

·         The Braingate 100-electrode array (below) has been implanted in a human patient (Hochberg Nature 2006, N10/06). Manufactured by Cyberkinetics

·         Review: Leuthardt EC N7/06

  

 

·         Micromachines and Microelectromechanical Systems: see Roy S N10/01 

 

 

 

Nanotechnology

·         “Neurosurgery in the realm of 10-9Elder JB N1/08

 

 

 


Vasospasm

·         Endothelin receptor antagonists: see Chow M N12/02

 

 

Psychosurgery

·         History: Heller N10/06

 

 

                  

Experimental TBI Treatment

·         Aminosteroids: There is no evidence to support the routine use of aminosteroids in the management of traumatic head injury. On the basis of the existing evidence from randomized trials of aminosteroids in head injury, it is not possible to refute the possibility of moderate but potentially clinically important benefits or harms. A further randomized controlled trial of tirilazad mesylate with 1156 participants has been completed, the results of which should become available in the near future. (Cochrane Database)

·         Calcium Channel Blockers: The authors found six eligible trials involving 1862 patients. The results indicate that there is insufficient evidence to support the use of calcium channel blockers. (Cochrane Database)

·         Excitatory Amino Acid Inhibitors: The case for efficacy of excitatory amino acid inhibitor therapy remains unproven. To date, no product has proven to be efficacious for improving the outcomes of brain-injured patients. Early termination, unpublished, and underpowered studies limit a clear appreciation of the merits of this form of intervention. Additional studies, some of which remain in progress, may more clearly define the efficacy and effectiveness issues. (Cochrane Database)

·         Hyperbaric Oxygen: In people with traumatic brain injury, the addition of HBOT significantly reduced the risk of death. Pooled data from the three trials with 327 patients that reported mortality, showed a significant reduction in the risk of dying when HBOT was added to the treatment regimen. However, there is little evidence that more survivors have a good outcome. There was a trend towards, but no significant increase in, the chance of a favourable outcome when defined as full recovery, Glasgow outcome score 1 or 2, or return to normal activities of daily living.  In two trials there was a reported incidence of 13% for significant pulmonary impairment in the group receiving HBOT versus 0% in the non-HBOT group. The routine application of HBOT to these patients cannot be justified from this review. In view of the modest number of patients, methodological shortcomings and poor reporting, this result should be interpreted cautiously. (Cochrane Database)

·         Hypothermia: There is no evidence that hypothermia is beneficial in the treatment of head injury. The earlier, encouraging, trial results have not been repeated in larger trials. The reasons for this are unclear. Hypothermia increases the risk of pneumonia and has other potentially harmful side-effects. Therefore, it would seem inappropriate to use this intervention outside of controlled trials (Cochrane Database)

·         Magnesium: There is currently no evidence to support the use of magnesium salts in patients with acute traumatic brain injury. (Cochrane Database)

·         Monoaminergic Agonists: The authors found three trials but none of these looked exclusively at patients with a severe brain injury, therefore there were no satisfactory studies of the effectiveness of monoaminergic agonists for severe TBI. Consequently, there is, at present, insufficient evidence to support the routine use of MAAs to promote recovery from TBI. (Cochrane Database)

Sequelae:

·         Coma: About half of people in a coma because of traumatic brain injury will wake within a year of the accident. Sensory stimulation methods vary greatly, from one or two hourly sessions of a day, through to shorter sessions every hour for 12 to 14 hours a day. The review found there is no strong evidence to determine whether sensory stimulation benefits people in comas. (Cochrane Database)

 

·         Reviews: Marshall LF N9/00

 

 

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Revised 6/1/09

Text Copyright 2009