e Real Heart of the Matter Neurology Newsletter COLLEGE OF MEDICINE CALIFORNIA NORTHSTATE UNIVERSITY June, 2016 From the President 1 Visions of Disease 2 erapeutic Hypothermia in Stroke Management 3 e Heart and the Brain, CNU Edition 7 Vascular Dementia 8 Etanercept: An Alternative Treatment for Stroke 9 Letter From the Editor 10 From the President: To the Neurites—Cheers to a successful first year of the CNU- COM Student Interest Group in Neurology. These newsletters, our inau- gural Brain Day and all the articles and studies we have swapped since the group’s inception are a testament to your dedication to our interest in neuroscience and the school’s reputation in the broader medical com- munity and our own. I sincerely thank you all. I would now like to invite our readers to enjoy our last newsletter of the school year, before our SIGN parts ways for two months to en- joy the proverbial “last summer” of medical school. Because we are in the cardiology block, the theme of this issue is on the cerebrovascula- ture. As a PhD student in the lab of a neurosurgeon who specialized in treating skull-base aneurysms (areas of weakness within the wall of an artery leading to a ballooning effect and making the artery more prone to serious rupture), I came to appreciate the complexity of this system. He would famously remark, at least to my awe-inspired ears, that I could take the cerebrovasculature from Loma Linda to San Francisco—all 500 miles of it. Well, here I am—pretty close, so thank you Dr. Wolff Kirsch. He also suggested to me that the smooth muscle cells that make up the walls of the arterial system of the brain are probably smarter than the neurons that do our thinking and that when those smooth muscle cells are destroyed, the brain—and its neurons—shrink under the crushing pressure of dementia. Fittingly then, Salil Babbar has provided you with an article on the specifics of Vascular dementia—an entity similar to and at one time compared to Alzheimer’s disease. Mohammad Aziz has ad- ditionally contributed an article on the controversial effects of hypother- mia treatment on stroke outcomes with commentary by Dr. Forshing Lui. Lastly, Nancy Li has graced you again with a humorous “neurocomic”, Page 1
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The Real Heart of the Matter
Neurology NewsletterCOLLEGE OF MEDICINE
CALIFORNIA NORTHSTATE UNIVERSITY
June, 2016
From the President 1
Visions of Disease 2
Therapeutic Hypothermia in Stroke Management 3
The Heart and the Brain, CNU Edition 7
Vascular Dementia 8
Etanercept: An Alternative Treatment for Stroke 9
Letter From the Editor 10
From the President: TotheNeurites—CheerstoasuccessfulfirstyearoftheCNU-COMStudentInterestGroupinNeurology.Thesenewsletters,ourinau-guralBrainDayandallthearticlesandstudieswehaveswappedsincethegroup’sinceptionareatestamenttoyourdedicationtoourinterestinneuroscienceandtheschool’sreputationinthebroadermedicalcom-munityandourown.Isincerelythankyouall. Iwouldnowliketoinviteourreaderstoenjoyourlastnewsletteroftheschoolyear,beforeourSIGNpartswaysfortwomonthstoen-joytheproverbial“lastsummer”ofmedicalschool.Becauseweareinthecardiologyblock,thethemeofthisissueisonthecerebrovascula-ture.AsaPhDstudentinthelabofaneurosurgeonwhospecializedintreatingskull-baseaneurysms(areasofweaknesswithinthewallofanarteryleadingtoaballooningeffectandmakingthearterymorepronetoseriousrupture),Icametoappreciatethecomplexityofthissystem.Hewouldfamouslyremark,atleasttomyawe-inspiredears,thatIcouldtakethecerebrovasculaturefromLomaLindatoSanFrancisco—all500milesofit.Well,hereIam—prettyclose,sothankyouDr.WolffKirsch.Healsosuggestedtomethatthesmoothmusclecellsthatmakeupthewallsofthearterialsystemofthebrainareprobablysmarterthantheneuronsthatdoourthinkingandthatwhenthosesmoothmusclecellsaredestroyed,thebrain—anditsneurons—shrinkunderthecrushingpressureofdementia.Fittinglythen,SalilBabbarhasprovidedyouwithanarticleonthespecificsofVasculardementia—anentitysimilartoandatonetimecomparedtoAlzheimer’sdisease.MohammadAzizhasad-ditionallycontributedanarticleonthecontroversialeffectsofhypother-miatreatmentonstrokeoutcomeswithcommentarybyDr.ForshingLui.Lastly,NancyLihasgracedyouagainwithahumorous“neurocomic”,
Page 1
“Vascular dementia is easily preventable if
detected and diagnosed early on, so it’s essential
for clinicians to be able to recognize all the various signs and symptoms of
visions of diseaseAnx-ray,culture,CT,evenMRI,Allofthesehinttowhere,how,andwhatwentawry.Isithisnose,theleftear,orwasitmid-thigh?Nono,itwasTrachomathatlefthimone-eyed.
Claude Monet painted “Waterlilly Pond,” in 1899. His vision problems
with cataracts didn’t begin until 1912.
A recent photograph of the bridge.
Current photograph of the same bridge, blurred as it might appear to someone with a moderate cataract.
Details from William Utermohlen’s self-por-traits, the first, made in 1967, the rest from 1996 the year following his diagnosis of Alzheimer’s disease, to 2000, charting his decline. Courtesy of the artist’s estate and GVArt Gallery, London
Oil paint; Dance Class at the Opera, 1872 by Edgar Degas.
Pastels; Ballet Dancers in the Wings, 1900 by Edgar Degas
“Stroke is the fifth lead-ing cause of death in the United States account-ing for one in every 20
deaths. ”
“Two randomized con-trolled trials published in the New England Jour-nal of Medicine in 2002 showed neuroprotective effects of therapeutic
hypothermia”
Page 4
Therapeutic Hypothermia in Stroke Management
StrokeisthefifthleadingcauseofdeathintheUnitedStatesaccountingforoneinevery20deaths.Thevastmajorityofstrokesareischemic(87%)andtheirmanagementrangesfromthrombolyticthera-pytosymptomaticmanagement.Therapyisdirectedatreducingneurondeathduetoischemiaorsubsequentreperfusion.Anewerapproachtocombattingneuronallossistherapeutichypothermia.Therapeutichy-pothermiahasbeenimplementedintothestandardofcareforcardiacarrestpatientsbytheAmericanHeartAssociation,however,itsuseinstrokemanagementremainsmuchmorecontroversial. Cardiacarrestresultsinglobalcerebralischemiaandchancesofreperfusioninjuryareimplicatedinneurologicaldecline.Tworandom-izedcontrolledtrialspublishedintheNewEnglandJournalofMedicinein2002showedneuroprotectiveeffectsoftherapeutichypothermia(32oC-34oC)incomatosepatientsafterout-of-hospitalventricularfibril-lationcardiacarrestwithin2hoursofreturnofspontaneouscirculationandmaintainedfor12-24hours(Kirkmanetal.,2014).Conversely,acuteischemicstrokedoesnotalwaysresultinglobalcerebralisch-emia.Localizedbraininfarctsmaybenefitfromtherapeutichypothermiaattheriskofcompromisingmetabolismincompetentregions.Further-more,returnofcirculationfollowingcardiacarrestistypicallyassociatedwithaccompanyingcerebralreperfusion.Instroke,theaffectedvesselmayremainoccludedfordays,orindefinitely,whichenhancesthesideeffectsofcoolingonotherpartsofthebody.Lastly,unlikecardiacarrestpatients,thoseundergoingacuteischemicstrokearenotusuallycoma-toseorendotracheallyintubatedandriskofshiveringandotherdiscom-fortpresentsanotherchallengefortreatment(Midorietal.,2010).Giventhesetrade-offs,currentclinicalapplicationtakesadvantageofthera-peutichypothermiainsymptomaticmanagementtolowerintracranialpressureandhypertensionwhileclinicaltrialsaregearedatoptimizingprotocolstoextractthemosttherapeuticbenefit. Themechanismsunderlyingtheneuroprotectiveeffectsofther-apeutichypothermiainstrokemanagement,aswellasitsassociatedcomplicationsandproposedmethodsofaccomplishingoptimumtherapywillbediscussedherein.Injury Following an ischemic event Adequatebloodflowdeliversoxygenandglucosetothebraininordertomaintainitsnormalfunction.Normalfunctionrequirestheinteg-rityofionicgradientsmaintainedbytransmembranechannels.Followinganacuteischemicevent,ionichomeostasisisdisrupted,whichleadstoaninfluxofcalciumandtheexcitatoryneurotransmitter,glutamate.Glutamateinducedexcitotoxicityleadstogenerationofreactiveoxygenspecies(ROS)andnitricoxide(NO)thatinduceapoptosisbydamagingcellstructures.Progressivecelldamageleadstodissipationofiongradi-entsestablishedacrossthecellmembrane,whichfurthercontributestoosmoticchangesthatresultincerebraledema.
-Mohammad AzizMS1, CNUCOM
“A 1o C drop in body tem-perature translates into a 6%-7% reduction in
cerebral metabolic rate ”
Neuroprotective Effects,A Multi-pronged Ap-
proach:
1) Decreasing cerebral metabolic demand
2) Modulatory on Glutumate
3) Inhibit Mitochondrial Apoptosis
4) Decrease Reperfusion Injury
Page 5
Cerebraledemacanprogresstoincreasedintracranialpressure(ICP)whichthreatenstocompressvitalstructuresandeventuallyher-niate.Inaddition,anoxiacausesmetabolicalterationswithelevatedlactateleadingtoacidosis.Thelocationandextentofthesechangesaredependentonthenatureofischemiawhichincludeslocation,metabolicdemandandlevelofcollateralbloodsupply.Neuroprotective effects of Hypothermia Cerebralmetabolicrateisdependentontemperature.A1o C dropinbodytemperaturetranslatesintoa6%-7%reductionincerebralmetabolicrate(Polderman,2009).Decreasingcerebralmetabolicratereducesutilizationofoxygenandglucose.Thislessenstheextentofanoxicinjuryfrommetabolicacidosisandlessexcitotoxicitybyloweringmetabolicdemand.Inadditiontoitseffectsintheimmediatestagesofacutestoke,therapeutichypothermiacanlowertheriskofreperfusioninjurybydecreasinginflammationcausedbytheresurgenceinbloodflow. Inearlyglutamateinducedexcitotoxicity,thereisaprotectivefunctionservedbynearbyastrocyteswhichuptakeglutamateviatheGLT-1transporter.Inprolongedischemia,however,thisfunctionrevers-esasinjurytoastrocytesbecomesmorepronounced.TheregurgitationofglutamateunleashesaheavyburdenontheneuronresultinginapotentinflammatoryresponsewithmoreROSrelease.Onelaborato-rystudyshowedareductioninNMDAreceptorphosphorylationandincreaseinGLT-1transporterinastrocytesinnewbornpigletswithinducedhypoxic-ischemicinjuryfollowedbytherapeutichypothermia(Wangetal.,2013). Therapeutichypothermiahasalsobeenshowntoinhibitintrinsic(mitochondrialbased)apoptosisbyloweringpro-apoptoticBCL-2fam-ilymemberssuchasBCL-2associatedX(BAX)andupregulatingan-ti-apoptoticproteinBcl-2,inhibitingcytochromecreleaseandcaspaseactivation(Fukudaetal.,2001,Phanithietal.,2000,Yenarietal.,2002andZhangetal.,2001).Furthermore,thetherapycanpreventendo-plasmicreticulumstressapoptosisthroughsuppressingC-EBP-homolo-gousprotein(CHOP)(Liuetal.,2013). Reperfusionmediatesinjurythroughprovidingoxygenforpro-ox-idantenzymessuchasNADPHoxidasetochurnoutmoreROS(Tangetal.,2011).Thisleadstodisruptionsinthebloodbrainbarrierwhichcanleadtohemorrhage.Hypothermiacanreducethisinflammationandlowertheriskofhemorrhage. Thereareothermechanismsofneuroprotectionmediatedbytherapeutichypothermiathataidneuronalrecoverypostischemia.Theselargelystemfromthepreservationofneuronalfunctionduringtheinitialischemicinsultbypacifyingtheinflammatoryresponseandlimitingdamagetothebraininfrastructure.Complications Thereareconsequencestodepressingthebody’snaturalinflam-matoryresponse;mainlyapropensityfordevelopinginfection.Uptoonethirdofischemicstrokepatientsdevelopinfection(Emsleyand
“There are consequences to depressing the body’s natural inflammatory re-sponse; mainly a propen-sity for developing infec-tion. Up to one third of ischemic stroke patients
develop infection”
“Therapeutic Hypother-mia is a controversial
intervention in the man-agement of acute ischemic stroke... Going forward, research is increasingly
directed towards clinical practice in order to attain
the greatest efficacy of treatment.”
Page 6
Hopkins,2008andMeiseletal.,2005).Asbodytemperatureisloweredto32oC,heartrateisloweredto40-45beats/min(BernardandBuist,2003,DeGeorgiaetal.,2004andStaikouetal.,2011).Cardiaccompli-cationsduetodecreasedheartrateincludeloweredmeanarterialpres-sureandcardiacoutput,arrhythmiasandmyocardialinfarction.Hema-tologically,thecoagulationcascadeisinducedintemperatureslessthan35oC(Polderman,2009).Thisischallengingconsideringstrokeitselfisacoagulation-fibrinolysisdisorder.Othercomplicationsincludeelectro-lytedisorder,hyperglycemia,insulinresistance,colddiuresis,andboweldisorders(Ziplingetal.,2015).Methods of Inducing hypothermia Unliketherapeutichypothermiaforcardiacarrest,therearenosetguidelinesforitsuseinthemanagementofacutestroke.Implementa-tioniscase-dependentandclinicaloutcomeshavenotbeenconsistent.Muchconsiderationisneededtodeterminethetemperatureatwhichtoinducehypothermiaandthedurationoftherapy.Earlyhypothermiawithalongercourseistypicallyassociatedwithbetteroutcomes.Mostinter-ventionshoverintheneighborhoodof32oC-35oC(Ziplingetal.,2015).Rewarmingisperformedslowly,payingcloseattentiontomarkerslikeintracranialpressure.Intermsoflocation,therapycanbelocalizedtothebrainortheentirebody.Optionsareavailableforintra-arterialcoolingandpharmacologicalcoolingaswell.Conclusion TherapeuticHypothermiaisacontroversialinterventioninthemanagementofacuteischemicstroke.Laboratorystudieswithanimalshaveproducedmuchmorepromisingresultsthanclinicalapplication.Currently,ithasbeenusedinconjunctionwithothertacticslikethrombo-lytics,mechanicalthrombectomy,hemicraniectomy,andotherpharma-cologicaltherapytolimitbraininjury.Goingforward,researchisincreas-inglydirectedtowardsclinicalpracticeinordertoattainthegreatestefficacyoftreatment.
Letter from the editorReadersofNeuroNewsletter, Iwouldliketopersonallyandsincerelythankyouforyourtimereadingthewonderfulnewsletteryouhavebeforeyou.WeweregladtosharewithyouNeuroNewsletters’educationalandentertainingcontent.Thisisourlastnewsletterfortheinaugural2015-2016schoolyear.WewillberestartingthenewsletterinSeptember,2016,andhopefullyshow-casepiecesfromournewclassof2020! Iwouldalsoliketothankthewritersthathavesubmittedanarticleforournewsletter.Itgoeswithoutsayingthatnoneofthiswouldhavebeenpossiblewithoutyourcontributions.Myhopeisthatthisexpe-riencehasbeenbothadevelopingadventureaswellasavehicletodisplayyourwonderfulwritingability.Ifirmlybelievethatthepeoplewhohavesentinarticlesarewellontheirwaytobecomingtalentedwriters,andviatheirstoriesoursocietywillfurtherprogresstoshedlightontheunknown. Theyearof2016bringswithitthestartofthesecondyearofourinauguralclasshereatCaliforniaNorthstateUniveristy,CollegeofMedi-cine,andwithitweareonestepfurtherinourpersonaldevelopmentasphysicians.Ourholisticapproachseekstoadvancenotonlyourmed-icalknowledge,butalsoourpersonality,perspective,andouraptitudeforlife-longlearning.Awonderfulmentorhasoncetoldme,“IfIhadtonameonethingthatmakesagoodphysician...itwouldbetohaveaninquisitivemind...tohaveaninsatiablethirstforknowledge,andperpet-uallyworktoseekoutanswers.”Ihopethatwe,asfuturephysicians,cantakethistoheart,andNeuroNewslettercanbeasmallcoginthemachineaswebecomethebestcitizensonearththatwecanbe.
-TrevorTsay
Neurology Newsletter, a monthly newsletter published by students in the Student Interest Group in Neurology (SIGN) at California Northstate University, College of Medicine (CNUCOM) is meant to bring abreast information in the ever changing field of neuroscience to ultimately provide our patients with excellent medical care and top-notch patient education. Our website can be found at http://cnu-comorgs.wix.com/student-groups . All correspondence should be e-mailed to [email protected]. Chief Editor: Trevor Joel TsayAssistant Editor: Rainy Dae ZhangFaculty Advisor: For-Shing Lui, MD, MRCP(UK), FRCP(Edinburg)