OsteopathicManipula0onintheManagementAutonomic

Neuropathy

JoshuaAlexander,DO,MPHScrippsClinic

Objec0ves

•  Differen0atelargefiber,smallfiber,&autonomic,polyneuropathy

•  DescribefeaturesofPOTS•  Formulatetreatmentforautonomicneuropathyusingosteopathicmanipula0on

Roadmap•  BasicPolyneuropathyReview•  SmallFiberNeuropathyRefresher•  Autonomicneuropathy

–  AllofthisistoarguethatOMMhasaroleinmanagementofdysautonomia

•  SomeAnatomyofcourse

•  Applica0onofosteopathicmanipula0on

Yale.edu

Polyneuropathy•  Impairmentofmul0pleperipheralnerves

–  Sensory,motor,orautonomic–  Small,large,orautonomicfibers

•  Smallfibers–  Painandtemperaturecarriedonsmallunmyelinatedorthinlymyelinatedfibers

–  Symptoms:burningortemperaturechanges•  Largefibers

–  AalphaandAbetalargefibers–sensory–  Agamma–motor–  Vibra0on,propriocep0on,touch/2-pointdiscrimina0on,lossofbulk

–  Symptoms:0ngling,pinsandneedles

Polyneuropathy

•  LargeFiber– Axonal,Demyelina0ng,orMixed– MotorvsSensoryvsMixed

•  AutonomicNeuropathycoveredindetaillater– Carriedonunmyelinatedorthinlymyelinatedfibers

•  SmallFiberNeuropathyandAutonomicNeuropathyoVenaccompanyeachother– Moreonthisinlessthanaminute

Polyneuropathy

•  AnatomicDistribu0on– Typicallylengthdependentaffec0ngthelowerlimbsfirst

– ThinkStockingGlove•  Thegloveisusuallynotaffected0llthethelowerlimbsareinvolveduptotheknees

– Therearemanyexcep0ons

•  Agoodresourceis:hXps://neuromuscular.wustl.edu

Pathophysiology–  Axonaldegenera0on

•  mostcommon•  “Dyingback”

–  Mostdistalpartoftheaxondies–  Typicaldistalsymmetricpolyneuropathy–  Usuallytoxicormetabolic–  Symptoma0c/suppor0ve

–  Walleriandegenera0on•  Distaldegrada0on•  Traumaornerveinfarc0on•  Symptoma0c/suppor0ve/0me

–  Segmentaldemyelina0on•  Axonspared•  Nervesheathimpaired•  CanbefocalmononeuropathybutmoreoVenseeninimmunemediated/

inflammatorypolyneuropathy•  Medicalmanagement

SmallFiber•  ThinlymyelinatedAδ

–  Mechanoreceptorsandthermoreceptors–  Pain–  Cold–  Preganglionicfibers(ANS)

•  UnmyelinatedCfibers–  Polymodalreceptors–  Nocicep0on–burningpain–  Itching–  Warm–  Maybecold–  Postganglionicfibers

•  Sweatglands,bloodvessels,heart,etc

SmallFibers

•  Sitinthedermis•  Exactpathophysiologyoftheirneuropathyisunknown– Autoan0bodiestoneuronalproteins–  Inflammatorycytokines– Dermalvasculi0s

SmallFiberNeuropathyDiagnosis•  Possible

–  Length-dependentsymptoms–  LossofPin/temp;allodynia/hyperalgesia

•  Probable–  Lengthdependent–  LossofPin/temp;allodynia/hyperalgesia–  NormalNCS

•  Definite–  Lengthdependentsymptoms–  LossofPin/temp;allodynia/hyperalgesia–  NormalNCS–  Reducedepidermalnervefiberdensityattheankle(SkinBiopsy)OR

abnormalQST(quan0ta0vesensorytes0ng)ThemistocleousAC,RamirezJD,SerraJ,etal.PractNeurol2014;14:368–379.

SmallFiberNeuropathyE0ology•  Metabolic

–  Pre-diabetes/diabetes/abnormalglucosemetabolismorrapidcorrec0on

–  VitaminB12deficiency–  Dyslipidemia–  Hypothyroidism–  CKD

•  Immune–  Sjogren’s–  Celiac–  Sarcoid–  RA–  SLE–  Vasculi0s–  InflammatoryBowelDisease–  Paraneoplas0c–  MonoclonalGammopathy–  Amyloid

•  Infec0on–  HIV–  Hepa00sC–  Influenza

•  Toxins–  ARV–  An0bio0cs–  Chemotherapy–  Flecanide–  Sta0n–  EtOH–  Sta0n–  VitaminB6

•  PrimaryHereditary–  Nav1.7and1.8muta0ons–  FamilialAmyloidAngiopathy–  Fabry’s–  Tangier’s

•  PrimaryIdiopathic–  IdiopathicSFN–  BurningMouthSyndrome

AutonomicNervousSystem

•  Sympathe0c•  Parasympathe0c•  Enteric

Sympathe0c

•  Hypothalamustotheintermediolateralgraycellcolumninthespinalcord(1storderefferent)–  Somatotopicorganiza0on

•  Preganglionicaxonsfromthecordprojecttothepostganglionicneurons(2ndorderefferent)ontheparavertebralsympathe0cgangliaattheirlevel,above,orbelow–  3cervical,10-12thoracic,4lumbarand4-5sacral– Mostarepairedganglia

Sympathe0c

•  Superiorcervicalganglion•  Middlecervicalganglion•  Inferiorcervicalganglion–  Inferiorcanfusewiththeupperthoracicganglia

Sympathe0cNervousSystem

•  Caudalmostgangliaatthecoccyxformtheunpairedganglionimpar

Sympathe0cNervousSystem

•  Fromparavertebralganglionthesympathe0cstravelwithspinalnerves,cranialnerves,orbloodvesselwalltotheirtarget

Parasympathe0c•  Brainstemandsacrum•  Parasympathe0cpreganglionicneurons

–  Eddinger-Westphal(III)inrostralmidbrain–  Superiorsalivatoryandlacrimalnuclei(VII)inthepon0netegmentum

–  Inferiorsalivatorynucleus(IX)periventriculargray–rostralmedulla

–  Nucleusambiguus(X)–medullare2cularforma2onposteriortotheinferiorolivarynucleus•  Oropharynx

–  DorsalMotorNucleus(X)–flooroftheforthventricle•  Thoraxandabdomen

–  CNXhasthelargestgroupofparasympathe=cfibersinthebody

NucleusTractusSolitarius•  ReceivessensoryinputfromanumberofcranialnervesincludingVagus.

•  Caro0dbody,aor0cbodies,SAnodeviathevagus

•  Taste,sensa0ontothemiddleear•  Receivesinputfromtheheart,lungs,GI,liver,etc

•  Thereisalotofvagaltonesetthroughherebecauseofthis

•  AutonomicReflexzone

DorsalMotorNucleusX

•  PleasereferenceNeXer

ANS•  Bidirec0onalconnectedbetweentargetandcentral

autonomicnetwork•  CentralAutonomicNetwork(CAN)

–  Medialprefrontalcortex–  Insularcortex–  Centralnucleusoftheamygdala–  Hypothalamus–  Periaqueductalgray–  Parabrachialnuclearcomplex–  NucleusAmbiguus–  NucleusTractussolitarius

•  R.PaulLee,DOdescribesareleaseforthisCAN–  Wewillnotdoithere

ANSDysfunc0on

DryMucusmembranesAnhydrosisAbnormalpupilsCons0pa0on/DiarrheaVomi0ngAbdominalpainEarlysa0ety/anorexiaIntes0nalpseudo-obstruc0on

Urinaryreten0onSkincolorchangesAbnormalheartrateOrthostasisErec0ledysfunc0on

E0ology

•  Diabetes•  Mul0systemAtrophy•  Guillain-Barre•  Sjogren’sSyndrome•  Paraneoplas0c

–  Smallcelllungcancer•  HIV•  Botulism•  Chagas(nowintheUS)•  Diphtheria•  Leprosy•  Rabies

•  AcuteDysautonomia•  Parkinsonism•  Neuronalintranuclear

inclusiondisease•  Myopathyandexternal

ophthalmoplegia,neuropathy,gastrointes0nalencephalopathy

•  Anumberofhereditarycondi0ons

POSTURALORTHOSTATICTACHYCARDIASYNDROME

AutonomicNervousSystem

POTS•  Thesepa0entsrangefrommildlyimpairedtobedridden•  Theywereusuallynormalproduc0vepeoplebefore

–  Thiscanbelostonthemedicalsystem–  Inseverecasestheirlivesareusuallydestroyedandtheyjustwanttobenormal

–  Labeledpsychiatric–  Symptomsconfusedwithanxiety

•  Especiallysinceitaffectswomenmorethanmen•  Theywillsearchforexo0cdiagnoses•  TheywillneedalotofhandholdingandTLC•  Severecasesmaytakeyearstorecover

–  1yearOMM,1yearPT,thenaddi0onalOMM

POTS-AutonomicNeuropathy•  Somees0matesarethat1%ofUSpopula0onhasPOTS•  Heartrateincrease≥30bpmwithin10minofupright

postureinadults.Heartrateincreaseof≥40bpmwithin10minisrequiredinadolescentsage12–19years

•  Absenceoforthosta0chypotensiondefinedasasustaineddropinbloodpressure≥20/10mmHgwithin3minofuprightposture

•  Symptomsoforthosta0cintolerancefor≥6months•  Absenceofovertcausesforsinustachycardiasuchasacute

physiologicals0muli,dietaryinfluences,othermedicalcondi0onsandmedica0ons

•  Tilttabletestwithorw/osudomotortes0ngandtranscranialdoppler

POTS•  Female:Male4:1•  Typically13-50yearsold•  13%withfamilyhistory•  Heterogeneous(Cardiogenicvsneurogenicvsstructural*)•  StartaVeracutestress

–  Surgery,viralillness,MVCetc.•  Blurryvision,brainfog,cogni0vedysfunc0on,chestpain,

lightheaded,nausea,fa0gue,cons0pa0on,acrocyanosis,sleepabnormali0es,anxious/brainstemfeeling

•  Onlyabout30%havesyncope•  LookforEhler’sDanlosTypeIII*,MastCellAc0va0onSyndrome,

ChronicFa0gueSyndrome,migraine,fibromyalgia,Sjogren’sandotherautoimmunecondi0ons,GIproblems(bloa0ng,chroniccons0pa0on)

Pathophysiology

•  50%ofPOTSpa0entshavedistalsmallfiberneuropathywithsympathe0cdenerva0on– Pa0entmaynotbeawareoftheneuropathy–  Impairedperipheralvascularresistanceinthelegswhenstandingduetobluntednorepinephrinethere•  Causesexcessivevenouspoolingà•  Sympathe0cac0va0onà•  Increaseheartratetomaintainbloodpressure

Pathophysiology

•  50%haveHyperadrenergicstate•  Excessiveorthosta0ctachycardia•  Mightberelatedtoexcessiveinterleukin-6•  Usuallyfromhypovolemiaorpar0alsympathe0cdenerva0on

•  Testorthosta0ccatecholamines15minutessupinethen15minutesstanding(okaytoleanagainstawall)

Pathophysiology

•  Norepinephrinetransporterdeficiency– Causeslossofsympathe0cac0va0onbydecreasingamountofNEtakenupatthesynapse

– GeneSLC6A2– Tricyclican0depressants,serotonin-norepinephrinereuptakeinhibitors,atomoxe0neimpactNET

Pathophysiology

•  Hypovolemia–  Lowbloodvolumewithdecreasedredbloodcellcount–  13%deficitinplasmavolumeinPOTS

•  Thoughttocauselowerstrokevolumeandcompensatorytachycardia

•  Impairedvascularandrenalresponsetohypovolemia–  AngiotensinIIlevelsarehighandBPisnormal

•  Fluidresponsive–  GiveLactatedRingersorisotonicsaline–  Oralrehydra0on

•  PleasereferenceArnoldetal.Posturaltachcardiasyndrome–diagnosis,physiology,andprognosis.AutonomicNeuroscience:BasicandClinical.2018.hXps://doi.org/10.1016/j.autneu.2018.02.005

•  Figures3and4

Pathophysiology

•  Immunemediated(somestudiesshow20%)

•  An0bodiestoganglionicacetylcholinereceptor

•  An0bodiestoalpha1andbetaadrenergicreceptorsandcardiaclipidproteins

•  Non-specificmarkers(e.g,ANA)posi0vein25%while31%havesomean0body+

•  IgGagainstcardiacproteins–  40iden0fied

POTSassocia=on:•  Sjögrensyndrome•  Ankylosingspondyli0s•  An0phospholipidsyndrome•  Behcet'sdisease

Celiacdisease•  Chronicimmunedemyelina0ng

polyneuropathy•  Inflammatoryboweldisease(Crohnand

ulcera0vecoli0s)•  Hashimoto'sthyroidi0s

Mul0plesclerosisNeuromyeli0sop0caRheumatoidarthri0sSarcoidosisSystemiclupuserythematosusJuvenilerheumatoidarthri0sAdultS0ll'sdiseaseUndifferen0atedconnec0ve0ssuedisease

Pathophysiology

•  Impairedcerebralautoregula0on•  Orthosta0cintolerancedespitenormalbloodpressure–  Isthisproblemcentralratherthanperipheral?

Pathophysiology

•  Decondi0oning–notsureifthisisprimaryorsecondary

•  Aerobicexerciseiscri0cal•  Isthehearttoosmall?

StructuralAssocia0ons

•  ThoracicOutletSyndrome–  Stellateganglioncompression?

•  Hypermobility–EhlersDanlostype3– AlsoassociatedwithMastCellAc0va0onSyndrome

•  MaybeChiariMalforma0on•  Eaglesyndrome–  Elongatedstyloid–  CompressionofCNX,IX,caro0d

StructuralAssocia0ons

•  Medianarcuateligamentsyndrome–  intermiXentobstruc0onofceliacorsuperiormesentericarteriesbythemedianarcuateligament•  celiacplexuscompression

– postprandialorpost-exer0onalabdominalpain

•  Pelvicveinvaricosi0es– Venouspooling

ArolefortheVagusNerveinTreatment?

•  Vagalnerves0mula0on– An0-inflammatory–  Showntoimproverheumatoidarthri0s,Crohn’s,Sjogrens

•  Regularexerciseimprovesvagaltone•  An0-inflammatorydiet•  Acupuncture•  Biofeedback•  Musictherapy•  Medita0on

Treatment•  Agreatcardiologistorautonomicneurologist•  Increasedsodiumandfluidintake•  Compressionstockings•  Aerobicexercise•  Isotonicsaline/LactatedRingersinfusions•  Betablockers

–  Metoprolol–  Corlanor

•  Alpha1agonist:Midodrine•  Florinefinsomecases•  L-Dopa,carbidopa•  SSRI/SNRI•  IVIG/PlasmaExchange/steroids/Rituximab

POTSAddi0onalInforma0on•  Arnoldetal.Posturaltachcardiasyndrome–diagnosis,physiology,

andprognosis.AutonomicNeuroscience:BasicandClinical.2018.hXps://doi.org/10.1016/j.autneu.2018.02.005

•  VerninoandS0les.Autoimmunityinposturalorthosta0ctachycardiasyndrome:currentunderstanding.AutonomicNeuroscience:BasicandClinical.2018.hXps://doi.org/10.1016/j.autneu.2018.04.005

•  Goodman.Evalua0onofposturalorthostasistachycardiasyndrome(POTS).AutonomicNeuroscience:BasicandClinical.2018.hXps://doi.org/10.1016/j.autneu.2018.04.004

•  Wellsetal.Posturaltachycardiasyndrome:currentperspec0ves.VascularHealthandRiskManagement.2018:14;1-11.

ISTHEREAROLEFOROMT?POTS

OMTforPOTS•  GoodkinandBellew2014describeOMTforPOTS

–  26yearoldfemalewithfa0gue,pre-syncope,heatintolerance,cogni0vedysfunc0on,diffusejointpain,insomnia,jawinjury

–  POTSdiagnosed,par0alresponsetoFlorinef,midodrine–  Ligamentousar0cularstrain–  Osteopathiccranialmanipula0vemedicine–  Pre-treatment–couldonlytolerate5minutesinahotshower–  Posttreatment–45minutes–  Wasabletoreducemidodrineandamphetaminefor8days–  Treatedagainandthis0meimprovedfor8weeks–  Treateda3rd0me28dayslaterandremainedcontrolledather18monthfollow-up

–  JAOANov2014;114:874-877

OMTforPOTS–GIsymptoms•  CromeensandGambler2010•  48yearoldmalewithdecadeofpost-prandialabdominalbloa0ng,

cramping,nauseaandvomi0ng,andPOTS,spinepainthroughout•  Bythe3rdtreatmentpa0enthadreducedGIsymptoms•  4thTreatmentdecreasedpain•  Requiredmaintenancetreatment•  SoV0ssue,muscleenergy,ar0culatory,ligamentousar0cular

strain,integratedneuromuscularrelease,ar0culatorytechniques

•  OsteopathicFamilyPhysician2010;2:144-147

OSTEOPATHICMANIPULATIONTECHNIQUES

Polyneuropathy

OsteopathicManipula0on

•  Largefiberneuropathy– Besttotreattheunderlyingcause– HoweverTreatmentofCSF,epineuralspaceandperineuralspacemightbehelpful

Today’sLabwillfocusonVagusBut…

•  AutonomicNeuropathy–  LineaAlbarelease

•  Releasetheceliacganglionandplexuswhileyouarethere–  Correctdysfunc0onoftherespiratoryandpelvicdiaphragm

–  CV4,mightneedlotsofthem–  TreatANSandstructuralabnormali0es

•  Treattheocciput/OA,sacrum,coccyx,–  Whenthepa=entishealthyenoughintegratethesystems–  Treattheganglionimpars

»  Trea0nghandonthesacro-coccygealjunc0onand0pofcoccyx–  Treatmidlineofthesacrum–  Releasethesympathe0cchainthere

•  Trea0ngthevagusnerveanditsnuclei(nextslide)

ForImages

•  Pleasereference:NeXer•  Blumenfeld:NeuroanatomythroughClinicalCases

VagusNerveAnatomy

•  ExitsMedulla–  Betweenoliveandinferiorcerebellarpeduncle

•  Jugularforamen–  Sensoryganglia

•  Superiorandinferior•  JoinsCNXIbelowtheinferiorsensoryganglion•  Descendsthroughthecaro0dsheathposterolateraltocaro0d

•  Medialtointernaljugularvein

RightVagus

•  Crossesanteriortosubclavianartery•  Fatbehindtheinnominatevessels•  Entersthoraxrightofthetrachea•  Risesbehindthehilumoftherightlung•  Coursesmediallytowardesophagus–  JoinstheleVvagustoformtheesophagealplexus

LeVVagus

•  CrossesanteriortotheleVsubclavianartery•  EntersthethoraxbetweentheleVcommoncaro0dandsubclavianarteries

•  DescendsonleVsideoftheaor0carch•  Behindthephrenicnerve•  BehindtherootoftheleVlung•  Mediallyanddownwardtoesophagus•  Meetsrightvagusàesophagealplexus

Vagus:GastricNerves

•  Esophagealplexusgivesrisetotheanteriorandposteriorgastricnerves

•  SupplyallabdominalorgansandGItracttothesplenicflexure

•  Rightvagusàposteriorgastricplexus– Posterioinferior

•  LeVvagusàanteriorgastricplexus– Anterosuperior

Vagus:CeliacNerve

•  Rightvagusnerve•  Celiacplexus

VagusandtheHeart

•  Esophagealplexus– Suppliesposteriorpericardium

•  Investsinthedeepcardiacplexus– Anteriortocarina–  Inferiorcardiacbranch

•  Rightsidefromtrunkofvagusatthetrachea•  LeVfromrecurrentlaryngealnerve

CardiacPlexus

•  Superficial– Undertheaor0carchanteriortotherightpulmonaryartery

– LeVsympathe0ctrunkandlowersuperiorcervicalcardiacbranchofthevagus

•  Deep– Anteriortothecarina,posteriortoaor0carch– Mixofsympathe0cfromtheandparasympathe0cfrominferiorcardiacbranchofvagus

DeepCardiacPlexus

•  Rightside– Anteriorandposteriorcoronaryplexus– Rightatrium

•  LeVside– Superficialcardiacplexus– LeVatrium– Posteriorcoronaryplexus

Okaylet’streat•  Occipitocervicalholdorvault–justbecomfortable–treatbyinten0on,ifyouneedtotreatlocally,

handsanteriorchestwallatthelevelofthecarina(sternalangle)andepigastricareaisfine•  DONOTINVADE;DONOTRUSH•  Getonthe4thventricle•  Moveanteriorandfinddorsalmotornerveofthevagus

–  Justlateraltothehypoglossalnucleus–pickonesidetotreatfirstthenbringintheother•  BringyouraXen0ontotheesophagealplexus–bridgetothedorsalmotornucleusofthevagus•  NowbringyouraXen0ontotheanteriorandposteriorgastricplexus•  Bridgeittotheesophagealplexusthenthedorsalmotornucleus•  NowbringyouraXen0ontotheceliacplexusanddothesameasabove•  BringyouraXen0ontothesuperficialanddeepcardiacplexus– treatandintegratewiththe

esophagealplexus•  Nowseethebigpictureandputitalltogether•  Nowreleasethenucleustractussolitariusthennucleusambiguus•  THISISTOOBIGATREATMENTFORASICKPATIENT

–  Treattheindividualcomponentsfirstandover0mestartlinkingthemtogether