HANDBOOK OF CLINICAL NEUROLOGY Series Editors MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 126 EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2014 ELSEVIERB.V. Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK 225WymanStreet,Waltham,MA02451,USA ©2014,ElsevierB.V.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical, includingphotocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwriting fromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissions policiesandourarrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthan asmaybenotedherein). 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ThePublisher PrintedinChina The Publisher's CommissioningEditor:MicaHaley policy is to use DevelopmentEditor:MichaelParkinson paper manufactured from sustainable forests ProjectManager:SujathaThirugnanaSambandam Designer/DesignDirection:AlanStudholme HandbookofClinicalNeurology3rdSeries Availabletitles Vol.79,Thehumanhypothalamus:basicandclinicalaspects,PartI,D.F.SwaabISBN9780444513571 Vol.80,Thehumanhypothalamus:basicandclinicalaspects,PartII,D.F.SwaabISBN9780444514905 Vol.81,Pain,F.CerveroandT.S.Jensen,eds.ISBN9780444519016 Vol.82,Motorneuronedisordersandrelateddiseases,A.A.EisenandP.J.Shaw,eds.ISBN9780444518941 Vol.83,Parkinson’sdiseaseandrelateddisorders,PartI,W.C.KollerandE.Melamed,eds.ISBN9780444519009 Vol.84,Parkinson’sdiseaseandrelateddisorders,PartII,W.C.KollerandE.Melamed,eds.ISBN9780444528933 Vol.85,HIV/AIDSandthenervoussystem,P.PortegiesandJ.Berger,eds.ISBN9780444520104 Vol.86,Myopathies,F.L.MastagliaandD.HiltonJones,eds.ISBN9780444518996 Vol.87,Malformationsofthenervoussystem,H.B.SarnatandP.Curatolo,eds.ISBN9780444518965 Vol.88,Neuropsychologyandbehaviouralneurology,G.GoldenbergandB.C.Miller,eds.ISBN9780444518972 Vol.89,Dementias,C.DuyckaertsandI.Litvan,eds.ISBN9780444518989 Vol.90,Disordersofconsciousness,G.B.YoungandE.F.M.Wijdicks,eds.ISBN9780444518958 Vol.91,Neuromuscularjunctiondisorders,A.G.Engel,ed.ISBN9780444520081 Vol.92,Stroke–PartI:Basicandepidemiologicalaspects,M.Fisher,ed.ISBN9780444520036 Vol.93,Stroke–PartII:Clinicalmanifestationsandpathogenesis,M.Fisher,ed.ISBN9780444520043 Vol.94,Stroke–PartIII:Investigationsandmanagement,M.Fisher,ed.ISBN9780444520050 Vol.95,Historyofneurology,S.Finger,F.BollerandK.L.Tyler,eds.ISBN9780444520081 Vol.96,Bacterialinfectionsofthecentralnervoussystem,K.L.RoosandA.R.Tunkel,eds.ISBN9780444520159 Vol.97,Headache,G.NappiandM.A.Moskowitz,eds.ISBN9780444521392 Vol.98,SleepdisordersPartI,P.MontagnaandS.Chokroverty,eds.ISBN9780444520067 Vol.99,SleepdisordersPartII,P.MontagnaandS.Chokroverty,eds.ISBN9780444520074 Vol.100,Hyperkineticmovementdisorders,W.J.WeinerandE.Tolosa,eds.ISBN9780444520142 Vol.101,Musculardystrophies,A.AmatoandR.C.Griggs,eds.ISBN9780080450315 Vol.102,Neuro-ophthalmology,C.KennardandR.J.Leigh,eds.ISBN9780444529039 Vol.103,Ataxicdisorders,S.H.SubramonyandA.Durr,eds.ISBN9780444518927 Vol.104,Neuro-oncologyPartI,W.GrisoldandR.Sofietti,eds.ISBN9780444521385 Vol.105,Neuro-oncologyPartII,W.GrisoldandR.Sofietti,eds.ISBN9780444535023 Vol.106,Neurobiologyofpsychiatricdisorders,T.SchlaepferandC.B.Nemeroff,eds.ISBN9780444520029 Vol.107,EpilepsyPartI,H.StefanandW.H.Theodore,eds.ISBN9780444528988 Vol.108,EpilepsyPartII,H.StefanandW.H.Theodore,eds.ISBN9780444528995 Vol.109,Spinalcordinjury,J.VerhaagenandJ.W.McDonaldIII,eds.ISBN9780444521378 Vol.110,Neurologicalrehabilitation,M.BarnesandD.C.Good,eds.ISBN9780444529015 Vol.111,PediatricneurologyPartI,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444528919 Vol.112,PediatricneurologyPartII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444529107 Vol.113,PediatricneurologyPartIII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444595652 Vol. 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds. ISBN 9780444534903 Vol.115,Peripheralnervedisorders,G.SaidandC.Krarup,eds.ISBN9780444529022 Vol.116,Brainstimulation,A.M.LozanoandM.Hallett,eds.ISBN9780444534972 Vol.117,Autonomicnervoussystem,R.M.BuijsandD.F.Swaab,eds.ISBN9780444534910 Vol.118,Ethicalandlegalissuesinneurology,J.L.BernatandH.R.Beresford,eds.ISBN9780444535016 Vol.119,NeurologicaspectsofsystemicdiseasePartI,J.BillerandJ.M.Ferro,eds.ISBN9780702040863 Vol.120,NeurologicaspectsofsystemicdiseasePartII,J.BillerandJ.M.Ferro,eds.ISBN9780702040870 Vol.121,NeurologicaspectsofsystemicdiseasePartIII,J.BillerandJ.M.Ferro,eds.ISBN9780702040887 vi AVAILABLETITLES(Continued) Vol.122,Multiplesclerosisandrelateddisorders,D.S.Goodin,ed.ISBN9780444520012 Vol.123,Neurovirology,A.C.TselisandJ.Booss,eds.ISBN9780444534880 Vol.124,Clinicalneuroendocrinology,E.Fliers,M.KorbonitsandJ.A.Romijn,eds.ISBN9780444596024 Vol.125,Alcoholandthenervoussystem,E.V.SullivanandA.Pfefferbaum,eds.ISBN9780444626196 Foreword Diabetesmellitusisamajorandworldwidecauseofprematureillnessanddeath,anditsglobalprevalencecontinuesto increase,probablyrelatedatleastinparttoincreasingobesityanddiminishedphysicalactivity.Bysomeestimates,in theUnitedStatesitsprevalenceamongadultsisalmost13%,anditaccountsforalmost14%ofhealthcareexpenditure, becauseofcomplicationssuchasstroke,peripheralneuropathy,myocardialinfarction,andkidneyandoculardisease. Fortunately,themostcommonvariety–type2diabetes–canbedetectedatanearlyorpreclinicalstage,andtreatment canavertcomplicationsandinfluencethelong-termoutcome. Withthesepointsinmind,weareparticularlypleasedtoincludeavolumeondiabetesinthepresentseriesofthe HandbookofClinicalNeurology.ItisavailablebothinprintandalsoinanelectronicformatonElsevier’sScience Directwebsite,whichfacilitatesaccessandsearchesfortopicsofparticularinterest. Thevolumecomprises36chaptersdividedintothreesections.Thefirst,whichcontains16chapters,discussesthe clinicalimpactofdiabetesonthenervoussystem.Althoughthefocusismainlyontheperipheralnervoussystem,there arechaptersonstroke,cognitivedisorders,infections,sexualdysfunction,andpsychosocialissues,aswellasamore generalchapterthatincludesdiscussionofsomeofthemajormetaboliccomplicationsofdiabetes.Thesecondsection contains seven chapters on diagnostic and therapeutic approaches to the neurological complications of diabetes, includingelectrophysiologic,pathologic,andimagingstudies.Inafinalsection,variousfundamentalstudiesconcern- ingtheneurologicdisturbancesindiabetesarediscussed. ThevolumehasbeenablyeditedbyProfessorDouglasZochodneoftheUniversityofAlberta,whohasmademany personal contributions to the field of experimental diabetic neuropathy and peripheral nerve regeneration, and by Professor Rayaz A. Malik of the University of Manchester, England and Weill Cornell Medical College in Qatar, Doha,Qatar, whoworksondiabeticneuropathy andcardiomyopathy inboth animal models and atatranslational levelinpatients.Theyhaveassembledanexcellentteamofcontributors,andwearegratefultothemallforcreating suchavaluableresource.Havingreadandcommentedoneachofthechaptersinourcapacityasserieseditors,weare confidentthatbothcliniciansandresearchersalikewillfindmuchtoappealtotheminthevolume. Asalways,itisapleasuretothankElsevier,ourpublishers–andinparticularMicaHaley,MichaelParkinson,and KristiAnderson–fortheirassistanceinthedevelopmentandproductionofthisvolume. MichaelJ.Aminoff Franc¸oisBoller DickF.Swaab Preface Withthecurrentepidemicofobesityanddiabetes,theprevalenceandconsequencesofdiabeticneuropathyaresetto increaseinboththedevelopedandthedevelopingworld.Theprevalenceofdiabeticneuropathyrangesfrom50%to 90%andmanifestsaspainfuldiabeticneuropathyinabout20%,erectiledysfunctioninabout40%,andfootulcer- ationin about 25%ofdiabetic patients.TherearecurrentlynoFDA approved therapies to prevent orrepair nerve damage,andonlythreeapprovedtherapiesforpainfuldiabeticneuropathyandanumberofnewtherapiesforerectile dysfunction. Given that approximately 33% of the direct costs for treatment of diabetes and its complications are attributedtodiabeticneuropathyandfootulceration,thisdemandsfurtherinvestmentforresearchinthisarea. Moderncentralandperipheralneuroimagingtechniqueshavesignificantlyimprovedourabilitytodiagnoseand monitortheprogressionofdiabeticneuropathy.Furthermore,molecularbiologyandtheomicsplatformtechnologies haverevealednovelpathwaysforthedevelopmentandtreatmentofdiabeticneuropathy.However,thetranslational impactofthesediscoverieswillonlyberealizedwhenoptimalsurrogateend-pointshavebeendeployedinclinicaltrials ofdiabeticneuropathy. Thisbookisdividedinthreemajorsections,andsetsthescenebypresentingthemajorsensory,motor,andauto- nomicmanifestationsofdiabeticneuropathyaswellasthecomplicationsofdiabetesthatinvolvethecentralnervous system.Aconsiderationofalternativepathologiesaffectingthenervoussystemofdiabeticpatientsprovidesamore holisticviewoftheneurologicmanifestationsinthesepatients.Chaptersonexperimentalobservationsexplorethe variedmechanisticpathwaysandnoveltherapiesfordiabeticneuropathy.Furthersectionsdealwithnoveldiagnostic andtherapeuticstrategiestoprovideclinicalinsightsintothemanagementofdiabeticneuropathyandotherneurologic complicationsofdiabetes. Wehaveendeavoredtoprovideanaccessiblebutcomprehensiveandup-to-dateresourceonclinical,experimental andtranslationalaspectsofdiabeticneuropathyforneurologists,diabetologists,andindeedanyotherhealthprofes- sionalswhotakecareofdiabeticpatients.WebelievethatthisvolumeoftheHandbookofNeurologywilltherefore benefitthemanyinvestigatorsandclinicalpractitionersworkinginthefieldofdiabeticneuropathyaswellasthemany patientswhosufferfromthisdevastatingdisease. DouglasW.Zochodne,MD,PhD RayazA.Malik,MBChB,PhD Contributors U.Alam A.J.M.Boulton CentreforEndocrinologyandDiabetes,Institute DepartmentofMedicine,UniversityofManchester; ofHumanDevelopment,CentralManchester DiabetesCentre,ManchesterRoyalInfirmary, UniversityHospitalsNHSFoundationTrust, Manchester,UKandDiabetesResearchInstitute, Manchester,UK UniversityofMiami,FL,USA V.Bril H.Andersen DivisionofNeurology,DepartmentofMedicine, DepartmentofNeurology,AarhusUniversityHospital, UniversityHealthNetwork,UniversityofToronto, Aarhus,Denmark Toronto,Canada C.S.Andreassen B.Calabek DepartmentofOtorhinolaryngologyandHead NeurologischeAbetilung,KaiserFranzJosefSpital, andNeckSurgery,AarhusUniversityHospital, Vienna,Austria Aarhus,Denmark N.A.Calcutt T.G.Arnason DepartmentofPathology,UniversityofCaliforniaSan DepartmentofAnatomyandCellBiologyand Diego,LaJolla,CA,USA DepartmentofMedicine,DivisionofEndocrinology andMetabolism,UniversityofSaskatchewan, B.Callaghan Saskatoon,Canada DepartmentofNeurology,UniversityofMichigan,Ann Arbor,MI,USA O.Asghar CentreforEndocrinologyandDiabetes, M.Cortez InstituteofHumanDevelopment,CentralManchester ImagingandNeurosciencesCenter,UniversityofUtah, UniversityHospitalsNHSFoundationTrust, SaltLakeCity,UT,USA Manchester,UK A.M.Demchuk DepartmentofClinicalNeurosciencesandRadiology, S.Azmi FoothillsMedicalCentre,Calgary,Alberta,Canada CentreforEndocrinologyandDiabetes,Institute ofHumanDevelopment,CentralManchester T.Didangelos UniversityHospitalsNHSFoundationTrust, 1stPropedeuticDepartmentofInternalMedicine, Manchester,UK MedicalSchool,AristotleUniversityofThessaloniki, “AHEPA”Hospital,Greece S.Bal DepartmentofClinicalNeurosciencesandRadiology, J.Doupis FoothillsMedicalCentre,Calgary,Alberta,Canada InternalMedicineandDiabetesDepartment,Salamis NavalHospital,Salamis,Greece G.J.Biessels DepartmentofNeurology,RudolfMagnusInstituteof P.J.Dyck Neurosciences,UniversityMedicalCenterUtrecht,The PeripheralNeuropathyResearchLaboratory,Mayo Netherlands Clinic,Rochester,MN,USA xii CONTRIBUTORS P.J.B.Dyck A.Kalsbeek DepartmentofNeurologyandPeripheralNeuropathy DepartmentofEndocrinologyandMetabolism, ResearchLaboratory,MayoClinicRochester, AcademicMedicalCenter,UniversityofAmsterdam, Rochester,MN,USA Amsterdam,TheNetherlands G.Ebenezer P.Kempler CutaneousNerveLaboratory,JohnsHopkinsUniversity FirstDepartmentofInternalMedicine,Semmelweis SchoolofMedicine,Baltimore,MD,USA University,Budapest,Hungary E.L.Feldman P.S.Koekkoek DepartmentofNeurology,UniversityofMichigan,Ann JuliusCenterforHealthSciencesandPrimaryCare, Arbor,MI,USA UniversityMedicalCenterUtrecht,Utrecht,The Netherlands P.Fernyhough R.S.Laughlin DepartmentofPharmacologyandTherapeutics, DepartmentofNeurology,MayoClinicRochester, UniversityofManitobaandDivisionof Rochester,MN,USA NeurodegenerativeDisorders,StBonifaceHospital ResearchCentre,Winnipeg,Manitoba,Canada S.E.LaFleur DepartmentofEndocrinologyandMetabolism, E.Fliers AcademicMedicalCenter,UniversityofAmsterdam, DepartmentofEndocrinologyandMetabolism, Amsterdam,TheNetherlands AcademicMedicalCenter,UniversityofAmsterdam, Amsterdam,TheNetherlands C.A.Lee-Kubli GraduateSchoolofBiomedicalSciences,Sanford- R.Freeman BurnhamInstituteforMolecularMedicineand DepartmentofNeurology,BethIsraelDeaconessMedical DepartmentofPathology,UniversityofCaliforniaSan Center,HarvardMedicalSchool,Boston,MA,USA Diego,LaJolla,CA,USA J.S.Gonzalez J.K.Mah FerkaufGraduateSchoolofPsychology,Yeshiva DivisionofPediatricNeurology,Departmentof UniversityandDiabetesResearchCenter,Albert Pediatrics,CummingSchoolofMedicine,Universityof EinsteinCollegeofMedicine,Bronx,NY,USA Calgary,Calgary,Alberta,Canada M.Goyal R.A.Malik DepartmentofClinicalNeurosciencesandRadiology, CentreforEndocrinologyandDiabetes,Institute FoothillsMedicalCentre,Calgary,Alberta,Canada ofHumanDevelopment,CentralManchester UniversityHospitalsNHSFoundationTrust, M.Greig Manchester,UKandWeillCornellMedicalCollegein DiabetesDepartment,RoyalHallamshireHospital, Qatar,Doha,Qatar Sheffield,UK J.McGavock M.D.Hill DepartmentofPediatricsandChildHealth,University StrokeUnit,FoothillsHospital,HotchkissBrainInstitute, ofManitobaandCentreforPhysicalActivityand UniversityofCalgary,Calgary,Alberta,Canada CardiometabolicHealthinYouth,ManitobaInstituteof ChildHealth,Winnipeg,Manitoba,Canada S.Javed CentreforEndocrinologyandDiabetes,Instituteof A.P.Mizisin HumanDevelopment,CentralManchesterUniversity DepartmentofPathology,SchoolofMedicine, HospitalsNHSFoundationTrust,Manchester,UK UniversityofCaliforniaSanDiego,LaJolla,CA,USA C.A.Jay S.Mohseni DepartmentofNeurology,UniversityofCalifornia DepartmentofClinicalandExperimentalMedicine, SanFranciscoandNeurologyService,SanFrancisco DivisionofCellBiology,FacultyofHealthSciences, GeneralHospital,SanFrancisco,CA,USA Link€opingUniversity,Link€oping,Sweden CONTRIBUTORS xiii H.Nukada A.G.Smith DepartmentofMedicine,UniversityofOtagoMedical DepartmentofNeurologyandDepartmentof School,Dunedin,NewZealandandNukadaInstitutefor Anesthesiology,UniversityofUtah,SaltLakeCity,UT, MedicalandBiologicalResearch,Chiba,Japan USA D.Pacaud B.E.Smith DivisionofPediatricEndocrinology,Departmentof DepartmentofNeurology,MayoClinic,Scottsdale,AZ, Pediatrics,CummingSchoolofMedicine,Universityof USA Calgary,Calgary,Alberta,Canada E.Smith N.Papanas DepartmentofClinicalNeurosciencesandRadiology, SecondDepartmentofInternalMedicine,Democritus FoothillsMedicalCentre,Calgary,Alberta,Canada UniversityofThrace,Alexandroupolis,Greece M.V.Solbrig B.Perkins DepartmentsofInternalMedicine(Neurology)and DivisionofEndocrinologyandMetabolism,Department MedicalMicrobiology,UniversityofManitoba, ofMedicine,UniversityHealthNetwork,Universityof Winnipeg,Manitoba,Canada Toronto,Toronto,Canada M.Tavakoli CentreforEndocrinologyandDiabetes,Instituteof I.N.Petropoulos HumanDevelopment,CentralManchesterUniversity CentreforEndocrinologyandDiabetes,Instituteof HospitalsNHSFoundationTrust,Manchester,UK HumanDevelopment,CentralManchesterUniversity HospitalsNHSFoundationTrust,Manchester,UKand S.Tesfaye WeillCornellMedicalCollegeinQatar,Doha,Qatar DiabetesDepartment,RoyalHallamshireHospital, Sheffield,UK M.Polydefkis CutaneousNerveLaboratoryandJohnsHopkins C.Toth BayviewEMGLaboratory,JohnsHopkinsUniversity DepartmentofClinicalNeurosciencesandHotchkiss SchoolofMedicine,Baltimore,MD,USA BrainInstitute,UniversityofCalgary,Calgary,Alberta, Canada G.E.H.M.Rutten JuliusCenterforHealthSciencesandPrimaryCare, T.Va´rkonyi UniversityMedicalCenterUtrecht,Utrecht,The FirstDepartmentofInternalMedicine,Universityof Netherlands Szeged,Szeged,Hungary R.E.Schmidt V.M.K.Verge DepartmentofPathologyandImmunology,Washington DepartmentofAnatomyandCellBiologyandCameco UniversitySchoolofMedicine,SaintLouis,MO,USA MSNeuroscienceResearchCenter,Universityof Saskatchewan,SaskatoonCityHospital,Saskatoon, D.Selvarajah Canada DiabetesDepartment,RoyalHallamshireHospital, Sheffield,UK A.Veves MicrocirculationLaboratoryandJoslin–BethIsrael J.E.Shaw DeaconessFootCenter,BethIsraelDeaconessMedical BakerIDIHeartandDiabetesInstitute,Melbourne, CenterandHarvardMedicalSchool,Boston,MA,USA Victoria,Australia L.Vileikyte A.A.F.Sima DepartmentofMedicine,UniversityofManchester, DepartmentsofPathologyandNeurology,WayneState Manchester,UK University,Detroit,MI,USA A.I.Vinik J.R.Singleton DiabetesCenterforEndocrineandMetabolicDisorders DepartmentofNeurology,UniversityofUtah,SaltLake andNeuroendocrineUnit,EasternVirginiaMedical City,UT,USA School,Norfolk,VA,USA xiv CONTRIBUTORS I.D.Wilkinson D.Ziegler AcademicRadiology,Departmentof InstituteforClinicalDiabetology,GermanDiabetes CardiovascularScience,RoyalHallamshire CenteratHeinrichHeineUniversity,LeibnizCenter Hospital,Sheffield,UK forDiabetesResearch;DepartmentofEndocrinology andDiabetology,UniversityHospital,Düsseldorf, N.M.Wilson Germany DepartmentofAnatomyandCellBiology, UniversityofKansasMedicalCenter, W.Zhang KansasCity,KS,USA DepartmentofPathology,WayneStateUniversity, Detroit,MI,USA D.E.Wright DepartmentofAnatomyandCellBiology, D.W.Zochodne UniversityofKansasMedicalCenter,KansasCity, DivisionofNeurology,DepartmentofMedicine, KS,USA UniversityofAlberta,Edmonton,Alberta,Canada