Extrapyramidalis krkpek

Dopaminergic pathways
The nigrostriatal pathway extends from the substantia nigra to the caudate nucleusputamen (neostriatum)
this pathway regulates movement behavior and is affected in PD1

The ventral tegmentum to mesolimbic forebrain pathway and tuberoinfundibular system may also be affected in PD
1. Schapira 1999

Circuitul motor si organizarea sa somatotopica

Circuitul motor, ( sagetile rosii conecteaza regiunile care moduleaza motilitatea membrului inferior au organizare somatotopica in bucla, cu regiunile pentru m.inf dorsal si medial, miscarile fetei ventral si lateral si miscarile m sup intre ele. Somatotopia din cortexul motor se mentine si in structurile subcorticale (Obeso)

Extrapyramidalis funkcik:
Automatikus mozgsok kivitelezse Alapizomtnus (mozgs, tarts) megszervezse Akarattl fggetlen mozgsok gtlsa Helyreigazt reflexek, vdekez mozgsok-tartsok

Extrapyramidalis krkpek: MOVEMENT DISORDERS

Hiperton-hipokinetikus: Parkinson-kr Hipoton-hiperkinetikus: chorea, hemiballismus Hiperton-hiperkinetikus: atetosis, dystonik (Wilson-kr)

Parkinson-kr s Parkinson szindrmk

Parkinsons Disease: Its like driving with the emergency brake on -Parkinsons patient -

Normal

Early PD

putamen

Parkinsons disease: Pathology

Normal PD
PET scan showing striatal fluorodopa uptake

Gross pathology of the mid brain

Substantia nigra

PK etiopathogenesis

Etiolgia 2. Krlettan 3. Patogenesis

1.

Etiologia
letkor mint rizik-tnyez 2. PK genetikja 3. Krnyezeti tnyezk 4. Ms tnyezk
1.

Dohnyzs Kv s koffein NSAID

Krlettan
DA szerepe parkinsonos krosods Braak - stdiumok

parkinsonos krosods
Lewy-body
eozinofil citoplasmatikus zrvnyok Structura: filamentumok F komponens:
-synuclein

Braak-stdiumok
PK kezdete
Bulbus olfactorius Nucl.dors.N.vag Plexus mesentericus

premotor Parkinsonismus
Szagls Constipatio RSBD (alvszavarok)...

P. premotor = P. non-motor P. nonmotor P. premotor

PK Patogenesis
Oxidativ stress UPS (ubiquitin-proteasome system) zavar mitochondrialis dysfunctio Excitotoxicitas Inflamatio Apoptozis

Etiologia
Oxidativ stress
Inflamatio Protein- aggregatio Excitoxicitas

mitochondrialis disfunctio

Apoptozis

Parkinson-kr etiopathogenesis

Clinical features of PD
Cardinal symptoms of PD:1
tremor rigidity bradykinesia postural instability
1809 1824 1827 1830 1831 1834

Other common signs include:2

shuffling gait cognitive symptoms micrographia (small writing) autonomic dysfunction sensory complaints (pain in muscles) hypomimia decreased blink rate affective symptoms (depression) loss of smell

1. Young 1999; 2. National Parkinson Foundation 2005

Disease progression
Dementia Psychosis Instability and falls Motor complications and dyskinesias Bilateral Unilateral

Disability

Time (years) Preclinical Signs and symptoms

Parkinson-kr kezelse
Dopaminerg szerek
L-dopa (gold-standard) Dopamin-agonistk MAO-B gtlk (selegilin, rasagilin) COMT gtlk

Nem-dopaminerg szerek
Anticholinergis szerek Amantadin

200 years of idiopathic Parkinsons syndrome treatment

Neuroprotection ? Neurorestoration ? Transplantation stem cells ? Deep brain stimulation

L-dopa
Anti-cholinergics 1817 James Parkinson Belladonna
Amantadine Selegiline I-COMT
Dopamine agonists (DA)

1800

1850

1900

1950

2000

Az idelis dopaminerg szer:

A striatalis dopaminerg receptorok lineris ingerlse Neuroprotektv hats A dopaminerg receptorok klnbz altpusainak szelektv ingerlse (???)

A Parkinson kr kezelsi stratgijnak f kihvsa:

A motoros komplikcik ksleltetse / megelzse a motoros teljestmnyek maximlis javtsa mellett.

Optimizing levodopa pharmacokinetics

With dual inhibition, significantly more levodopa reaches the brain, with a 30-50% reduction in plasma variability
Gordin et al. 2002

A dopaminerg szerek farmakokinetikja:

T (ra) L-dopa Bromocriptin Pergolide Cabergolin Pramipexole Ropinirole 1 1,5 38 3 20 48 60 79 36

adagols > 3 x/ nap 3 x/ nap 3 x / nap 1 / nap 3 x/ nap 3 x / nap

Levodopa ksztmnyek
Levodopa(mg) Madopar 200 100 + + PDDI(mg) 50 (benserazid) 25

250 + 25 (carbidopa) Nakom (Sinemet) Isicom Egyszeri levodopa adag 150-200 mg (max.) ! Retard ksztmnyek nem vltak be.

StalevoTM (levodopa+carbidopa+entacapone)

StalevoTM 50 StalevoTM 100

levodopa/carbidopa/entacapone (50 / 12.5 / 200 mg) levodopa/carbidopa/entacapone (100 / 25 / 200 mg) levodopa/carbidopa/entacapone (150 / 37.5 / 200 mg)

StalevoTM 150

Stalevo PI, 2003

Dopamin agonistk
Dopamin receptorok - D1 (D1, D5) - D2 (D2, D3, D4)
Pramipexol (Mirapexin)
Affinits :D3>D2>D4 Kezd adag 3x0,25 mg, max. adag 3x1,5 mg

Ropinirol (Requip)
D2 Kezd adag 3x0,25 mg, max. adag 16-24mg/nap

Nem-dopaminerg szerek
Anticholinergis szerek
Korai fzisban Fiatal, tremor dominans Nem demens !

Amantadin
Hidrochlorid (Viregyt): p.o. Szulfonat (PK-Merz):p.o., i.v. 2x100mg Antidyskinetikus hats

DIAGNOSTIC
DEREGLRI FUNCIONALE NESEMNIFICATIVE

Anthony H. V. Schapira (Istambul, 2001)

SELEGILIN

AGONITI DOPAMINERGICI

DEREGLRI FUNCIONALE SEMNIFICATIVE

L-DOPA COMT-I

ALTE

AGONITI DOPAMINERGICI

NECESITATEA CRETERII TONUSULUI DOPAMINERGIC

FLUCTUAII MOTORII COMT-I modificare doz Agoniti dopaminergici indicaie chirurgical

creterea dozei / frecvenei L-dopa COMT-I

agoniti creterea dozei de agoniti dopaminergici schimbarea agonitilor L-dopa agoniti complementari (Cabergolina)

BOALA PARKINSON AVANSAT

Indicaie chirurgical

Alt medicaie

L-dopa COMT-I

Sebszi kezels

A Parkinson-kr ksi stdiumainak komplikcii

1. A kezelsi stratgik ltal induklt komplikcik 2. A Parkinson kr termszetes lefolysbl ered

A szubsztitcis kezels t vtizede utn:

post-L-Dopa tnetegyttes
5-10 ves krnikus L-dopa kezelst kveten a betegek tbbsgnl motoros komplikcik jelentkeznek (motoros fluktucik, dyskinesisek) A tnetek egy rsze nem befolysolhat L-dopval: Vegetatv zavarok Poszturlis zavarok freezing jelensg dementia Klinikai megfigyelsek s ksrletes modellek L-dopa felgyorsthatja a Parkinson-krban zajl neurodegeneratv folyamatokat.

A terpis stratgia
trtkelse

Effects of chronic levodopa dosing

Levodopa therapy may only fully control the symptoms of PD for a few years, after which symptoms begin to re-emerge before the next scheduled dose this is known as wearing-off1,2
ON time
Sy m al pt le om vi s at a ed re

Wearing-off period

gi be s rn om tu pt re m to Sy

OFF time

Medication starts to work

Time

PD medication

PD medication

PD medication

1. Olanow et al 2001; 2. Adler 2002

Response fluctuations
ON time

OFF time

Time

ON-OFF fluctuations

PD medication

PD medication

PD medication

ON time

Delayed ON
Time

OFF time

PD medication

PD medication

Balancing PD symptoms and dyskinesia

Antidyskinetic strategies are associated with aggravation of PD symptoms1 For many patients, it is currently not possible to induce periods of good mobility without dyskinesia
Early PD
Clinical effect
Dyskinesia threshold

Moderate PD
Clinical effect
Dyskinesia threshold

Advanced PD
Dyskinesia threshold Response threshold

Clinical effect

Response threshold

Response threshold

PD 2 4 therapy Time (h)

PD 2 4 therapy Time (h)

PD 2 4 therapy Time (h)

1. Olanow et al 2001

A motoros komplikcik felosztsa:

1. Hypokinetikus jelensgek:
wearing- off jelensg hirtelen off megksett on, no on hajnali akinesia cscsdzis akinesia freezing jelensg (lecvekel) cscsdzis dyskinesis (chorea) Paroxysmalis hyperkinesis Bifzisos dyskinesis( D-I-D)

2. Hyperkinetikus jelensgek:

3. Dystonis jelensgek: - hajnali dystonia - Cscsdzis dystonia - End-of-dose dystonia

Vegetativ zavarok
Szkrekeds:
3-nl kevesebb szklet/ ht 50-80% trendi vltozsok (rostds !), bsges folyadkbevitel, mozgs Szkletlgytk ( lactulose 10-20 g/nap) Laxativumok, bents

Vegetativ zavarok II
Vizeletrtsi zavarok:
Nicturia, imperativ s gyakori vizelsi knyszer, neheztett rts 40-70% Ok: detrussor hyperreflexia (anticholinerg szerek megvonsa !), kismedencei izomzat relaxatios zavara Esti folyadkbevitel megszortsa Oxybutinin 5-10 mg

Depressio Parkinson-krban
A betegek 50-60 % depressis lesz
(4-szer gyakoribb, mint az tlaglakossgban)

50 % major depressio 40 % dysthymia vagy minor depressio 10 % atypusosdepressio, reaktv hangulatzavar Pramipexole !!

Depressio Parkinson- krban II.

Jellemzk:
a depressio a bevezet tnet (25 %) ritkn extrm slyos slyossga nem korrell a mozgszavar slyossgval

Depressio Parkinson-krban III.

ingerlkenysg, fradkonysg gyakori szorongs, alvszavar a depressio slyosbtja a kognitv zavarokat szignifiknsan megnveli a dementia kialakulsnak a rizikjt mindkt betegsg prognzisa rosszabb suicidium ritka

Dementia Parkinson-krban Hajlamost tnyezk:

a betegsg kezdete idsebb korban hossz krlefolys (3-szor gyakoribb,
mint az tlaglakossgban)

tremor dominans forma levodopa relatv hatstalansga a depressio rizikfaktor

Dementia Parkinson-krban II
Korai jelentkezse a Parkinson-kr ellen szl Subcorticalis dementia
figyelem-zavar szerzett ismeretek felhasznlsnak zavara

Anticholinerg szerek, amantadin slyosbbtjk !!

Hepato-cerebralis degeneratio (Wilson-kr)

Genetikailag determinlt anyagcserezavar (Cu) Ceruloplasmin szint (N: 20-40mg%) cskken Rz-anyagcsere zavar:
Ceruloplasmin vagy Szrum Cu Vizeletben a Cu rts Rz szaporodik fel: KIR, mj, cornea, vese

Kt klinikai forma:
Wilson-kr: perioralis dyskinesia, nyels- s hangkpzsi zavarok, psichs t., mjelgt., KayserFleischer gyr ritka (ksn) Westphal-Strmpell pseudosclerosis: komplex dyskinesis a vgtagokon, pyramisjelek, nystagmus, skandl beszd, Kayser-Fleischer gyr gyakori

Hepato-cerebralis degeneratio (Wilson-kr)

Kezels:
Rzrts:
D-penicilamin (Cuprenil): 1-2g/nap p.o. Gyakori mellkhats (alergia, LED, miasthenia sy,nefrosis sy) EDTA 1g/nap DMP 2-5mg/ttkg

Rzbevitel cskkents:
Kerlni: kposzta, bors, gomba, di, csokold, mogyor Ioncserl gyantk: Carborexin 10-20 g/nap Rzmegkts a blben: K-szulft, MgO