Role of Neurotropic Vitamin

7/23/2019 Role of Neurotropic Vitamin

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THE ROLE OF NEUROTROPIC

VITAMIN IN NEUROLOGIC

DISORDERS



NEUROTROPIC VITAMIN IN

NEUROLOGIC DISORDER

Sering dijumpai:

- Diabetic

polyneuropathy

- Carpal tunnel

syndrome- Lumbal-cervical

radiculopathy

- pain

Jarang dijumpai:•Wernicke ensealopati

•Subacute Combined Degeneration



Batasan Nyeri

Pengalaman sensoris dan emosionalsensoris dan emosional , tidak

menyenangkan terkait dengan jejas jaringan

yang nyata atau potensial atau yang dapatdigambarkan sebagai suatu kerusakan

jaringan.

The International Association for the Study of Pain(IASP,), adopted from Merskey.



Classifications of Pain

Acute

Chronic

Duration

Nociceptive

MixedPathophysiology

Neuropathic



TISSUE INJURY ORINFLAMMATION

•Arthritis•Trauma•Burn

NEUROPATHI PAIN

• !ia"eti# ne$ro%ath&• Trigeminal Neuralgia• Nerve root compression

( erniated disc !

ENTRAL PAIN

• Posttalamic stroke• "ultiple sclerosis• Psycologic mecanisms

#$ % TricyclicsPysical terapy andpsycoterapy

&ensory nerve

& y m p a t e t i c

n e r v e

'asomotorand tropiccanges

S&m%atheti#all&mediated %ain're(le) s&m%atheti#d&stro%h& *

#$ % Peno$ybenamine&ympatetic nerve block

#$ % N&)*+sNarcotics

#$ % Tricyclics (e.g.,amitriptyline!,carbamaepine, penytoin,capsaicin

Sites of origin of pain within the nociceptive pathway





+$rning, (eeling li-e the (eet are on (ire

Sta""ing, li-e shar% -ni.es Lan#inating, li-e ele#tri# sho#-s

Free/ing, li-e the (eet are on i#e,altho$gh the& (eel 0arm to to$#h

"odified by "eliala --



HIPERALGESIAHIPERALGESIA

#eaksi yang meningkat teradap stimulus#eaksi yang meningkat teradap stimulusnyerinyeri(noksius!(noksius!

ALODINIAALODINIA

Nyeri akibat stimulus yang tidak nyeri (non/Nyeri akibat stimulus yang tidak nyeri (non/noksius0noksius0inocuousinocuous!!





E)am%lesPeri%heral• Posterpetic neuralgia• Trigeminal neuralgia• +iabetic periperal neuropaty

•Postsurgical neuropaty

• Posttraumatic neuropatyentral• Poststroke painCommon descriptors2

• Burning• Tingling• 1ypersensitivity to touc or cold

E)am%les • Pain due to inflammation• 2imb pain after a fracture• 3oint pain in osteoartritis

• Postoperative visceral pain Common descriptors2

• )cing• &arp• Trobbing

E)am%les • Lo0 "a#- %ain 0ith

radi#$lo%ath&• er.i#al

radi#$lo%ath&• Cancer pain• Carpal tunnel

syndrome

Mi)ed PainPain 0ith

ne$ro%athi# andno#i#e%ti.e#om%onents

Ne$ro%athi# Pain

Pain initiated or #a$sed "& a%rimar& lesion or d&s($n#tion

in the ner.o$s s&stem'either %eri%heral or

#entral ner.o$s s&stem*1

No#i#e%ti.e Pain

Pain #a$sed "& inj$r& to"od& tiss$es

'm$s#$los-eletal,#$taneo$s or .is#eral*2

PRESENTATION ACROSS PAIN STATES VARIES

4. *nternational )ssociation for te &tudy of Pain. *)&P Pain Terminology.3 #aja et al. in 5all P+, "elack # (6ds!. Te$tbook of pain. 7t 6d. 4888.944/:;



SENSI IZA ION OF NOCICEP ORS IN

INFLAMMA ION

Prostaglandins %rod$#ed inres%onse to tiss$e inj$r&4in#rease sensiti.it& o(no#i#e%tor '%ain*

No#i#e%tor then releasess$"stan#e P, 0hi#h dilates"lood .essels and in#reasesrelease o( in(lammator&mediators, s$#h as

+rad&-inin 'redness 5 heat*

S$"stan#e P also %romotesdegran$lation o( mast #ells,0hi#h release histamine's0elling*

14

6<

Pain/sensitive tissue

Pain($l stim$l$s

Prostaglandin

S$"stan#e P

Histamine

Mast #ell+lood .essel

+rad&-inin

No#i#e%tor

S$"stan#e P

26

1



Fase Infamasi (1)

• )kut% Pelepasan autakoid%= 1istamin % vasodilatasi, permeabilitas

vaskular

= &erotonin % permeabilitas= Bradikinin % vasodilatasi, nyeri

= Prostaglandin % vasodilatasi, permeabilitas

kemotaksis= 2eukotrin % permeabilitas, kemotaksis



The ontin$$m o( Pain1

<1 month

Time to resolution

3-6 months

AcutePain

ChronicPain

•Usually obvious tissue damage

•Increased nervous systemactivity

•Pain resolves upon healing

•Serves a protective function

•Pain for 3-6 months ormore2

•Pain beyond expectedperiod of healing2

•Usually has no protectivefunction3

•egrades health andfunction3

!" #ole $%" &osp Physician" 2''2(3)*23-3'"

2"+ur, and ,ifu.i" $onica/s 0anagement of Pain" 2''!"3" #hapman and Stillman" Pain and +ouch" !116"

Insult



EXAMPLE OF CHRONIC NOCICEPTIVE PAIN:

OSTEOARTHRITIS OF THE NEE

Normal jointOsteoarthritis

S&no.ial

mem"rane

artilage

S&no.ial(l$id

Joint#a%s$le

In(lammationas "ones r$"

together

Thinned#artilage



Fase Infamasi (2)

• &ubakut% aktivasi respon imun

• kronik% pelepasan mediator%

= *2/4, *2/, *2/< % aktivasi limfosit, produksiprostaglandin

= TNF7 8 %rod$-si %rostaglandin

= *nterferon

= P+>? % kemotaksis @ proliferasi fibroblast



SENSITIZATION OF CENTRAL NERVOUS S!STEM

Imm$ne #ells

Ma#ro%hage

Mi#roglia

Mono#&te

Inj$r&

Imm$ne res%onse

&to-ines

hemo-ines

S$r(a#eantigens

Adenosinetri%hos%hate

anna"inoids

Ne$ro%e%tides

9l$tamate

+rad&-inin

O:72

Ind$#ed nitri#o)ides&nthase

Sensiti/ationo( #entralner.o$ss&stem

TNF ;, gro0th (a#tors, IL 1 ,IL <

=itamin

+ #om%le)



Ne$roanatomi dan Pato(isiologi N&eri

• Bagian dari sistim saraf yang bertanggung jaAabuntuk sensasi dan persepsi nyeri dapat dibagimenjadi tiga area, yaitu%

= 3aras afferent

= &&P (susunan saraf pusat!

= 3aras efferent



THE PAIN PATH"A!

Pain PerceptionBrain

Dorsal Root

Ganglion

Dorsal Horn

Nociceptor

Spinal Cord

Gottschalk A et al. Am Fam Physician. 2001;!"1#$#%&'.(ields H) et al. Harrison’s Principles of Internal Medicine. 1##&"*!%&.



Jaras Aerent Jaras Aerent

• Nociceptors (reseptor nyeri! jaras afferentberakir pada kornu dorsalis dari medulaspinalis 'ne$ron a((erent %ertama*

• Ne$ron a((erent -ed$a membentuk bagianspinal dari jaras afferent sampai talamus(traktus spinotalamikus!

• Ne$ron -etiga terbentuk mulai talamus sampaike korteks serebri



PERCEPTION

O!"#ATION

TRAN$I$$ION

TRAN$!"CTION

PI 4 S%5I%S %7%+S

PAIN



!orsal Horn

!orsal rootganglion

Peri%heral sensor&Ner.e (i"ers

A

Aδ

Large(i"ers

Small(i"ers

There are Two Sensory Afferent NeuronsThere are Two Sensory Afferent Neurons

!" Large myelinated #β ibers•$ery ast conduction velocity•%espond to innocuous stimuli

&" Small myelinated #δ ' C unmyelinated ibers•Slo( conduction velocity•%espond to no)ious stimuli





NORMAL IMPULSE

RANSMISSION

S$"stan#e P

Pres&na%ti#ne$ron

S&na%ti# #le(t

9l$tamate

Posts&na%ti#ne$ron

NM!A re#e%tor is

"lo#-ed "& Mg2>

AMPAre#e%tor

NM!Are#e%torN?71

Im%$lses rea#h terminals o( %res&na%ti# ne$ron



S$"stan#e P

Pres&na%ti#ne$ron

S&na%ti# #le(t

9l$tamate is released into s&na%ti# #le(t

9l$tamate

Posts&na%ti#ne$ron

AMPAre#e%tor

NM!Are#e%torN?71

NM!A re#e%tor

remains "lo#-ed"& Mg2>

NORMAL IMPULSE TRANSMISSION



S$"stan#e P

Pres&na%ti#ne$ron

S&na%ti# #le(t

9l$tamate "inds to AMPA re#e%tor and im%$lse is transmitted to %osts&na%ti# ne$ron

9l$tamate

Posts&na%ti#ne$ron

NM!A re#e%tor

remains "lo#-ed"& Mg2>

N?71

NORMAL IMPULSE TRANSMISSION

AMPAre#e%tor



PERIP%ERA#ACTI&IT' CENTRA#$EN$ITIATION

!ecreasethreshol to*eri*heral

stimuli

Increases*ontaneou

acti+it,E-*ansion o.

rece*ti+e

/el

%,*eral0esiaAllo,niaTissue ama0e

Ner+e ama0e

$*ontaneous*ain



DEVELOPMENT OF CENTRAL SENSITIZATION

Inj$r& or tra$ma #a$ses in#reased ner.e a#ti.it&

NM!Are#e%torN?71

S$"stan#e P

S&na%ti# #le(t

Posts&na%ti#ne$ron

Pres&na%ti#ne$ron

9l$tamate

AMPAre#e%tor

NM!A re#e%tor is"lo#-ed "& Mg2>

and =itamin



S$"stan#e P and e)#essi.e le.els o( gl$tamate are released into the s&na%ti# #le(t

NM!Are#e%torN?71

NM!A re#e%tor is

"lo#-ed "& Mg2>

and =itamin


S$"stan#e P

S&na%ti# #le(t

Posts&na%ti#ne$ron

Pres&na%ti#ne$ron

9l$tamate

AMPAre#e%tor



S$"stan#e P "inds to N?71 re#e%tors, #a$sing NM!A re#e%tors to release Mg2> ions

N?71NM!A

re#e%tor


S$"stan#e P

S&na%ti# #le(t

Posts&na%ti#ne$ron

Pres&na%ti#ne$ron

9l$tamate

AMPAre#e%tor



9l$tamate mole#$les #an no0 "ind to AMPA and NM!A re#e%tors


S$"stan#e P

S&na%ti# #le(t

Posts&na%ti#ne$ron

Pres&na%ti#ne$ron

9l$tamate

AMPAre#e%tor



In#reased im%$lses transmitted to %osts&na%ti# ne$ron


S$"stan#e P

S&na%ti# #le(t

Posts&na%ti#ne$ron

Pres&na%ti#ne$ron

9l$tamate



N0 P '

+ C C

&P

>lu B+N?

)"P)/#

)/#

Na

N4

>s>D044 N"+)/#

Ca

6P>s

)C

&cr

P) c)"P

CEF02EF

NE& NE*ncreased e$citability

P)

PCγ

c)"P+)>

*P<

TrkB

P2C )C

P>6

NE

P>6

Carpenter and +ickenson, --:"odified "eliala --

ATI=ATION AN! SENSI@ITATION!ORSAL HORN NEURONS Pre7s&na%ti#

Post7s&na%ti#



E(e- Analgeti- dan Ne$ro%rote-ti( dari

=itamin Ne$rotro%i-'@immerman, 2B*

4.N"+) receptor antagonism

.Block at Ca cannels

<.Blok of cytokine formation (eg% TN?/G! and

receptor Binding



Terima asih atasTerima asih atasPerhatiann,aPerhatiann,a







+ipe yeri $erdasar,an



+ipe yeri $erdasar,aneuro8siologi

• N&eri nosise%siN&eri nosise%si, diinduksi ole eksitasi nosiseptor

= yang memiliki fungsi proteksi

= yang dapat mengalami eksitasi kronik akibatpenyakit

• N&eri ne$ro%ati-, diinduksi ole kerusakan ataupenyakit pada sistim saraf

= )kibat eksitasi abnormal dari sistem nosiseptif.

• Sindroma n&eri #am%$ran= Terdapat komponen neuropatik dan nosiseptif secara

bersamaan atau berurutan.



lasi/asi N,eri

• Berdasarkan aAitan (onset!, maka nyeridapat di/kelompokkan dalam%

= Nyeri akut

= Nyeri kronik

= Breakthrough pain (Peningkatan intensitas nyeri pada

kondisi nyeri kronik!.







NE#")2 vs. E) 3E*NT

thi#-ened #a%s$lethi#-ened #a%s$le

Osteoarthriti# -neeOsteoarthriti# -neeNormal -neeNormal -nee

#&st (ormation#&st (ormation

s#lerosis ins#lerosis ins$"#hondral "ones$"#hondral "one

(i"rillated #artilage(i"rillated #artilage

s&no.ial h&%ertro%h&s&no.ial h&%ertro%h&

osteo%h&te (ormationosteo%h&te (ormation

#a%s$le#a%s$le

#artilage#artilage

s&no.i$ms&no.i$m

"one"one

ACR(PACR(PSource* 50S +raining 0odule






Pain Rating S#ales

1 Pain Intensit& S#ale

- 4 < 7 : ; H 8 4-

Mild Moderate Se.erePain threshold

Pain toleran#e



PAIN MEDIATORS

Aa C ara#hidoni# a#id4 +? C "rad&-inin4 P9 C %rostaglandin

ell !amage

+rain

S%inal #ord

Aa ? > +?

P9

No#i#e%tor

Pe%tides, eg, SU+STANE P

HISTAMINE

SEROTONIN

Mast ell

Platelet



PERIPHERAL SENSITIZATION

ell !amage In(lammation S&m%atheti#Terminals

Release o( %ain and in(lammator& mediatorse3g3 "rad&-inin, H>, %rostaglandins

No#i#e%tor• entral sensiti/ation

• H&%eralgesia

• Allod&nia

High Threshold

Lo0 Threshold

S%inal #ord



H!PERALGESIA

Primar&• Sensiti/ation o( %rimar& ne$rons → ↓ threshold to

no)io$s stim$li within site of injury

• Ma& in#l$de res%onse to inno#$o$s stim$li

∀ ↑ %ain (rom s$%ra threshold stim$li

Se#ondar&

• Sensiti/ation o( %rimar& ne$rons in surroundinguninjured areas

Raja SN, et al3 In8 Dall P+, Mel/a#- R, eds3 Textbook of Pain3 th ed4 1811G3



ALLOD!NIA

• Pain e.o-ed "& inno#$o$s stim$li

• entral sensiti/ation→

%ain%rod$#ed "& A (i"ers1

• Possi"l& mediated "& s%inal NM!A

re#e%tors2

13 Dool( J3 Drugs3 14's$%%l *81G323 !olan S, Nolan AM3 Neuroreport3 141'6*8G23



Ung-a%an N&eri

• Aching I nyeri• Stabbing I tertusuk 0

tikam• Tender I nyeri tekan• Tiring I nyeri melelakan

• Numb I baal• Dull I nyeri tumpul• Crampy I nyeri kram• Throbbing I nyeri seperti

tercekik• Gnawing I nyeri seperti

digigit• Burning I rasa terbakar

• Shooting I rasa menyentak• Sharp I nyeri tajam• Exhausting I nyeri melelakan• Nagging I peri• nbearable I tidak

tertaankan• S!uee"ing I seperti diremas• #ressure I seperti ditekan• #enetrating I rasa tertembus• $iserable I menyusakan

• %adiating I menjalar• Deep I nyeri dalam

Pokdisus Nyeri. Penuntun Praktis Nyeri

Neuropatik, 2!



Terminologi Se%$tar N&eri

• Allod&nia= Nyeri yang disebabkan ole stimulus secara

normal tidak menimbulkan nyeri

• H&%eralgesia

= #espon yang berlebian teradap stimulusyang secara normal menimbulkan nyeri.

• H&%er%athia

= &indroma dengan nyeri bercirikan reaksi nyeriabnormal teradap stimulus, kususnyastimulus berulang, seperti peninggian batasambang.

Pokdisus Nyeri. Penuntun Praktis Nyeri Neuropatik, 2!



Terminologi Se%$tar N&eri

• H&%oalgesia= berkurangnya respon nyeri teradap stimulus

yang dalam keadaan normal menimbulkannyeri

Paresthesia

= &ensasi abnormal, yang tidak menyenangkanbaik spontan ataupun dengan pencetus .

• Ne$ralgia

= Nyeri pada daera distribusi saraf.



+erminologi Seputar yeri

• Analgesia= 1ilangnya respon nyeri teradap stimulus yang dalam

keadaan normal menimbulkan nyeri.

• Anesthesia dolorosa

= Nyeri pada area atau regio yang semestinya bersifatanestetik.

• a$salgia= &indroma yang timbul pada lesi saraf paska trauma

yang ditandai nyeri seperti terbakar, alodinia,iperpatia yang menetap, seringkali bercampurdengan disfungsi vasomotor serta sudomotor dankemudian diikuti ole gangguan trofik.



NE#")2 vs. #) &JNE'*K"

NormalNormal

Rhe$matoid S&no.itisRhe$matoid S&no.itis

"$rsitis"$rsitis

tendonitistendonitis

s&no.itiss&no.itis

"one"one

#artilage#artilage

lining #elllining #ellh&%er%lasiah&%er%lasia

%ann$s%ann$s

%ol&mor%h%ol&mor%he)$datee)$date

(i"rosis(i"rosis

mono#&temono#&te

monon$#learmonon$#learin(iltratein(iltrate





9$ideline8



Ameri#an Pain So#iet&Treatment o( hroni# Pain in OA

Yes

• Mild pain

• Acetaminophen*

• Moderate-to-severepain/inflammation

• COX-2 selectiveNSAID

Condct !I ris"factor anal#sis

Not hi$h ris"

• Nonselective NSAID

%i$h ris"

• Nonselective NSAIDpls &&I ormisoprostol

• Intra-articlarin'ection of h#alronicacid for "nee pain

• Intra-articlar$lcocorticoid in'ection

for other 'oint pain

YesContined

pain(

Continedpain(

&ls) as needed• Nonpharmacol

o$icinterventions

• !lcosamine

•

+ramadol• Ad'nctives

• Intra-articlarh#alronicacid

•

Sr$icalintervention

Contined pain(

*&aracetamol in some Adapted from A&S Arthritis !idelines)22,

9$ideline8



• Mild pain

• Acetaminophen.

• Moderate-to-severepain/inflammation

• COX-2 selectiveNSAID

YesContinedpain(

&ls) as needed

• Nonpharmacolo$icinterventions

• !lcosamine

• +ramadol

• Ad'nctives

• Intra-articlarh#alronic acid

• Sr$icalintervention

*DMAD 0 disease-modif#in$antirhematic dr$,

9$ideline8Ameri#an Pain So#iet&

Treatment o( hroni# Pain in RA

Condct !I ris" factoranal#sis 1as in OA

al$orithm

Contined painand

inflammation( Yes

More or lessa$$ressivedisease(

•

Slfasala3ine

• Slfasala3ine

• Methotre4ate

• 5eflnomide

• 6iolo$ictherap#

5ess

More

DMADs*

Adapted from A&S Arthritis !idelines)22,

" l i d l "



"ultimodal "anagementof E) and #)

Nonpharmacologic74ercise/8ei$ht loss

&h#sical therap#

Other

Surgical Osteotom#

Arthroplast#

Pharmacologic Anal$esics

Anti-inflammator# a$ents

DMADs

%arris C, Geriatrics, 9::;<=>;:-=?,%och@er$ MC et al, Arthritis Rheum, 9::<;>9;-=,%och@er$ MC et al, Arthritis Rheum, 9::<;>9=9-?,

AC Ad %oc Committee on Clinical !idelines, Arthritis Rheum,-

" di ti f ti i



"edications for neuropatic pain

N6% norepineprine9 :1T% :/ydro$ytryptamine9 N"+)% N/"etyl +/)spartate9

&N#*% selective norepineprine reuptake inibitor9 &&#*% selective serotonin reuptake inibitor9 TC)% tricyclicantidepressants

Al%ha adrenergi# agentsO%ioidsSNRIsSSRIsTramadol

TAs

!es#ending inhi"itor& %ath0a&s

'NEHT, o%ioid re#e%tors*

entral sensiti/ation

Peri%heral me#hanisms

9a"a%entinLamotrigineLe.etira#etam

O)#ar"a/e%inePrega"alin

!e)tromethor%han?etamineMethadoneMemantine

NM!A

a2>

ar"ama/e%ineLamotrigineLido#aineO)#ar"a/e%ineTo%iramateTAs

Na>



Pharma#ologi#al Treatment Strategies +asedPharma#ologi#al Treatment Strategies +ased

on Signs and S&m%tomon Signs and S&m%tom

PheriperalPheriperal

sensiti9ationsensiti9ation

+opical anaesthetic +opical anaesthetic

:%0;<:%0;<

;idocain local;idocain local

infusion or bloc,infusion or bloc,

+opical #apsaicin +opical #apsaicin

StaticStatic

0echanical0echanical

and +hermaland +hermal&yperalgesia&yperalgesia

Stimulus-evoked Signs:Stimulus-evoked Signs:

ProbableProbable

0echanism0echanismSuggestedSuggested

+reatment +reatmentSign=SymptomSign=Symptom

P b blP b blS t d + t tS t d + t tSi =Si =



%xperimentally *%xperimentally *

>ind-up>ind-up

#linically *#linically *

centralcentralsensiti9ation ofsensiti9ation of

δδ 8bres8bres

+opical anaesthetics :%0;< +opical anaesthetics :%0;<

;idocain local infusion or bloc,;idocain local infusion or bloc,

+opical #apsaicin +opical #apsaicin

nticonvulsant :#b9?Phenytoin<nticonvulsant :#b9?Phenytoin< nti-arrhytmics=anaestheticsnti-arrhytmics=anaesthetics

:0exiletine and ;ignocain:0exiletine and ;ignocain

+ricyclic antidepressant +ricyclic antidepressant

:mitriptyline<@:mitriptyline<@

PunctatePunctate

&yperal-&yperal-

gesiagesia

%ctopic%ctopic

dischargedischarge

:aA channel:aA channel

accumulation<accumulation<

nticovulsantnticovulsant

:#arbama9epin?Phenytoin<:#arbama9epin?Phenytoin<

nti-arrhytmics=anaestheticsnti-arrhytmics=anaesthetics

:0exiletine and ;ignocaine<:0exiletine and ;ignocaine<



euromaeuromaBSign/BSign/

ProbableProbable

0echanism0echanismSuggested +reatmentSuggested +reatmentSign=Sign=

SymptoSympto

mm



#entral#entral

sensiti9ation ofsensiti9ation of

ββ 8bres8bres #entral#entral

reorgani9ation ofreorgani9ation of

ββ 8bres8bres

;oss of inhibitory;oss of inhibitorycontrolscontrols

CabapentinCabapentin

$aclofen$aclofen

pioidspioids

#lonidine#lonidine +ricyclic +ricyclic

antidepressantantidepressant

:mitriptyline<:mitriptyline<

;ocal anaesthetic;ocal anaesthetic

bloc,bloc,

SympatheticSympathetic

ganglion bloc,adeganglion bloc,ade

0 anta onist0 anta onist

llodyniallodynia

ProbableProbable


+reatment +reatmentSign=Sign=

SymptomSymptom



•• %ctopic%ctopic

discharges of discharges of ββ

8bres8bres

•• nticonvulsantsnticonvulsants


•• nti-nti-arrhytmics=anaestheticsarrhytmics=anaesthetics


•• +ricyclic antidepressant +ricyclic antidepressant


ysaesthesiysaesthesi

asas


discharges of discharges of ββ 8bres8bres

•• nticonvulsantsnticonvulsants

:#arbama9epin? Phenytoin<:#arbama9epin? Phenytoin<

•• nti-nti-

arrhytmics=anaestheticsarrhytmics=anaesthetics


•• +ricyclic antidepressants +ricyclic antidepressants


ParaesthesiaParaesthesia

ss

Stimulus-independent symptoms:Stimulus-independent symptoms:

ProbableProbable



SymptomSymptom



•• PheripheralPheripheral

sensiti9ationsensiti9ation

•• ;oss of inhibitory;oss of inhibitory

mechanismmechanism

•• %ctopic discharge of #%ctopic discharge of #

8bres8bres

+opical anaesthetics +opical anaesthetics

:%0;<:%0;<

;idocaine local infusion or;idocaine local infusion or

bloc,bloc,

+opical #apsaicin +opical #apsaicin CabapentinCabapentin

$aclofen$aclofen

#lonidine#lonidine


:mitriptyline<:mitriptyline< PhenytoinPhenytoin

#ontinuou#ontinuou

s burnings burning

painpain

ProbableProbable

0echanism0echanism

SuggestedSuggested

+reatment +reatment

Sign=Sign=

SymptomSymptom




discharge of #discharge of #

8bres8bres

•• nticonvulsantnticonvulsant


••ntiarrhytmics=anaestheticsntiarrhytmics=anaesthetics

:0exiletine and ;ignocain<:0exiletine and ;ignocain<

•• +ricyclic antidepressant +ricyclic antidepressant

:mitriptyline<:mitriptyline<

•• Cabapentin @Cabapentin @

ParoxismaParoxisma

l shootingl shooting

ofoflancinatinlancinatin

g paing pain

ProbableProbable



SymptomSymptom



1#S*!



affecting sleepmood

mobility

ability to Aork interpersonal relationsips overall self/Aort and independence.

PAINF"# !IA3ETICNE"ROPAT%'

impact on patients* +uality o lie

Cynthia,&.

/ain associated (ith neuropathy caused by D0

DIABETIC NEUROPATHY :1#S*!



DIABETIC NEUROPATHY :

SIGNS AND SYMPTOMS

SENSORY MOTOR AUTONOMIC

Post!eSpontaneous pain2urning

/ricking

S+uee3ing4ingling5

6nie-like

Lancinating

7lectric shock

#ching

4robbing

8ree3ing

4ightness

Stimulus-evoked pain

#llodynia5

1yperalgesia

Ne"at!e

9umbness5

Deadness

Loss o sensationLoss o balance

Weakness

atrophy

Sudomotor

/upilary

Cardiovaskular

rinary

;astrointestinal

Se)ualDistal /ro)imal 8ocal

allodynia foot ulceration

1#S*!



1#S*!



&tage of +PN

&tage of neuropaty %

• No neuropaty

• Clinical neuropaty %

Cronic painful

)cute painful

• Painless Ait complete0partial sensory loss

• 2ate complications

<=nternational 9europathy ;uidelines>

1#S*!



!IA9NOSIS OF !IA+ETIPERIPHERAL NEUROPATHY

• &ymptoms• &igns

• Test for autonomic function

• 6lectrodiagnostic• Luantitative sensory testing

)ssess pysical, emotional and social functionand psycological comorbidity

(depression, an$iety, substance abuse!

min4 256

1#S*!



!IA9NOSIS OF !IA+ETIPERIPHERAL NEUROPATHY '#onKt*

Eter metods of assesment %

• Nerve Biopsy

• Nerve 6$posure %

"icroelectrode and epineurial vessel potograpy @

fluorescein angiograpy "icroligt/guide spectropotometry

• &kin Biopsy

• Corneal Confocal "icroscopy

• "#* M

1#S*!





The presence o& symptom and'or sign

o& peripheral ner(e dys&unction in people with diabetes a&ter exclusion

o& other causes

Da#et$ Per%hera& Neuro%ath$:Da#et$ Per%hera& Neuro%ath$:

(Soliman & Gellido, 2002)(Soliman & Gellido, 2002)

C&assf$aton of Da#et$ Neuro%athyC&assf$aton of Da#et$ Neuro%athy



• +iffuse Neuropaty♣ +istal symmetric sensorimotor polyneuropaty

♣ )utonomic neuropaty• &udomotor neuropaty

• Cardiovascular autonomic neuropaty

• >astrointestinal neuropaty• >enitourinary neuropaty

♣ &ymmetric promi$al loAer limb motor neuropaty(amyotropy!

• ?ocal Neuropaty♣ Cranial neuropaty

♣ #adiculopaty0ple$opaty

♣ 6ntrapment neuropaty

C&assf$aton of Da#et$ Neuro%athyC&assf$aton of Da#et$ Neuro%athy

Thomas, 1997



Tiga &tase Neuropati +iabetika (N+!

Ne$ro%ati ($ngsional. Tidak tampak adanya kelainan patologik Perubaan biokimiaAi /// timbul gejala #eversibel

Ne$ro%ati str$-t$ral

Terjadi kerusakan struktural serabut saraf yangmenimbulkan gejala #eversibel

?ematian ne$ron ematian neuron menyebabkan penurunan kepadatan

serabut saraf

*rreversibel

Vinik, 2002



Teori Terjadinya N+• Teori metabolik

= 1iperglikemia

• Teori 'askuler= Terjadi penurunan aliran dara ke endoneurium yang

disebabkan ole adanya resistensi pembulu dara akibatiperglikemi.• ?e-$rangan Neurotrophic factor

= Penurunan Nerve >roAt ?actor (N>?! //// transportaksonal yang retrograde (dari organ target menuju badan

sel! terganggu.= Penurunan kadar N>? pada kulit pasien +" berkorelasi

positif dengan adanya gejala aAal small &ibers sensoryneuropathy



1yperglycemia and Nervous &ystem

• *ncreases te production and stabiliation ofreactive o$ygen species (#E&! damageperiperal neurons, particularly mitocondria= apoptosis via caspases and proapoptotic Bcl proteins

mitocondrial damage and neuronal impairment= 2oss of &cAann cells, myelinated a$ons, and sensory

neurons in +#>

• +N) content is decreased in a$onopaty associated

Ait diabetic neuropaty

Leininger, 2007



1yperglycemia and Nervous &ystem

• Neuronal mitocondrial +N) is more prone too$idative damage tan is glial mitocondrial +N)= possibly contributing to neuropatic progression

• +isruption of mitocondrial membranes indiabetic neuropaty induces local apoptosis

• NeA terapeutic potential% anti Bcl protein prevent Bcl action and apoptosis preserves

neuronal function= #esearc is still in progress

Leininger, 2007

"itocondria and +iabetic Neuropaty



O '

( )

O ' ( )

1 ?

e-

=

==

===

Co@!

e-

Cyto-C

e-

1?

1 ?

1?

=$

$

A&

O'( )

A& 1&A # D / ? /

i # 4 /

1&A&

1&

A

? A&

&1&A

& ;S1 ;SS;

CatalaseSAD

0itochondrial D9# Damage

9 # D 1

9 # D

?

=nner

0itochondrial

membrane0atri) 0itochondrial

membrane damage

=ntermembrane

space

Auter

0itochondrial

membrane

Leininger, 2007

p y



Polyneuropathy is caused by the degeneration of axon terminals and results in symmetricdistal sensory loss Dith shading to normal sensation" compression neuropathy oftenresults in demyelination Dith the axon left relatively intact" Sensory loss folloDs aradicular pattern" >hen the neuronal cell body dies the condition is calledEneuronopathy"E If the cell body is in the sensory ganglion the condition is often referredto as Eganglionopathy"E +he pattern is usually random

A-onal *ol,neuro*ath,!em,elinatin0 Neuro*ath,Neurono*ath, (7an0liono*at

FT:NP



&7CC&7$C

&7$C

&7$C

C3O8C#T7

7#"TAATE

PEPTI!E$Altere Pro*erties

Altere Acti+it,

5oDbotham et al? 2'''

#

Ca99

NMDA **

AMPA

+anate

Hy%ere,ta#&ty

O%o-s

GABA

&7$C

C3O8C#T7

Na9

Modifikasi Meliala, 2003

Ca'*

Ca'*

Ca'*Na'*

Na*

M"'*

3RAINPAINPAINN; PAINNO PAIN

%'PERA#7E$IA ANA#7E$IA

INTRACE..U.AR SECOND MESSENGERMECHANISM O/ NOCICEPTOR SENSITI0ATION O8C



A!EN'#C'C#A$E

cAPATP

PA

7I7s

A2 1a

:9

9

%'PERA#7E$IAP7I2

<(R)= 16($) A!EN 6:%TP7E2 i%ETE

ANA#7E$IAA!EN

A1

P

7s A!EN'#C'C#A$E

ATP cAP

PA

;evine F 5eichling? !11

Modifikasi Meliala, 2003

7I

Na 29

C3OPOI!

Na 29

Patopysiology of +N



• E$idative stress

• )dvance glycation end products ()>6&!

• Protein inase C (PC!

• Polyol PatAay ?lu$

Patopysiology of +N

Patopysiology of diabetic neuropaty



p y gy p y







lassi(i#ation o( !N



As&mmetri#ne$ro%athies

Cranial mononeuropaty&omaticmononeuropaties+iabetic toracicradiculoneuropaty

+iabetic radiculople$usneuropaty

S&mmetri# !istalPol&ne$ro%athies

2arge fiber0distalsymmetric polyneuropaty&mall/fiber neuropaty+iabetic autonomicneuropaty

+iabetic neuropaticcace$ia

lassi(i#ation o( !N

Dianna @uan" Diabetic 9europathy" e0edicine" pdate"ActB,& Cited"EE&F





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Role of Neurotropic Vitamin

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