Google Terjemahan PD

4/8/2019 Google Terjemahan
emedicine.medscape.com
Penyakit Parkinson
Diperbarui: 24 Jan 2019
Penulis: Robert A Hauser, MD, MBA; Pemimpin Redaksi: Selim R Benbadis, MD
Ikhtisar
Latihan Essentials
Penyakit Parkinson (PD) adalah salah satu gangguan neurologis yang paling umum, mempengaruhi sekitar 1% orang
yang berusia lebih dari 60 tahun dan menyebabkan kecacatan progresif yang dapat diperlambat, tetapi tidak dihentikan,
dengan pengobatan. 2 temuan neuropatologis utama pada penyakit Parkinson adalah hilangnya neuron dopaminergik
berpigmen dari substantia nigra pars compacta dan keberadaan tubuh Lewy dan neurit Lewy. Lihat gambar di bawah.
Badan Lewy adalah inklusi eosinofilik intracytoplasmic, sering dengan halo, yang mudah terlihat pada neuron berpigmen,
seperti yang ditunjukkan dalam slide histologis ini.
Mereka mengandung alpha-synuclein terpolimerisasi;
oleh karena itu, penyakit Parkinson adalah sinukleinopati.
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Tahapan dalam pengembangan patologi terkait penyakit Parkinson (PD) (path.).
Diadaptasi dari Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Tahapan dalam pengembangan patologi
terkait penyakit Parkinson.
Res Jaringan Sel.
2004 Okt; 318 (1): 121-34.
Tanda dan gejala
Gejala klinis awal penyakit Parkinson meliputi:
Getaran
Penurunan ketangkasan yang halus
Lengan ayun yang berkurang di sisi yang terlibat pertama
Suara lembut
Ekspresi wajah berkurang
Gangguan tidur
Gangguan perilaku gerak mata cepat (REM); hilangnya atonia normal selama tidur REM)
Mengurangi indra penciuman
Gejala disfungsi otonom (mis. Konstipasi, kelainan keringat, disfungsi seksual, dermatitis seboroik)
Perasaan umum tentang kelemahan, malaise, atau lassitude
Depresi atau anhedonia
Keterlambatan dalam berpikir
Tanda-tanda motorik meliputi:
Biasanya asimetris
Temuan awal yang paling umum adalah tremor istirahat di ekstremitas atas
Seiring waktu, pasien mengalami bradikinesia progresif, kekakuan, dan kesulitan gaya berjalan
Postur aksial menjadi semakin fleksibel dan langkah menjadi lebih pendek
Ketidakstabilan postural (gangguan keseimbangan) adalah fenomena yang terlambat
Gejala nonmotor
Gejala nonmotor sering terjadi pada penyakit Parkinson dini. Pengakuan kombinasi gejala nonmotor dan motorik dapat
meningkatkan diagnosis dini dan intervensi dini, yang seringkali menghasilkan kualitas hidup yang lebih baik.
Lihat Presentasi Klinis untuk lebih detail.
Diagnosa
Penyakit Parkinson adalah diagnosis klinis. Tidak ada biomarker laboratorium untuk kondisi ini, dan temuan pada
pencitraan resonansi magnetik rutin dan pindaian tomografi terkomputerisasi tidak biasa.
Diagnosis klinis membutuhkan 2 dari 3 tanda kardinal:
Getaran istirahat
Kekakuan
Bradykinesia
Lihat Workup untuk lebih detail.
Pengelolaan
Tujuan dari manajemen medis penyakit Parkinson adalah untuk memberikan kontrol tanda dan gejala selama mungkin
sambil meminimalkan efek samping.
Terapi obat simtomatik
Biasanya memberikan kontrol yang baik terhadap tanda-tanda motorik penyakit Parkinson selama 4-6 tahun
Levodopa / carbidopa: Standar emas untuk pengobatan simtomatik
Penghambat monoamine oksidase (MAO) -B: Dapat dipertimbangkan untuk pengobatan awal penyakit dini
Agonis dopamin lainnya (misalnya, ropinirole, pramipexole): Monoterapi pada penyakit awal dan terapi tambahan
pada penyakit sedang hingga lanjut
Agen antikolinergik (mis. Trihexyphenidyl, benztropine): Obat lini kedua hanya untuk tremor
Perawatan untuk gejala nonmotor
Sildenafil citrate (Viagra): Untuk disfungsi ereksi
Polietilen glikol: Untuk sembelit
Modafinil: Untuk mengantuk siang yang berlebihan
Methylphenidate: Untuk kelelahan (potensial untuk penyalahgunaan dan kecanduan)
Stimulasi otak dalam
Prosedur bedah pilihan untuk penyakit Parkinson
Tidak melibatkan penghancuran jaringan otak
Dapat dibalik
Dapat disesuaikan saat penyakit berkembang atau terjadi efek samping
Prosedur bilateral dapat dilakukan tanpa peningkatan efek samping yang signifikan
Lihat Pengobatan dan Obat untuk lebih detail.
Latar Belakang
Penyakit Parkinson diakui sebagai salah satu gangguan neurologis yang paling umum, mempengaruhi sekitar 1%
individu yang berusia lebih dari 60 tahun. Ada 2 temuan neuropatologis utama: hilangnya neuron dopaminergik berpigmen
pada substantia nigra pars compacta (SNpc) dan keberadaan tubuh Lewy (lihat gambar berikut). Sebagian besar kasus
penyakit Parkinson (penyakit Parkinson idiopatik [IPD]) dihipotesiskan karena kombinasi faktor genetik dan lingkungan.
Namun, belum ada penyebab lingkungan dari penyakit Parkinson yang telah terbukti. Penyebab genetik yang diketahui
dapat diidentifikasi pada sekitar 10% kasus, dan ini lebih sering terjadi pada pasien yang lebih muda.
Perbandingan kasar dari penampilan substantia nigra antara otak normal dan otak yang terkena penyakit Parkinson.
Perhatikan substantia nigra berpigmen baik di spesimen otak normal di sebelah kiri.
Di otak pasien penyakit Parkinson di sebelah kanan, hilangnya substantia nigra berpigmen karena depopulasi neuron
berpigmen diamati.
Gambaran motorik klasik dari penyakit Parkinson biasanya mulai secara diam-diam dan muncul perlahan selama
beberapa minggu atau bulan, dengan tremor menjadi gejala awal yang paling umum. 3 tanda utama penyakit Parkinson
adalah tremor istirahat, kekakuan, dan bradikinesia. Ketidakstabilan postural (gangguan keseimbangan) kadang-kadang
terdaftar sebagai fitur kardinal keempat. Namun, gangguan keseimbangan pada penyakit Parkinson adalah fenomena
yang terlambat, dan pada kenyataannya, penurunan keseimbangan yang menonjol dalam beberapa tahun pertama
menunjukkan bahwa penyakit Parkinson bukan diagnosis yang benar. (Lihat Presentasi.)
Ketika seorang pasien datang dengan tremor, dokter mengevaluasi riwayat pasien dan temuan pemeriksaan fisik untuk
membedakan tremor penyakit Parkinson dari jenis-jenis tremor lainnya. Pada pasien dengan parkinsonisme, perhatian
yang cermat terhadap anamnesis diperlukan untuk menyingkirkan penyebab seperti obat, racun, atau trauma. (Lihat
Diagnosis Banding.) Penyebab umum lainnya dari tremor termasuk tremor esensial, tremor fisiologis, dan tremor
distonik.
Tidak diperlukan penelitian laboratorium atau pencitraan pada pasien dengan presentasi khas penyakit Parkinson. Pasien
tersebut berusia 55 tahun atau lebih dan memiliki parkinsonisme progresif dan asimetris yang lambat dengan tremor
istirahat dan bradikinesia atau kekakuan. Tidak ada tanda-tanda merah seperti disfungsi otonom yang menonjol,
gangguan keseimbangan, demensia, atau kelainan gerakan mata. Dalam kasus seperti itu, diagnosis pada akhirnya
dianggap dikonfirmasi setelah pasien menjalani terapi dopaminergik (levodopa atau agonis dopamin) sebagaimana
diperlukan untuk kontrol gejala motorik dan menunjukkan manfaat yang kuat dan berkelanjutan. (Lihat Workup.)
Studi pencitraan dapat dipertimbangkan, tergantung pada diagnosis banding. Magnetic resonance imaging (MRI) otak
dapat dipertimbangkan untuk mengevaluasi kemungkinan penyakit serebrovaskular (termasuk keadaan multi-infark), lesi
yang menempati ruang, hidrosefalus tekanan normal, dan gangguan lainnya.
Iodine-123-berlabel fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-nortroptane (FP-CIT I123) (Ioflupane, DaTscan)

tomografi terkomputasi emisi foton tunggal (SPECT) dapat dipertimbangkan dalam kasus parkinsonisme yang tidak pasti
untuk membantu membedakan gangguan terkait dengan hilangnya neuron dopamin (penyakit Parkinson dan
parkinsonisme atipikal, termasuk atrofi sistem multipel [MSA] dan kelumpuhan supranuklear progresif [PSP]) dari
gangguan yang tidak terkait dengan hilangnya neuron dopamin (misalnya, tremor esensial, tremor distonik, vaskular)
parkinsonisme, parkinsonisme atau tremor yang diinduksi oleh obat, kondisi psikogenik). [1]
Levodopa digabungkan dengan inhibitor decarboxylase perifer (PDI), seperti carbidopa, tetap menjadi standar emas untuk
perawatan gejala gejala motorik penyakit Parkinson. Ini memberikan manfaat antiparkinson terbesar dengan efek
samping paling sedikit dalam jangka pendek. Namun, penggunaan jangka panjangnya dikaitkan dengan perkembangan
fluktuasi dan diskinesia. Selain itu, penyakit ini terus berkembang, dan pasien menumpuk cacat jangka panjang. (Lihat
Perawatan.)
Agonis dopamin seperti pramipexole (Mirapex) dan ropinirole (Requip) dapat digunakan sebagai monoterapi untuk
memperbaiki gejala pada penyakit Parkinson dini atau sebagai tambahan levodopa pada pasien yang mengalami fluktuasi
motorik. Inhibitor monoamine oksidase (MAO) -B, seperti selegilin (Eldepryl) dan rasagilin (Azilect) memberikan manfaat
ringan sebagai monoterapi pada penyakit dini dan sebagai tambahan levodopa pada pasien dengan fluktuasi motorik.
(Lihat Obat.) Entacapone (Comtan), penghambat catechol-o-methyltransferase (COMT), mengurangi metabolisme perifer
levodopa, sehingga membuat lebih banyak levodopa tersedia untuk masuk ke otak dalam periode yang lebih lama; agen
ini digunakan sebagai tambahan untuk levodopa pada pasien dengan fluktuasi motorik.
Anatomi
Penyakit Parkinson sebagian besar merupakan kelainan ganglia basal, yang merupakan sekelompok nukleus yang
terletak di dasar otak depan. Striatum, terdiri dari berekor dan putamen, adalah kompleks nuklir terbesar dari ganglia
basal. Striatum menerima input rangsang dari beberapa area korteks serebral, serta input penghambatan dan rangsang
dari sel dopaminergik dari substantia nigra pars compacta (SNc). Input kortikal dan nigral ini diterima oleh neuron
proyeksi berduri, yang terdiri dari 2 jenis: input yang memproyeksikan langsung ke segmen internal globus pallidus (GPi),
situs keluaran utama ganglia basal; dan mereka yang memproyeksikan ke segmen eksternal globus pallidus (GPe),
membangun jalur tidak langsung ke GPi melalui subthalamic nucleus (STN).
Untuk ilustrasi inti subthalamic, lihat gambar di bawah ini.
Bagian sagital, 12 mm lateral garis tengah, menunjukkan inti subthalamic (STN) (lavender).
STN adalah salah satu target bedah yang disukai untuk stimulasi otak dalam untuk mengobati gejala penyakit Parkinson
lanjut.
Tindakan jalur langsung dan tidak langsung mengatur output neuronal dari GPi, yang memberikan input penghambatan
tonik ke inti thalamik yang memproyeksikan ke area motor primer dan tambahan.
Patofisiologi
Tidak ada spesifik, kriteria standar ada untuk diagnosis neuropatologis penyakit Parkinson, karena spesifisitas dan
sensitivitas temuan karakteristiknya belum ditetapkan secara jelas. Namun, berikut ini adalah 2 temuan neuropatologis
utama pada penyakit Parkinson:
Hilangnya neuron dopaminergik berpigmen dari substantia nigra pars compacta
Kehadiran tubuh Lewy dan Lewy neurites
Hilangnya neuron dopamin terjadi paling menonjol di ventral lateral substantia nigra. Sekitar 60-80% neuron dopaminergik
hilang sebelum tanda-tanda motorik penyakit Parkinson muncul.
Beberapa individu yang dianggap normal secara neurologis pada saat kematian mereka ditemukan memiliki tubuh Lewy
pada pemeriksaan otopsi. Badan-badan Lewy yang insidental ini telah dihipotesiskan untuk mewakili fase presimtomatik
penyakit Parkinson. Prevalensi tubuh Lewy insidental meningkat dengan bertambahnya usia. Perhatikan bahwa tubuh
Lewy tidak spesifik untuk penyakit Parkinson, seperti yang ditemukan dalam beberapa kasus parkinsonisme atipikal,
penyakit Hallervorden-Spatz, dan gangguan lainnya. Meskipun demikian, mereka adalah temuan patologi yang khas dari
penyakit Parkinson.
Sirkuit motor pada penyakit Parkinson
Sirkuit motor basal ganglia memodulasi output kortikal yang diperlukan untuk pergerakan normal (lihat gambar berikut).
Representasi skematis ganglia basalis - sirkuit motor thalamokortikal dan neurotransmiternya dalam keadaan normal.
Dari operasi Vitek J. Stereotaxic dan stimulasi otak dalam untuk penyakit Parkinson dan gangguan pergerakan.
Dalam: Watts RL, Koller WC, eds.
Gangguan Gerakan: Prinsip dan Praktik Neurologis.
New York: McGraw-Hill, 1997: 240.
Hak Cipta, McGraw-Hill Companies, Inc. Digunakan dengan izin.
Sinyal dari korteks serebral diproses melalui sirkuit motorik ganglia-thalamokortikal basal dan kembali ke area yang
sama melalui jalur umpan balik. Output dari sirkuit motor diarahkan melalui segmen internal globus pallidus (GPi) dan
substantia nigra pars reticulata (SNr). Output penghambatan ini diarahkan ke jalur talamokortikal dan menekan gerakan.
Ada dua jalur dalam sirkuit basal ganglia, jalur langsung dan tidak langsung, sebagai berikut:
Pada jalur langsung, aliran keluar dari striatum secara langsung menghambat GPi dan SNr; neuron striatal yang
mengandung reseptor D1 merupakan jalur langsung dan proyek ke GPi / SNR
Jalur tidak langsung mengandung koneksi penghambatan antara striatum dan segmen eksternal globus pallidus
(GPe) dan antara GPe dan subthalamic nucleus (STN); neuron striatal dengan reseptor D2 adalah bagian dari jalur
tidak langsung dan proyek ke dokter
STN memberikan pengaruh rangsang pada GPi dan SNr. GPi / SNr mengirimkan keluaran penghambatan ke nukleus
lateral ventral (VL) dari thalamus. Dopamin dilepaskan dari neuron nigrostriatal (substantia nigra pars compacta [SNpc])
untuk mengaktifkan jalur langsung dan menghambat jalur tidak langsung. Pada penyakit Parkinson, penurunan striatal
dopamin menyebabkan peningkatan output penghambatan dari GPi / SNR melalui jalur langsung dan tidak langsung (lihat
gambar berikut).
Representasi skematis ganglia basalis - sirkuit motor thalamokortikal dan perubahan relatif dalam aktivitas neuron pada
penyakit Parkinson.
Dari operasi Vitek J. Stereotaxic dan stimulasi otak dalam untuk penyakit Parkinson dan gangguan pergerakan.
Dalam: Watts RL, Koller WC, eds.
Gangguan Gerakan: Prinsip dan Praktik Neurologis.
New York: McGraw-Hill, 1997: 241.
Digunakan dengan izin baik.
Hak Cipta, McGraw-Hill Companies, Inc.
Peningkatan penghambatan jalur thalamocortical menekan pergerakan. Melalui jalur langsung, penurunan stimulasi
dopamin striatal menyebabkan penurunan penghambatan GPi / SNR. Melalui jalur tidak langsung, penurunan inhibisi
dopamin menyebabkan peningkatan inhibisi GPe, sehingga menyebabkan disinhibisi STN. Peningkatan keluaran STN
meningkatkan keluaran penghambatan GPi / SNr ke thalamus.
Etiologi
Meskipun etiologi penyakit Parkinson masih belum jelas, sebagian besar kasus dihipotesiskan karena kombinasi faktor
genetik dan lingkungan. Penyebab genetik Parkinson yang diketahui saat ini adalah sekitar 10% dari kasus.
Penyebab lingkungan
Faktor risiko lingkungan yang umumnya terkait dengan perkembangan penyakit Parkinson termasuk penggunaan
pestisida, hidup di lingkungan pedesaan, konsumsi air sumur, paparan herbisida, dan kedekatan dengan tanaman industri
atau tambang. [2]
Sebuah meta-analisis dari 89 studi, termasuk 6 studi prospektif dan 83 kasus-kontrol, menemukan bahwa paparan
pestisida dapat meningkatkan risiko untuk PD sebanyak 80%. [3, 4] Paparan terhadap paraquat pembunuh gulma atau
ke fungisida maneb atau mancozeb sangat beracun, meningkatkan risiko PD sekitar 2 kali lipat. Banyak agen yang
diteliti tidak lagi digunakan di Amerika Serikat dan Eropa; namun, beberapa masih ditemukan di negara-negara
berkembang. [3, 4]
Dalam studi kontrol kasus, PD dikaitkan dengan pajanan pada semua jenis pestisida, herbisida, insektisida, dan pelarut,
dengan risiko berkisar antara 33% hingga 80%. [3, 4] Peningkatan risiko PD juga dikaitkan dengan kondisi proksi
paparan. untuk polutan organik, seperti pertanian, air minum yang baik, dan kehidupan pedesaan. Selain itu, risiko
tampaknya meningkat dengan lama paparan. [3, 4]
Institut Nasional Kesehatan-AARP Diet dan Studi Kesehatan, serta meta-analisis studi prospektif, menemukan bahwa
asupan kafein yang lebih tinggi dikaitkan dengan risiko penyakit Parkinson yang lebih rendah pada pria dan wanita.
Asosiasi serupa ditemukan untuk merokok dan risiko penyakit Parkinson. [5] Mekanisme biologis yang mendasari
hubungan terbalik antara kafein atau merokok dan risiko penyakit Parkinson tidak dijelaskan dengan baik.
Interferensi MPTP dengan fungsi mitokondria
Beberapa individu diidentifikasi mengembangkan parkinson setelah injeksi 1-metil-4-fenil-1,2,3,6-tetrahidropiridin (MPTP).

Pasien-pasien ini mengembangkan bradikinesia, kekakuan, dan tremor, yang berkembang selama beberapa minggu dan
membaik dengan terapi penggantian dopamin. MPTP melewati sawar darah-otak dan dioksidasi menjadi 1-metil-4-
fenilpiridinium (MPP +) oleh monoamine oxidase (MAO) -B. [6]
MPP + terakumulasi dalam mitokondria dan mengganggu fungsi kompleks I dari rantai pernapasan. Kemiripan kimia
antara MPTP dan beberapa herbisida dan pestisida menunjukkan bahwa racun lingkungan seperti MPTP mungkin
menjadi penyebab penyakit Parkinson, tetapi tidak ada agen khusus yang telah diidentifikasi. Meskipun demikian,
aktivitas kompleks I mitokondria berkurang pada penyakit Parkinson, menunjukkan jalur umum dengan parkinsonisme
yang diinduksi MPTP.
Hipotesis oksidasi
Hipotesis oksidasi menunjukkan bahwa kerusakan radikal bebas, yang dihasilkan dari metabolisme oksidatif dopamin,
berperan dalam pengembangan atau perkembangan penyakit Parkinson. Metabolisme oksidatif dopamin oleh MAO
mengarah pada pembentukan hidrogen peroksida. Biasanya, hidrogen peroksida dibersihkan dengan cepat oleh
glutathione, tetapi jika hidrogen peroksida tidak dibersihkan secara memadai, hal itu dapat mengarah pada pembentukan
radikal hidroksil yang sangat reaktif yang dapat bereaksi dengan lipid membran sel untuk menyebabkan peroksidasi lipid
dan kerusakan sel. Pada penyakit Parkinson, kadar glutathione berkurang berkurang, menunjukkan hilangnya
perlindungan terhadap pembentukan radikal bebas. Zat besi meningkat dalam substantia nigra dan dapat berfungsi
sebagai sumber elektron donor, sehingga mendorong pembentukan radikal bebas.
Penyakit Parkinson dikaitkan dengan peningkatan pergantian dopamin, penurunan mekanisme perlindungan (glutathione),
peningkatan zat besi (molekul pro-oksidasi), dan bukti peningkatan peroksidasi lipid. Hipotesis ini telah menimbulkan
kekhawatiran bahwa peningkatan pergantian dopamin karena pemberian levodopa dapat meningkatkan kerusakan
oksidatif dan mempercepat hilangnya neuron dopamin. Namun, tidak ada bukti jelas bahwa levodopa mempercepat
perkembangan penyakit.
Faktor genetik
Jika faktor genetik penting dalam penyakit tertentu, kesesuaian pada kembar monozigot (MZ) yang identik secara genetik
akan lebih besar daripada pada kembar dizigotik (DZ), yang hanya berbagi sekitar 50% gen. Studi kembar penyakit
Parkinson awal umumnya menemukan tingkat kesesuaian yang rendah dan serupa untuk pasangan MZ dan DZ.
Namun, faktor genetik pada penyakit Parkinson tampaknya sangat penting ketika penyakit ini dimulai pada atau sebelum
usia 50 tahun. Dalam sebuah penelitian terhadap 193 kembar, kesesuaian keseluruhan untuk pasangan MZ dan DZ
serupa, tetapi pada 16 pasangan kembar di mana penyakit Parkinson didiagnosis pada atau sebelum usia 50 tahun,
semua 4 pasangan MZ, tetapi hanya 2 dari 12 pasangan DZ, yang sesuai. [7]
Identifikasi beberapa keluarga dengan penyakit Parkinson keluarga memicu minat lebih lanjut pada genetika penyakit.
Dalam satu keluarga besar di Salerno, Italia, 50 dari 592 anggota memiliki penyakit Parkinson; analisis hubungan
menunjukkan suatu wilayah dalam pita 4q21-23, dan sekuensing mengungkapkan substitusi A-untuk-G pada basis 209
dari gen alfa-synuclein. [8] Disebut PD-1, kode mutasi ini untuk substitusi threonine untuk alanin dengan asam amino 53.
Individu-individu ini ditandai dengan usia awal penyakit (usia rata-rata, 47,5 tahun), perkembangan yang cepat (usia rata-
rata saat kematian, 56,1 tahun), kurangnya tremor, dan respons yang baik terhadap terapi levodopa. [8] Lima keluarga
kecil Yunani juga ditemukan memiliki mutasi PD-1.
Dalam keluarga Jerman, mutasi titik yang berbeda pada gen alpha-synuclein (substitusi C untuk G pada basis 88,
menghasilkan substitusi prolin untuk alanin pada asam amino 30) menegaskan bahwa mutasi pada gen alpha-synuclein
dapat menyebabkan Parkinson penyakit. [9] Beberapa mutasi familial tambahan dalam gen alpha-synuclein telah
diidentifikasi dan secara kolektif disebut PARK1. Sekarang jelas bahwa mutasi ini merupakan penyebab penyakit
Parkinson yang sangat langka.
Sebanyak 18 lokus dalam berbagai gen kini telah diusulkan untuk penyakit Parkinson. Mutasi dalam 6 lokus ini (SNCA,
LRRK2, PRKN, DJ1, PINK1, dan ATP 13A2) adalah penyebab parkinsonisme familial yang divalidasi dengan baik. [10]
Warisan adalah autosom dominan untuk SNCA dan LRRK2 (meskipun mutasi LRRK2 menunjukkan penetrasi variabel).
Warisan bersifat resesif autosomal untuk PRKN, DJ1, PINK1, dan ATP13A2. Selain itu, polimorfisme dalam SNCA dan
LRRK2, serta variasi dalam MAPT dan GBA, adalah faktor risiko untuk penyakit Parkinson. [10]
(Untuk informasi lebih lanjut tentang gen / lokus yang mendasari parkinsonisme monogenik dan gen / lokus kerentanan
untuk penyakit Parkinson, lihat Tabel 1 dan 2, masing-masing, dalam The Genetics of Parkinson Disease. [10])
Dalam satu penelitian terhadap 953 pasien dengan penyakit Parkinson dengan usia pada awal 50 tahun atau lebih muda,
64 pasien (6,7%) memiliki mutasi PRKN, 1 pasien (0,2%) memiliki mutasi DJ1, 35 pasien (3,6%) memiliki LRRK2
mutasi, dan 64 pasien (6,7%) mengalami mutasi GBA. [11] . Mutasi lebih sering terjadi pada pasien dengan usia mulai
30 tahun atau lebih muda (40,6%) dibandingkan pada mereka dengan usia saat onset antara 31 dan 50 tahun (14,6%);
lebih umum pada pasien keturunan Yahudi (32,4%) dibandingkan pasien non-Yahudi (13,7%); dan lebih umum pada
pasien yang melaporkan riwayat keluarga tingkat pertama penyakit Parkinson (23,9%) dibandingkan pasien tanpa riwayat
keluarga (15,1%). [11]
Meskipun mekanisme mutasi genetik yang menyebabkan penyakit Parkinson tidak diketahui, bukti sampai saat ini
menyatu pada mekanisme yang berkaitan dengan agregasi protein abnormal, degradasi protein yang dimediasi oleh
ubiquitin, disfungsi mitokondria, dan kerusakan oksidatif.
Perubahan dan agregasi konformasi alfa-synuclein
Alpha-synuclein yang teragregasi secara abnormal adalah komponen utama dari tubuh Lewy dan neurit Lewy, yang
merupakan temuan patologis yang khas pada penyakit Parkinson. Mutasi dan multiplikasi missense pada gen SNCA
yang mengkodekan alpha-synuclein, meskipun jarang, menyebabkan penyakit Parkinson dominan autosomal. Namun,
studi asosiasi genome juga menunjukkan hubungan antara SNCA dan penyakit Parkinson sporadis.
Disfungsi alfa-synuclein tampaknya memainkan peran sentral dalam patogenesis penyakit Parkinson, dan memahami
hubungannya dengan proses penyakit memegang janji besar untuk pengembangan penyembuhan.
Alpha-synuclein adalah protein asam amino 140 yang dibuka pada pH netral. Namun, ketika terikat pada membran atau
vesikel yang mengandung fosfolipid asam, dibutuhkan struktur alfa-heliks. Biasanya, alpha-synuclein ditemukan terutama
di terminal presynaptic neuronal dan dapat memainkan peran dalam perakitan dan fungsi SNARE (protein N-
ethylmaleimide-sensitif faktor pengaktif reseptor protein) protein yang terlibat dalam pelepasan neurotransmitter.
Dalam kondisi tertentu, alfa-synuclein berkumpul menjadi oligomer yang secara bertahap dikonversi ke struktur fibrillary
yang kaya beta yang membentuk tubuh Lewy dan neurit pada penyakit Parkinson. Sebagian besar bukti saat ini
menunjukkan bahwa itu adalah oligomer larut menengah yang beracun bagi neuron.
Berbagai mekanisme telah dikemukakan mengenai bagaimana alpha-synuclein yang teragregasi secara abnormal dapat
mengerahkan neurotoksisitas. [12] Satu hipotesis menunjukkan bahwa alpha-synuclein oligomer dapat mempromosikan
pembentukan pori-pori yang dapat ditembus ion pada membran neuron, yang menyebabkan peningkatan masuknya
kalsium. Pembentukan pori yang tidak tepat juga dapat menyebabkan kebocoran neurotransmitter dari vesikel sinaptik ke
dalam sitosol. Selain itu, ekspresi berlebih dari alpha-synuclein telah terbukti merusak aktivitas kompleks I mitokondria,
dan alpha-synuclein oligomer mungkin memiliki efek langsung pada membran mitokondria. Bukti lain menunjukkan
bahwa oligomerisasi alpha-synuclein dapat menyebabkan gangguan sitoskeletal, kemungkinan oleh efek pada protein
penstabil mikrotubulus, tau. [13]
Kadar alpha-synuclein yang meningkat meningkatkan agregasi abnormal. level biasanya diatur oleh keseimbangan antara
sintesis dan degradasi. Penggandaan SNCA menyebabkan peningkatan sintesis alpha-synuclein dan dapat
menyebabkan penyakit Parkinson. Alpha-synuclein tampaknya terdegradasi oleh sistem proteasome di mana-mana dan
jalur autophagy-lysosome. Beberapa mutasi genetik yang terkait dengan penyakit Parkinson dapat menyebabkan
penurunan degradasi alpha-synuclein. Sebagai contoh, peningkatan risiko penyakit Parkinson pada pembawa mutasi
GBA (gen beta-glukoserebrosidase), yang menyandikan enzim lisosom glukoserebrosidase, mungkin disebabkan oleh
disfungsi lisosom dan akibat dari akumulasi alfa-synuclein dan oligomerisasi.
Bagaimana proses penyakit Parkinson dimulai tidak diketahui. Namun, setelah diinisiasi, ia dapat diperbanyak dengan
proses prionlike di mana protein yang salah mengartikan templated misfolding molekul protein lainnya. Pada penyakit
Parkinson, patologi synuclein dimulai di batang otak bawah dan olfactory bulb, naik ke otak tengah, dan akhirnya
mempengaruhi neokorteks. Satu set pengamatan yang mendukung proses prionlike berasal dari pengalaman dengan
cangkok dopaminergik janin ditransplantasikan ke striata pasien dengan penyakit Parkinson, karena cangkokan ini
mengembangkan tubuh Lewy, menunjukkan penularan penyakit graft inang. [14]
Mencegah penyebaran agregasi alpha-synuclein abnormal mungkin menjadi kunci untuk memperlambat atau
menghentikan perkembangan penyakit Parkinson.
Melanoma
Selama bertahun-tahun, telah ada spekulasi tentang hubungan antara PD dan melanoma. Awalnya, itu berteori bahwa
levodopa menyebabkan peningkatan risiko kanker kulit, tetapi penelitian tidak mengkonfirmasi hal ini. Namun, uji coba
selanjutnya telah menemukan peningkatan risiko melanoma pada pasien dengan PD. Satu studi tertentu yang dilakukan
pada 2017 menemukan bahwa pasien Parkinson memiliki sekitar 4 kali lipat peningkatan risiko mengalami melanoma
yang sudah ada sebelumnya. [15, 16] Studi lain menemukan risiko menjadi 7 kali lipat. [17]
Diabetes
Dalam sebuah penelitian kohort yang besar, para peneliti menemukan bahwa orang dengan diabetes tipe 2 memiliki risiko
32% lebih tinggi untuk terserang penyakit Parkinson di kemudian hari dibandingkan mereka yang tidak menderita
diabetes. Penelitian ini melibatkan 2 juta orang dengan diabetes tipe 2 dan membandingkannya dengan kelompok
referensi dari 6.173.208 orang tanpa diabetes dan hasilnya menunjukkan peningkatan yang signifikan dari penyakit
Parkinson dalam kelompok diabetes tipe 2 (rasio bahaya [SDM], 1,32, interval kepercayaan 95%). [CI], 1,29 - 1,35; P
<0,001). Peningkatan relatif lebih besar pada pasien dengan komplikasi diabetes dan pada individu yang lebih muda
dengan diabetes tipe 2 berusia 25 hingga 44 tahun. [18]
Epidemiologi
Penyakit Parkinson diakui sebagai salah satu gangguan neurologis yang paling umum, mempengaruhi sekitar 1%
individu yang berusia lebih dari 60 tahun. Insiden penyakit Parkinson diperkirakan 4,5-21 kasus per 100.000 penduduk per
tahun, dan perkiraan prevalensi berkisar antara 18 hingga 328 kasus per 100.000 penduduk, dengan sebagian besar studi
menghasilkan prevalensi sekitar 120 kasus per 100.000 penduduk. Variasi yang luas dalam estimasi insiden dan
prevalensi global yang dilaporkan mungkin merupakan hasil dari sejumlah faktor, termasuk cara pengumpulan data,
perbedaan dalam struktur populasi dan kelangsungan hidup pasien, penentuan kasus, dan metodologi yang digunakan
untuk mendefinisikan kasus. [19]
Insiden dan prevalensi penyakit Parkinson meningkat dengan bertambahnya usia, dan usia rata-rata serangan adalah
sekitar 60 tahun. Onset pada orang yang lebih muda dari 40 tahun relatif tidak umum. Penyakit Parkinson sekitar 1,5 kali
lebih umum pada pria daripada pada wanita.
Prognosa
Sebelum pengenalan levodopa, penyakit Parkinson menyebabkan kecacatan parah atau kematian pada 25% pasien
dalam 5 tahun onset, 65% dalam 10 tahun, dan 89% dalam 15 tahun. Tingkat kematian akibat penyakit Parkinson adalah
3 kali lipat dari populasi umum yang cocok dengan usia, jenis kelamin, dan asal ras. Dengan diperkenalkannya levodopa,
angka kematian turun sekitar 50%, dan umur panjang diperpanjang beberapa tahun. Ini diduga disebabkan oleh efek
simptomatik levodopa, karena tidak ada bukti jelas yang menunjukkan bahwa levodopa memiliki sifat progresif dari
penyakit ini. [20, 21]
American Academy of Neurology mencatat bahwa fitur klinis berikut dapat membantu memprediksi laju perkembangan
penyakit Parkinson [22]:
Usia yang lebih tua saat onset dan kekakuan awal / hipokinesia dapat digunakan untuk memprediksi (1) laju
perkembangan motorik yang lebih cepat pada mereka yang menderita penyakit Parkinson yang baru didiagnosis
dan (2) perkembangan penurunan kognitif dan demensia yang lebih dini; Namun, awalnya dengan tremor dapat
memprediksi perjalanan penyakit yang lebih jinak dan manfaat terapi yang lebih lama dari levodopa
Tingkat perkembangan motorik yang lebih cepat juga dapat diprediksi jika pasien adalah laki-laki, memiliki
komorbiditas terkait, dan memiliki ketidakstabilan postur / kesulitan berjalan (PIGD)
Usia yang lebih tua saat onset, demensia, dan penurunan responsif terhadap terapi dopaminergik dapat
memprediksi penempatan rumah jompo yang lebih awal dan penurunan kelangsungan hidup
Pendidikan Pasien
Pasien dengan penyakit Parkinson harus didorong untuk berpartisipasi dalam pengambilan keputusan mengenai kondisi
mereka. [23] Selain itu, individu dan pengasuh mereka harus diberi informasi yang sesuai untuk keadaan penyakit
mereka dan tantangan yang diharapkan atau berkelanjutan. [21] Dukungan dan masalah psikososial harus ditangani dan
/ atau dirujuk ke pekerja sosial atau psikolog sesuai kebutuhan.
Pencegahan jatuh harus didiskusikan. Institut Nasional Inggris untuk Keunggulan Kesehatan dan Klinis memiliki
beberapa dokumen panduan termasuk dokumen untuk pasien dan perawat.
Masalah lain yang umumnya perlu ditangani pada waktu yang tepat dalam perjalanan penyakit termasuk penurunan
kognitif, perubahan kepribadian, depresi, disfagia, kantuk dan kelelahan, dan gangguan kontrol impuls. Informasi
tambahan juga sering diperlukan untuk perencanaan keuangan, masalah asuransi, aplikasi disabilitas, dan penempatan
(fasilitas tempat tinggal berbantuan, panti jompo).
Untuk informasi edukasi pasien, lihat Pusat Sistem Otak & Saraf, serta Penyakit Dementia Parkinson.
Presentasi
Sejarah
Timbulnya tanda motorik pada penyakit Parkinson biasanya asimetris, dengan temuan awal yang paling umum adalah
tremor istirahat asimetris pada ekstremitas atas. Seiring waktu, pasien melihat gejala yang terkait dengan bradikinesia
progresif, kekakuan, dan kesulitan gaya berjalan. Lengan yang terkena pertama mungkin tidak berayun penuh saat
berjalan, dan kaki di sisi yang sama dapat mengikis lantai. Seiring waktu, postur aksial menjadi semakin tertekuk dan
langkah menjadi lebih pendek.
Beberapa gejala nonmotor biasanya mendahului tanda motorik pada penyakit Parkinson. Sebagian besar pasien penyakit
Parkinson memiliki pengurangan substansial dalam fungsi penciuman (bau) pada saat tanda-tanda motorik muncul.
Namun, entah ini tidak diperhatikan oleh pasien atau pasien mungkin tidak menyadari bahwa itu adalah bagian dari
penyakit. Gejala premotor umum lainnya adalah kelainan perilaku gerak mata cepat (REM). Dalam kondisi ini, individu
menunjukkan gerakan selama tidur REM yang sering digambarkan sebagai gerakan memukul atau menendang. Ada juga
sejumlah faktor risiko setengah baya untuk pengembangan penyakit Parkinson di kemudian hari. Ini termasuk sembelit
dan kantuk berlebihan di siang hari, meskipun mereka jauh dari spesifik untuk penyakit Parkinson.
Dalam sebuah penelitian di Inggris, frekuensi gejala nonmotor pada 159 pasien dengan penyakit Parkinson yang baru
didiagnosis ditemukan secara signifikan lebih besar daripada pada 99 pasien kontrol yang cocok dengan usia yang sehat
(rata-rata, 8,4 vs 2,8). [24] Gejala nonmotor yang paling umum dialami pada pasien dengan penyakit Parkinson awal
dalam penelitian ini adalah sebagai berikut [25]:
Air liur berlebihan
Kelupaan
Urgensi urgensi
Hyposmia
Sembelit
Gejala klinis awal pada penyakit Parkinson meliputi:
Getaran
Penurunan ketangkasan yang halus; misalnya, kurangnya koordinasi dengan kegiatan seperti bermain golf atau
berpakaian (sekitar 20% pasien pertama kali mengalami kejanggalan di satu tangan)
Lengan ayun yang berkurang di sisi yang terlibat pertama
Suara lembut
Ekspresi wajah berkurang
Gangguan tidur
RBD, di mana ada hilangnya atonia normal selama tidur REM: Dalam satu penelitian, 38% pria berusia 50 tahun
dengan RBD dan tidak ada tanda-tanda neurologis yang berkembang menjadi parkinsonisme [26]; pasien
"mewujudkan impian mereka" dan dapat menendang, memukul, berbicara, atau menangis dalam tidur mereka
Mengurangi indra penciuman
Gejala disfungsi otonom, termasuk sembelit, kelainan keringat, disfungsi seksual, dan dermatitis seboroik
Perasaan umum tentang kelemahan, malaise, atau lassitude
Depresi atau anhedonia
Keterlambatan dalam berpikir
Tanda-tanda motorik awal yang umum dari penyakit Parkinson termasuk tremor, bradikinesia, kekakuan, dan distonia.
Getaran
Meskipun tremor adalah gejala awal yang paling umum pada penyakit Parkinson, terjadi pada sekitar 70% pasien, itu
tidak harus hadir untuk membuat diagnosis. Tremor paling sering digambarkan oleh pasien sebagai kegoncangan atau
kegugupan dan biasanya dimulai pada satu ekstremitas atas dan pada awalnya mungkin intermiten. Getaran ekstremitas
atas umumnya dimulai di jari atau ibu jari, tetapi juga bisa dimulai di lengan bawah atau pergelangan tangan. Setelah
beberapa bulan atau tahun, tremor dapat menyebar ke ekstremitas bawah ipsilateral atau ekstremitas atas kontralateral
sebelum menjadi lebih umum; Namun, asimetri biasanya dipertahankan.
Tremor dapat sangat bervariasi, muncul hanya dengan stres, kecemasan, atau kelelahan. Secara klasik, tremor penyakit
Parkinson adalah tremor istirahat (terjadi pada ekstremitas pada posisi istirahat) dan menghilang dengan aksi atau
penggunaan ekstremitas, tetapi ini tidak terlihat pada semua pasien. Awalnya, getaran itu mungkin diperhatikan selama
kegiatan seperti makan atau membaca koran. Meskipun penyakit Parkinson jarang menyebabkan tremor yang mengenai
kepala atau leher, tremor pada dagu, bibir, atau lidah tidak jarang terjadi. Seperti halnya tremor lainnya, amplitudo
meningkat dengan stres dan membaik saat tidur.
Bradykinesia
Bradykinesia mengacu pada lambatnya gerakan. Gejala bradikinesia bervariasi dan dapat digambarkan oleh pasien
dengan berbagai cara. Ini mungkin termasuk rasa kelemahan subjektif, tanpa kelemahan sebenarnya pada pemeriksaan
fisik; kehilangan ketangkasan, kadang-kadang digambarkan oleh pasien sebagai "pesan tidak sampai ke anggota tubuh";
kelesuan; atau pegal-pegal saat melakukan tindakan berulang.
Bradikinesia wajah ditandai oleh penurunan kecepatan kedipan dan ekspresi wajah. Bicara dapat menjadi lebih lembut,
kurang berbeda, atau lebih monoton. Dalam kasus yang lebih maju, ucapan tidak jelas, diartikulasikan dengan buruk, dan
sulit dimengerti. Air liur adalah gejala awal yang tidak umum dalam isolasi tetapi dilaporkan secara umum (terutama air
liur malam hari) kemudian dalam perjalanan penyakit.
Bradikines truncal menghasilkan kelambatan atau kesulitan untuk bangkit dari kursi, berputar di tempat tidur, atau
berjalan. Jika berjalan dipengaruhi, pasien dapat mengambil langkah yang lebih kecil dan gaya berjalan berkurang.
Beberapa pasien mengalami ketidakmampuan transien untuk berjalan, seolah-olah kaki mereka membeku ke lantai.
"Pembekuan" ini terlihat umum pada pasien dengan penyakit yang lebih lanjut; ini lebih menonjol karena pasien berusaha
untuk menavigasi pintu atau area sempit dan dapat menyebabkan pasien terjebak di belakang furnitur atau tidak dapat
melewati ambang pintu dengan mudah.
Pada ekstremitas atas, bradikinesia dapat menyebabkan tulisan tangan kecil dan mudah (yaitu, mikrografia) dan
kesulitan menggunakan tangan untuk kegiatan tangkas seperti menggunakan kunci atau peralatan dapur. Pada
ekstremitas bawah, bradikinesia unilateral biasanya menyebabkan lecet kaki di tanah, karena tidak diangkat saat ayunan
kaki. Ini juga dapat digambarkan sebagai menyeret satu kaki.
Kekakuan
Beberapa pasien mungkin menggambarkan kekakuan pada tungkai, tetapi ini mungkin mencerminkan bradikinesia lebih
dari kekakuan. Kadang-kadang, individu dapat menggambarkan perasaan kekakuan ratchety ketika menggerakkan
anggota badan, yang mungkin merupakan manifestasi dari kekakuan roda gigi.
Dystonia
Dystonia adalah gejala awal yang umum pada penyakit Parkinson onset muda, yang didefinisikan sebagai onset gejala
sebelum usia 40 tahun. Dystonia pada penyakit Parkinson umumnya terdiri dari pembalikan kaki secara tidak sengaja
(inversi) atau turun (fleksi plantar), sering dikaitkan dengan kram atau nyeri di kaki. Dorsofleksi jempol kaki juga dapat
terjadi. Distonia umum lainnya pada penyakit Parkinson adalah adduksi lengan dan siku, menyebabkan tangan
beristirahat di depan perut atau dada. Postur distonik dapat bertambah dan menyusut, terjadi karena kelelahan atau
aktivitas.
Apakah postur bungkuk disebabkan oleh distonia truncal adalah masalah perdebatan. Satu studi menunjukkan bahwa
postur bungkuk mungkin karena patah tulang belakang akibat defisiensi vitamin D dengan hiperparatiroidisme
kompensasi. [27] Suplemen vitamin D dapat mengurangi risiko postur bungkuk.
Pemeriksaan fisik
Ada 4 tanda kardinal penyakit Parkinson, dengan 2 dari 3 yang pertama yang tercantum di bawah ini diperlukan untuk
membuat diagnosis klinis. Tanda kardinal keempat, ketidakstabilan postural (kesulitan keseimbangan), muncul terlambat
pada penyakit, biasanya setelah 8 tahun atau lebih.
Getaran istirahat
Kekakuan
Bradykinesia
Ketidakstabilan postur tubuh
Getaran istirahat
Tremor istirahat dinilai dengan meminta pasien merilekskan lengan di pangkuan saat dalam posisi duduk. Memiliki
pasien menghitung keras mundur dari 10 dapat membantu mengeluarkan tremor. Lengan juga harus diamati dalam posisi
terentang untuk menilai tremor postural, dan tremor kinetik (tremor dengan gerakan sukarela) dapat diamati selama tes
jari-ke-hidung. Meskipun tremor istirahat adalah karakteristik tremor dari penyakit Parkinson, banyak pasien penyakit
Parkinson juga memiliki beberapa tremor postural dan / atau kinetik.
Kekakuan
Kekakuan mengacu pada peningkatan resistensi terhadap gerakan pasif tentang sendi. Perlawanan dapat berupa halus
(pipa timah) atau berosilasi (roda gigi cogweling). Cogwheeling dianggap mencerminkan tremor daripada kekakuan dan
mungkin hadir dengan tremor yang tidak terkait dengan peningkatan nada (yaitu, tremor esensial). Kekakuan biasanya
diuji dengan melenturkan dan memperpanjang pergelangan tangan pasien yang rileks dan dapat dibuat lebih jelas dengan
meminta pasien melakukan gerakan sukarela, seperti mengetuk, dengan anggota tubuh kontralateral.
Bradykinesia
Bradykinesia mengacu pada lambatnya gerakan tetapi juga termasuk berkurangnya gerakan spontan dan penurunan
amplitudo gerakan. Bradikinesia juga dinyatakan sebagai mikrografia (tulisan tangan kecil), hipomimia (penurunan
ekspresi wajah), penurunan kecepatan blink, dan hipofonia (bicara halus). Dengan demikian, tingkat kedipan pasien dan
ekspresi wajah harus diperhatikan.
Selain itu, kecepatan dan amplitudo gerakan dinilai dengan meminta pasien membuka tangannya (masing-masing
anggota tubuh dinilai secara individual) dan mengetuk ibu jari dan jari telunjuknya berulang-ulang, mencoba melakukan
gerakan sebesar dan secepat mungkin. Demikian pula, pasien harus diminta untuk mengetuk jari-jari kaki masing-masing
sebesar dan secepat mungkin. Akhirnya, pasien harus diminta untuk bangkit dari posisi duduk dengan tangan bersilang
untuk menilai kemampuan untuk bangkit dari kursi. Pasien kemudian diamati sambil berjalan untuk menilai panjang dan
kecepatan langkah, serta lengan ayun.
Ketidakstabilan postur tubuh
Ketidakstabilan postur tubuh mengacu pada ketidakseimbangan dan hilangnya refleks yang benar. Kemunculannya pada
pasien dengan penyakit Parkinson merupakan tonggak penting, karena sangat tidak cocok untuk perawatan dan sumber
kecacatan yang umum pada penyakit lanjut. Stabilitas postural biasanya dinilai dengan membuat pasien berdiri dengan
mata terbuka dan kemudian menarik bahu mereka kembali ke arah pemeriksa. Pasien diberitahu untuk siap untuk
pemindahan dan untuk mendapatkan kembali keseimbangan mereka secepat mungkin. Mengambil 1 atau 2 langkah
mundur untuk mendapatkan kembali keseimbangan dianggap normal. Pemeriksa harus siap untuk menangkap pasien
jika mereka tidak dapat mendapatkan kembali keseimbangan.
Disfungsi laring dan disfagia
Ketika pasien berbicara, kenyaringan vokal, intonasi, dan kualitas, termasuk fluiditas bicara dan artikulasi, harus dinilai.
Mempertahankan fonasi vokal (mis., "Ah") untuk durasi maksimum, menghitung hingga 50, dan membaca suatu bagian
yang menguji artikulasi (mis., Bagian pelangi) memberikan contoh-contoh ucapan yang masuk akal. Mendengarkan
dengan seksama suara keras dan intonasi yang berkurang atau berkurang dan peningkatan pernapasan dan suara serak
membantu membedakan penyakit Parkinson dari gangguan hiperkinetik seperti disfonia spasmodik. [28]
Suara yang lembut dan monoton, tremor vokal, artikulasi yang buruk, kecepatan bicara yang bervariasi, masalah dengan
inisiasi bicara, dan kualitas seperti kegagapan adalah karakteristik dari penyakit Parkinson. Mungkin gejala vokal yang
paling jitu adalah kontras yang tajam antara volume vokal kebiasaan (lembut dan berkurang) dan respons pasien terhadap
permintaan untuk meningkatkan kenyaringan. Permintaan untuk "mengatakan itu lagi, dua kali lebih keras" sering
menghasilkan peningkatan kenyaringan, kualitas suara yang meningkat, dan peningkatan dramatis dalam kejelasan
bicara.
Disfagia sering terjadi, terutama pada penyakit Parkinson lanjut. Manifestasi dapat berkisar dari meneteskan air liur ke
aspirasi.
Seorang otolaryngologist dapat melakukan penilaian yang lebih rinci tentang disfungsi laring pada pasien dengan
penyakit Parkinson, menggunakan pemeriksaan neurolaring dan stroboskopi. Karena distorsi dapat terjadi ketika lidah
dipegang ke depan selama stroboskopi yang kaku, pemeriksaan neurolaring sebaiknya dilakukan dengan melihat laring
dengan laringoskop yang fleksibel. Pangkal tenggorokan dievaluasi untuk mobilitas pita suara, paresis atau kelumpuhan,
koordinasi gerakan, kelincahan, kelesuan, fleksibilitas, dan penggunaan otot-otot tambahan selama fonasi sementara
pasien mengucapkan berbagai frasa dan suku kata. Gangguan hiperfungsional dan hipofungsional seringkali dapat
dibedakan dengan mengisolasi kelompok otot abduktor dan aduktor. Laring juga divisualisasikan saat istirahat.
Stroboskopi kaku memainkan peran penting dalam penilaian karakteristik getaran lipatan vokal, termasuk adanya massa,
lesi, atau kelainan konfigurasi jaringan parut dan glotis, termasuk pola penutupan elips, asimetri fase, dan penutupan fase
abnormal. Pemeriksaan stroboskopi dan neurolaring merupakan pelengkap dalam evaluasi pasien dengan penyakit
Parkinson. Temuan stroboskopi yang umum pada penyakit Parkinson termasuk atrofi pita suara yang sebenarnya atau
bukti lain ketidakmampuan glotis, termasuk gelombang kejar atau fase tertutup yang lebih pendek.
Kumpulan sekresi, penurunan sensasi, dan aspirasi juga merupakan karakterisasi dari penyakit Parkinson laring. Lipatan
vokal yang lumpuh menunjukkan Parkinson-plus syndrome (PPS) sebagai etiologi untuk parkinsonisme jika terdapat
aspek-aspek lain dari diagnosis.
Perez et al menemukan bahwa tremor vokal hadir pada 55% pasien dengan penyakit Parkinson. [29] Menariknya, hanya
35% pasien dengan penyakit Parkinson menunjukkan tremor pita suara yang sedang beristirahat, sedangkan sisanya
menunjukkan tremor kinetik. Tremor pada dasarnya adalah gerakan laring vertikal. PPS ditemukan memiliki insiden
tremor vokal yang lebih tinggi (64%), dengan sebagian besar tremor terletak di arytenoid. Para penulis tidak menemukan
tremor laring vertikal pada pasien dengan PPS. [29]
Disfungsi otonom
Disfungsi otonom sering terjadi pada pasien dengan penyakit Parkinson. Hipotensi ortostatik sering menjadi perhatian
pada penyakit lanjut, dan gangguan motilitas usus dapat menyebabkan sembelit dan, kadang-kadang, muntah atau
gangguan penyerapan. Gejala-gejala kemih, retensi, dan infeksi kandung kemih dapat terjadi, dan disfungsi ereksi tidak
jarang. Selain itu, banyak pasien mencatat episode berkeringat.
Disfungsi otonom yang menonjol, terutama inkontinensia urin terang atau hipotensi ortostatik yang mendalam, mungkin
menyarankan atrofi sistem multipel (MSA) daripada penyakit Parkinson.
Gangguan kardiopulmoner
Postur tubuh pasien yang tertekuk dengan penyakit Parkinson dapat menyebabkan kyphosis, menyebabkan penurunan
kapasitas paru-paru, dan menghasilkan pola penyakit paru yang restriktif.
Pementasan
Para peneliti telah mengusulkan sistem pementasan untuk meningkatkan penilaian tingkat keparahan penyakit Parkinson
secara keseluruhan. Dalam sebuah penelitian observasional, cross-sectional dari 933 pasien dengan penyakit Parkinson,
Ray Chaudhuri dan rekan menemukan perbedaan yang luas antara keparahan gejala nonmotor yang diukur dengan Skala
Gejala NonMotor (NMSS) dan gejala motor yang diukur dengan skala Hoehn dan Yahr [30, 31] Para peneliti mengusulkan
sistem pementasan untuk beban gejala nonmotor berdasarkan skor NMSS, yang berkorelasi dengan ukuran kecacatan
dan kualitas hidup. Sistem staging menilai beban gejala nonmotor (NMSB) pada skala 0 (tanpa NMSB) hingga 4 (NMSB
sangat parah). [30, 31]
Depresi
Mengingat tingginya prevalensi gangguan mood pada penyakit Parkinson, pasien ini harus diskrining secara teratur untuk
depresi. Namun, penilaian depresi pada pasien dengan penyakit Parkinson diperumit oleh fakta bahwa beberapa gejala
penyakit Parkinson tumpang tindih dengan gejala depresi (misalnya, facies seperti topeng, insomnia, perlambatan
psikomotorik, sulit berkonsentrasi, kelelahan). Rasa bersalah dan menyalahkan diri sendiri kurang menonjol pada depresi
pada pasien dengan penyakit Parkinson, sedangkan kecemasan dan pesimisme lebih menonjol.
Demensia
Hoops et al menemukan bahwa pada penyakit Parkinson, Montreal Cognitive Assessment (MoCA) lebih unggul daripada
Mini-Mental State Examination (MMSE) untuk skrining untuk gangguan kognitif ringan atau demensia. [32] MoCA dan
MMSE menunjukkan validitas diskriminan keseluruhan yang sama untuk mendeteksi gangguan kognitif, tetapi sebagai
instrumen skrining, MoCA lebih baik daripada MMSE (64% vs 54% diagnosa yang benar). [32]
Prevalensi demensia pada penyakit Parkinson berkisar antara 20-40%, dengan penyakit ini memberikan peningkatan
risiko 2 hingga 6 kali lipat dibandingkan dengan populasi kontrol. [33] Banyak pasien dengan penyakit Parkinson
mengalami penurunan fungsi eksekutif, bahkan pada awal penyakit. [33] Gangguan kognitif substansial dan demensia
biasanya terjadi 8 tahun atau lebih setelah timbulnya fitur motorik.
Demensia umumnya terjadi terlambat pada penyakit Parkinson; disfungsi kognitif yang substansial dalam 1 tahun setelah
onset fitur motorik menunjukkan diagnosis penyakit tubuh Lewy, penyakit yang berkaitan erat dengan penyakit Parkinson
dan ditandai dengan adanya tubuh Lewy kortikal. Pada kelompok usia yang terkena, komorbiditas dengan gangguan
neurodegeneratif lainnya, khususnya penyakit Alzheimer dan penyakit serebrovaskular, adalah umum. Prevalensi depresi
yang relatif tinggi pada pasien dengan penyakit Parkinson adalah perancu lain dalam diagnosis demensia penyakit
Parkinson.
Fungsi eksekutif, memori jangka pendek, dan kemampuan visuospasial dapat terganggu pada pasien dengan penyakit
Parkinson, tetapi aphasia tidak ada. Dalam sebuah penelitian jangka panjang Australia yang membandingkan tindakan
neuropsikologis antara pasien dengan penyakit Parkinson yang memiliki demensia dini (<10 tahun dengan onset
penyakit) dan mereka dengan demensia lanjut, para peneliti melaporkan bahwa demensia pada parkinson tampaknya
terjadi pada sekitar usia 70 tahun terlepas dari saat timbulnya penyakit Parkinson. [34] Namun, meskipun demensia awal
dan akhir memiliki efek yang serupa dalam ranah kognitif, individu dengan onset parkinson yang dini memiliki
kemampuan linguistik yang terpelihara sebelum timbulnya demensia. [34]
Parkinsonisme atipikal
Parkinsonisme atipikal, atau sindrom Parkinson-plus, adalah gangguan neurodegeneratif primer yang memiliki gambaran
parkinson dan dikaitkan dengan presentasi klinis kompleks yang mencerminkan degenerasi dalam berbagai sistem saraf.
Pasien dengan parkinsonisme atipikal biasanya memiliki prognosis yang lebih buruk daripada mereka yang menderita
penyakit Parkinson, dan parkinsonism yang atipikal merespons dengan buruk terhadap perawatan penyakit standar anti-
Parkinson.
(Untuk informasi lebih lanjut, lihat Parkinson-Plus Syndromes untuk informasi terperinci mengenai petunjuk klinis,
pemeriksaan, diagnosis banding, dan pengobatan parkinsonism atipikal, termasuk atrofi sistem multipel, palsi
supranuklear progresif, parkinsonism-dementia-amyotrophic lateral sclerosis complex, degenerasi ganglion kortikobasal,
dan penyakit tubuh Lewy difus.)
DDx
Pertimbangan Diagnostik
Gangguan tremor yang paling umum adalah penyakit Parkinson dan tremor esensial. Ketika seorang pasien datang
dengan tremor, dokter harus memberikan perhatian khusus pada bagian-bagian tubuh yang terlibat, posisi / kondisi di
mana tremor terjadi (yaitu, istirahat, postural, kinetik, niat), dan frekuensi tremor. Penting juga untuk mencari tanda-tanda
potensial yang terkait. Pasien harus diperiksa untuk bukti parkinsonisme (bradikinesia, kekakuan, ketidakstabilan
postural), distonia, dan tanda-tanda neurologis lainnya.
Sebuah tremor aksi 8-12 Hz (postural / kinetik) dari ekstremitas atas yang untuk sementara waktu diatasi dengan minum
alkohol adalah karakteristik tremor esensial, sedangkan keberadaan tremor rest pil-rolling, bradikinesia, dan kekakuan
konsisten dengan penyakit Parkinson dan berpendapat terhadap tremor esensial.
Pada pasien dengan parkinsonisme, perhatian yang cermat terhadap anamnesis diperlukan untuk menyingkirkan
penyebab sekunder seperti obat-obatan, racun, atau trauma. Obat yang menghambat reseptor dopamin striatal, seperti
metoklopramid dan neuroleptik, dapat menyebabkan parkinsonisme yang diinduksi oleh obat. Toksin tertentu seperti
MPTP (1-metil-4-fenil-1,2,3,6-tetrahidropiridin) dan mangan (pada tingkat paparan yang tinggi) juga dapat menyebabkan
parkinsonisme.
Pertimbangkan untuk mengevaluasi pasien dengan parkinson untuk osteoporosis dan osteopenia. Dalam meta-analisis
dari 23 studi, Tornsey dan rekannya menemukan bukti bahwa individu dengan penyakit Parkinson memiliki peningkatan
risiko osteoporosis dan osteopenia. [35, 36] Analisis yang dikumpulkan dari 2 studi, misalnya, menunjukkan bahwa pada
pasien dengan Penyakit Parkinson, rasio odds untuk mengembangkan osteoporosis, bila dibandingkan dengan kontrol
yang sehat, adalah 2,61, meskipun peningkatannya lebih rendah pada pria daripada wanita.
Analisis dari 14 studi menemukan kepadatan mineral tulang pada pasien dengan penyakit Parkinson secara signifikan
lebih rendah di pinggul, tulang belakang lumbar, dan leher femur, sedangkan, setelah pemeriksaan 9 studi, para peneliti
memperkirakan bahwa risiko patah tulang dua kali lipat pada pasien Parkinson. [35, 36]
Gambaran klinis awal yang menunjukkan parkinsonisme atipikal daripada penyakit Parkinson meliputi yang berikut ini
[22]:
Jatuh saat presentasi atau awal penyakit
Respons buruk terhadap levodopa
Simetri saat onset penyakit
Perkembangan penyakit yang cepat
Tidak ada getaran
Disautonomia (misalnya inkontinensia urin, inkontinensia fekal, kateterisasi untuk retensi urin, kegagalan ereksi
persisten, hipotensi ortostatik simtomatik yang menonjol)
Parkinsonisme atipikal biasanya dikaitkan dengan sedikit atau tidak ada tremor, kesulitan bicara dan keseimbangan yang
relatif dini, dan sedikit atau tidak ada respons terhadap obat-obatan dopaminergik. Multiple system atrophy (MSA) relatif
simetris dan ditandai oleh parkinsonisme, seringkali dengan beberapa kombinasi disfungsi otonom, kortikospinal, dan
serebelar. Palsi supranuklear progresif (PSP) relatif simetris dan ditandai oleh parkinsonisme dengan kejatuhan dini
(sering pada tahun pertama) dan palsi pandangan supranuklear di mana pasien mengalami kesulitan dengan pandangan
ke bawah secara sukarela. Degenerasi ganglionik kortikobasal (CBD) biasanya sangat asimetris dan ditandai oleh
kortikal (kesulitan mengidentifikasi objek, apraxias) dan basal ganglionik (biasanya ditandai kekakuan pada lengan).
Penyakit tubuh Lewy ditandai dengan disfungsi kognitif yang substansial dalam 1 tahun setelah onset parkinsonisme.
Halusinasi sering terjadi.
Pasien dengan onset parkinsonisme sebelum usia 40 tahun harus diuji untuk penyakit Wilson, dimulai dengan
pengukuran serum seruloplasmin dan evaluasi oftalmologis untuk cincin Kayser-Fleischer.
Diagnosis Banding
Penyakit Alzheimer
Stroke kardioembolik
Chorea pada Dewasa
Degenerasi Ganglionik Basal Kortikal
Demensia Dengan Badan Lewy
Dystonia-Responsif Dopamin
Tremor Esensial
Neurodegeneration Terkait Pantothenate Kinase (PKAN)
Penyakit Huntington
Sindrom Lacunar
Multiple System Atrophy
Neuroacanthocytosis
Manifestasi Neurologis dari Demensia Vaskular
Hydrocephalus Tekanan Normal
Atropi Olivopontocerebellar
Sindrom Parkinson-Plus
Palsy Supranuclear Progresif
Degenerasi Striatonigral
Bekerja
Bekerja
Pertimbangan Pendekatan
Penyakit Parkinson adalah diagnosis klinis. Tidak ada biomarker laboratorium yang ada untuk kondisi ini, dan temuan
pada pencitraan resonansi magnetik rutin (MRI) dan pemindaian tomografi terkomputasi (CT) tidak biasa. Positron
emission tomography (PET) dan single-photon emission CT (SPECT) dapat menunjukkan temuan yang konsisten dengan
penyakit Parkinson, dan pengujian penciuman dapat memberikan bukti yang mengarah pada penyakit Parkinson, tetapi
studi ini tidak secara rutin diperlukan. (Pengujian penciuman dapat mengungkapkan hiposmia, yang dapat mendahului
tanda-tanda motorik penyakit Parkinson selama beberapa tahun. [37] Namun, kehilangan penciuman tidak spesifik dan
juga dapat terjadi pada penyakit Alzheimer.)
Tidak diperlukan penelitian laboratorium atau pencitraan pada pasien dengan presentasi tipikal. Pasien tersebut berusia
55 tahun atau lebih dan memiliki parkinsonisme progresif dan asimetris yang lambat dengan tremor istirahat dan
bradikinesia atau kekakuan. Pasien yang tidak memiliki tremor umumnya harus dipertimbangkan untuk evaluasi MRI
untuk mengecualikan lesi otak seperti stroke, tumor, atau demielinasi.
Pada pasien dengan presentasi yang tidak biasa, pengujian diagnostik dapat diindikasikan untuk mengecualikan
gangguan lain dalam diagnosis diferensial. Tes semacam itu mungkin termasuk serum seruloplasmin, sphincter
electromyography, atau lumbar puncture.
Konsentrasi seruloplasmin serum diperoleh sebagai tes skrining untuk penyakit Wilson pada pasien yang lebih muda dari
40 tahun yang datang dengan tanda-tanda parkinsonian. Jika tingkat ceruloplasmin rendah, pengukuran ekskresi
tembaga urin 24 jam dan pemeriksaan slit-lamp untuk cincin Kayser-Fleischer harus dilakukan. Hasil abnormal pada
elektromiografi sfingter urin telah dicatat pada pasien dengan multiple system atrophy (MSA).
A substantial and sustained response to dopamine medications (dopamine agonists or levodopa) helps confirm a
diagnosis of Parkinson disease. It is unclear whether acute levodopa or apomorphine challenge has any advantage over
clinical diagnostic criteria.[22] Over time, diagnostic accuracy improves as the progression of signs and symptoms and
response to medications unfolds.
In the general community, there is a high diagnosis error rate between Parkinson disease and essential tremor. For
movement disorder neurologists, when an erroneous diagnosis of Parkinson disease is made, the most likely correct
diagnoses are the atypical parkinsonisms (MSA, progressive supranuclear palsy [PSP], corticobasal ganglionic
degeneration [CBD]). Early in the disease course, it may be very difficult to distinguish between Parkinson disease and
the atypical parkinsonisms. These disorders also do not have laboratory biomarkers, and, therefore, distinguishing among
them is based on clinical criteria. Olfactory testing may help differentiate Parkinson disease from PSP and CBD, but
olfaction is also reduced in MSA.
Radiologic Studies
Pencitraan resonansi magnetik
Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors, multi-infarct state, hydrocephalus, and the
lesions of Wilson disease. MRI should be obtained in patients whose clinical presentation does not allow a high degree of
diagnostic certainty, including those who lack tremor, have an acute or stepwise progression, or are younger than 55
years.
The following MRI indicates where a thalamic stimulator is typically placed.
Axial, fast spin-echo inversion recovery magnetic resonance image at the level of the posterior commissure. The typical
target for placing a thalamic stimulator is demonstrated (cross-hairs).
Below is a coronal MRI following bilateral subthalamic nuclei deep brain stimulation.
Postoperative coronal magnetic resonance image (MRI) demonstrating desired placement of bilateral subthalamic nuclei-
deep brain stimulation (STN-DBS) leads.
PET and SPECT scanning
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scanning are useful
diagnostic imaging studies, but these are not routinely required. Different radioligands permit imaging of different
components or abnormalities within the brain.
At the onset of motor signs, patients with Parkinson disease show an approximately 30% decrease in18 F-dopa
(fluorodopa) uptake on PET imaging in the contralateral putamen.18 F-Dopa is taken up by the terminals of dopamine
neurons and converted to18 F-dopamine. The rate of striatal18 F accumulation reflects transport of18 F-dopa into
dopamine neurons and its decarboxylation to18 F-dopamine, which is stored in dopamine nerve terminals in the striatum.
Thus,18 F-dopa PET imaging provides an index of remaining dopamine neurons. However, this study is not widely
available, is usually not covered by insurance, and is currently generally considered a research tool.
Carbon-11 (11 C)-nomifensine and cocaine analogues such as123 I-beta-CIT (iodine-123-labeled carboxymethoxy-3beta-4-
iodophenyl-nortropane) and123 I-FP-CIT (fluoropropyl-CIT) bind to dopamine reuptake sites on nigrostriatal terminals and
provide an index of the remaining dopamine neurons. Ioflupane (123 I) (DaTscan) is a radiopharmaceutical agent that is
indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adults
with suspected Parkinsonian syndromes (PSs). This agent may be used to help differentiate essential tremor from tremor
due to PSs (idiopathic Parkinson disease [IPD] and Parkinson-plus syndromes [PPS]).[1] Analysis of data from 2 clinical
trials demonstrated that the use of ioflupane with iodine-123 and single-photon emission computed tomography (SPECT)
scanning to diagnose early-stage Parkinson's disease performed as well as clinical assessment at 1-year follow-up.[38,
39]
Deficits on123 I SPECT scans indicate a dopamine deficiency syndrome but do not differentiate Parkinson disease from
atypical parkinsonisms, including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Ioflupane
SPECT imaging reveals a dopamine deficiency in Parkinson disease, MSA, PSP, corticobasal ganglionic degeneration,
and Lewy body disease. This study is normal in essential tremor, dystonic tremor, medication-induced parkinsonism or
tremor, psychogenic disorders, and in normal individuals.
Histologic Findings
Classic pathologic findings in Parkinson disease include degeneration of the neurons containing neuromelanin, especially
in the substantia nigra and the locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic inclusions called
Lewy bodies (see the following image). The primary biochemical defects are loss of striatal dopamine, which results from
degeneration of dopamine-producing cells in the substantia nigra, as well as hyperactivity of the cholinergic neurons in the
caudate nucleus.
Badan Lewy adalah inklusi eosinofilik intracytoplasmic, sering dengan halo, yang mudah terlihat pada neuron berpigmen,
seperti yang ditunjukkan dalam slide histologis ini.
Mereka mengandung alpha-synuclein terpolimerisasi;
oleh karena itu, penyakit Parkinson adalah sinukleinopati.
Lewy bodies in the locus coeruleus from a patient with Parkinson disease.
Alpha-synuclein is a major structural component of Lewy bodies; all Lewy bodies stain for alpha-synuclein, and most also
stain for ubiquitin. Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense
cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not
pathognomonic, of Parkinson disease. Lewy bodies are also found in the cortex, nucleus basalis, locus ceruleus,
intermediolateral column of the spinal cord, and other areas.
According to the Braak hypothesis, Lewy body pathology in the brain begins in the olfactory bulb and lower brainstem
and slowly ascends to affect dopamine neurons in the substantia nigra and, ultimately, the cerebral cortex.[40] Lewy
body pathology is also observed in autonomic nerves of the gut and heart.
Tusukan Lumbar
Lumbar puncture should be considered if signs of normal-pressure hydrocephalus (NPH) are observed (eg, incontinence,
ataxia, dementia). In NPH, clinical signs characteristically improve after removal of about 20 mL of cerebrospinal fluid.
Dopa-responsive dystonia should be considered in patients with juvenile-onset dystonia and parkinsonism, particularly
with diurnal fluctuations in symptoms. In such patients, a trial of levodopa is critical. Additional tests for this condition
include measurement of CSF concentrations of biopterin, neopterin, and the neurotransmitter metabolites homovanillic
acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). In both forms of dopa-
responsive dystonia, an altered pattern of decreases in these compounds is observed.
In the "Parkinson's Progression Markers Initiative" cross-sectional study of 63 drug-naive patients with early-stage PD and
39 healthy controls, CSF levels of the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau
phosphorylated at threonine 181 (P-tau181), and α-synuclein were lower in the PD patients than in the controls. Aβ1-42
and P-tau181 were significant predictors of Parkinson's disease, and T-tau and α-synuclein were associated with the
severity of motor dysfunction. In particular, lower Aβ1-42 and P-tau181 concentrations were associated with the postural
instability–gait disturbance–dominant PD phenotype, but were not associated with the tremor-dominant or intermediate
phenotypes.[41, 42]
See Lumbar Puncture for detailed information on indications for the procedure, contraindications, and a step-by-step
discussion containing images and video on how to perform the procedure.
Pengobatan
Pertimbangan Pendekatan
Tujuan dari manajemen medis penyakit Parkinson adalah untuk memberikan kontrol tanda dan gejala selama mungkin
sambil meminimalkan efek samping. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is
not instituted at or shortly after diagnosis.[43]
Symptomatic and neuroprotective therapy
Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective (disease modifying)
therapy. At this time, there is no proven neuroprotective or disease-modifying therapy.
Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI), remains the gold standard of symptomatic
treatment for Parkinson disease. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic
circulation, allowing for greater levodopa distribution into the central nervous system. Levodopa provides the greatest
antiparkinsonian benefit for motor signs and symptoms, with the fewest adverse effects in the short term; however, its
long-term use is associated with the development of motor fluctuations (“wearing-off”) and dyskinesias. Once fluctuations
and dyskinesias become problematic, they are difficult to resolve.
Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment of early disease. These drugs provide mild
symptomatic benefit, have excellent adverse effect profiles, and, according to a Cochrane review, have improved long-term
outcomes in quality-of-life indicators by 20-25%.[44]
Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic benefit and delay the development of
dyskinesia compared with levodopa. Proactively screen patients receiving oral dopamine agonists for adverse events. A
review of the Cochrane and PubMed databases from 1990 to 2008 found that these agents caused a 15% increase in
adverse events such as somnolence, sudden-onset sleep, hallucinations, edema, and impulse control disorders (eg,
pathologic gambling, shopping, and Internet use; hypersexuality; and hoarding).[45] Note that patients may be reluctant
to mention these events or may not attribute them to their treatment.
Symptomatic anti-Parkinson disease medications usually provide good control of motor signs of Parkinson disease for 4-
6 years. After this, disability often progresses despite best medical management, and many patients develop long-term
motor complications, including fluctuations and dyskinesias. Additional causes of disability in late disease include
postural instability (balance difficulty) and dementia. Thus, symptomatic therapy for late disease requires different
strategies.
Neuroprotective therapy aims to slow, block, or reverse disease progression; such therapies are defined as those that
slow underlying loss of dopamine neurons. Although no therapy has been proven to be neuroprotective, there remains
interest in the long-term effects of MAO-B inhibitors. Other agents currently under investigation include creatine and
isradipine.
The younger the patient, the more emphasis the authors place on long-term considerations to guide early treatment.
Young patients have a longer life expectancy and are more likely to develop motor fluctuations and dyskinesias. For older
patients and those with cognitive impairment, less emphasis is placed on long-term considerations; instead, the focus is
on providing adequate symptomatic benefit in the near term, with as few adverse effects as possible.
For patients who have motor fluctuations and dyskinesias that cannot be adequately managed with medication
manipulation, surgery is considered. The principal surgical option is deep brain stimulation (DBS), which has largely
replaced neuroablative lesion surgeries. Levodopa/carbidopa intestinal gel infusion is available in some countries and is in
clinical trials in others, including the United States.[12]
Nonmotor symptoms
It is now recognized that in Parkinson disease, nonmotor symptoms may be as troublesome as, or more troublesome
than, motor symptoms. Nonmotor symptoms can be categorized as autonomic, cognitive/psychiatric, and sensory[46]
and may include depression, dementia, hallucinations, rapid eye movement (REM) sleep behavior disorder (RMD),
orthostatic hypotension, and constipation. Nonmotor symptoms can also fluctuate, especially depression, pain,
numbness, paresthesia/dysesthesia, akathisia, and restless-legs syndrome. Recognition of nonmotor symptoms of
Parkinson disease is essential for appropriate management.[46]
Screen Parkinson disease patients for depression, and treat it when present. An evidence-based guideline from the
American Academy of Neurology (AAN) reports that physician recognition of depression is low in Parkinson disease, at
less than 30% of clinically proven cases. There are many factors that confound its diagnosis in these patients; and
depression has the single largest effect on the quality of life of patients with Parkinson disease.[26, 47]
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations
included the following[48] :
Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction
Polyethylene glycol may be considered to treat constipation
Modafinil should be considered for patients who subjectively experience excessive daytime somnolence
For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters
that are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for
poor sleep quality
Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but
there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that
of restless-legs syndrome
Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)
Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence,
anxiety, and RMD
Symptomatic Therapy, Early Disease

Medications commonly used for symptomatic benefit of motor symptoms in early Parkinson disease include levodopa,
monoamine oxidase (MAO)-B inhibitors, and dopamine agonists.
Levodopa
Levodopa, coupled with a peripheral dopa decarboxylase inhibitor such as carbidopa, remains the standard of
symptomatic treatment for Parkinson disease. Ini memberikan manfaat antiparkinson terbesar dengan efek samping
paling sedikit dalam jangka pendek. However, long-term use of levodopa is associated with the development of
fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve. These
adverse effects are the reason to consider delaying the initiation of levodopa if other alternatives are able to control
symptoms.
Levodopa/carbidopa is introduced at a low dose and escalated slowly. Carbidopa inhibits the decarboxylation of levodopa
to dopamine in the systemic circulation, allowing for greater levodopa delivery into the central nervous system.
Currently available levodopa preparations in the United States include levodopa/carbidopa immediate-release (IR) tablets
(Sinemet), levodopa/carbidopa controlled-release (CR) tablets (Sinemet CR), and levodopa/carbidopa orally disintegrating
tablets (Parcopa). The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa IR, but it dissolves on the
tongue without the need to swallow it with water. The orally disintegrating tablet is not absorbed in the mouth but travels in
the saliva to absorption sites in the proximal small bowel (where other levodopa preparations are also absorbed).
Levodopa/carbidopa is also available in combination with entacapone, a catechol-O-methyltransferase (COMT) inhibitor.

When entacapone is given in conjunction with levodopa and carbidopa, plasma levels of levodopa are higher and more
sustained than after administration of levodopa and carbidopa alone. Levodopa/carbidopa/entacapone is useful in
advanced Parkinson disease in patients with motor fluctuations. In the STRIDE-PD (STalevo Reduction In Dyskinesia
Evaluation) study, patients with early Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed
more dyskinesia than patients treated with levodopa/carbidopa; therefore, levodopa/carbidopa/entacapone is not
recommended for treatment of early disease.[49]
Levodopa in combination with a dopa decarboxylase inhibitor is started at a low dose and slowly titrated to control clinical
symptoms. Most patients experience a good response on a daily levodopa dosage of 300–600 mg/day (usually divided 3
or 4 times daily) for 3–5 years or longer. Doses higher than those necessary to control symptoms adequately should be
avoided, because higher doses increase the risk for the development of dyskinesia.[50] If nausea occurs, the levodopa
dose can be taken immediately following a meal. Additional measures to alleviate nausea include adding extra carbidopa
or introducing domperidone (available outside the United States). Other side effects include dizziness and headache. In
elderly patients, confusion, delusions, agitation, hallucinations, and psychosis may be more commonly seen.
MAO-B inhibitors
MAO-B inhibitors, such as selegiline and rasagiline, may be used for early symptomatic treatment of Parkinson disease.
These medications provide mild symptomatic benefit, have excellent adverse effect profiles, and may improve long-term
outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many patients. When the
MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another medication (eg, a dopamine
agonist or levodopa) can be added.
Selegiline is indicated as adjunctive therapy (5 mg every morning; maximum, 10 mg/day) in the treatment of Parkinson
disease in patients being treated with levodopa/carbidopa. Rasagiline is indicated for the treatment of the signs and
symptoms of Parkinson disease as initial monotherapy (1 mg/day) and as adjunctive therapy (0.5-1.0 mg/day) to
levodopa. Potential side effects include nausea, headaches, and dizziness.
Agonis dopamin
Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, is associated with fewer motor
fluctuations and dyskinesias than levodopa alone in prospective, double-blind studies. Subsequent analyses of these
studies indicate that the benefit of dopamine agonists in delaying motor symptoms is due to their ability to delay the need
for levodopa/carbidopa.[51, 52] Commonly used dopamine agonists include pramipexole and ropinirole.
Dopamine agonists provide symptomatic benefit that is comparable to that with levodopa/carbidopa in early disease, but
these agents lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease. Dopamine
agonists provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by themselves, but they
have more adverse effects than levodopa, including sleepiness, hallucinations, edema, and impulse control disorders.
However, these adverse effects resolve upon lowering the dose or discontinuing the medication.
Dopamine agonists are commonly reserved for younger individuals (< 65-70 years) who are cognitively intact. When the
dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms, levodopa can
be added. However, dopamine agonists may provide good symptom control for several years before levodopa is required.
For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more
robust and cognitively intact the patient, the more likely the authors are to treat with a dopamine agonist before levodopa
and add levodopa/carbidopa when necessary. For patients with cognitive impairment and those older than 70 years—who
may be prone to adverse effects, such as hallucinations, from dopamine agonists—and for those likely to require
treatment for only a few years, the authors may elect not to use a dopamine agonist and instead depend on levodopa/PDI
(peripheral decarboxylase inhibitor) as primary symptomatic therapy.
When introducing a dopamine agonist, it is important to start at a low dose and escalate slowly. The dose should be
titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects emerge.
The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations,
somnolence, and impulse control disorders. Nausea can usually be reduced by having the patient take the medication
after meals. Domperidone, a peripheral dopamine agonist available outside the United States, is very helpful in relieving
refractory nausea.
Patients on dopamine agonists should be routinely asked about sleepiness, sudden onset of sleep, and impulse control
disorders such as pathologic gambling, shopping, internet use, and sexual activity. These adverse effects typically resolve
with reduction in dose or discontinuation of the medication. Patients should be warned not to drive if they are experiencing
undue sleepiness. They should also be warned about the possibility of impulse control disorders and the need to let their
physician know if such an effect occurs.
Agen antikolinergik
Anticholinergic agents can be used for patients who have disability due to tremor that is not adequately controlled with
dopaminergic medication, but these are not first-line drugs, because of their limited efficacy and the possibility of
neuropsychiatric side effects. Anticholinergic medications provide good tremor relief in approximately 50% of patients but
do not meaningfully improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication but
not another, a second anticholinergic agent usually can be tried if the first is not successful. These medications should be
introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion,
and hallucinations. Adverse cognitive effects are relatively common, especially in elderly persons.
One of the most commonly used anticholinergic is trihexyphenidyl. The initial dose of trihexyphenidyl should be low and
gradually increased. It is recommended to begin therapy with a single 1-mg dose. Dosage can be titrated by 1 mg each
week or so, until a total of 4-6 mg is given daily or until satisfactory control is achieved. Some patients may require higher
doses. Benztropine (Cogentin) is also commonly used, with an initial dose of 0.5-1 mg daily at bedtime. Dose can be
titrated at weekly intervals in increments of 0.5 mg to a maximum of 6 mg/day.
Amantadine
Amantadine is an antiviral agent that has antiparkinsonian activity. Its mechanism of action is not fully understood, but
amantadine appears to potentiate CNS dopaminergic responses. It may release dopamine and norepinephrine from
storage sites and inhibit the reuptake of dopamine and norepinephrine. Amantadine may offer additional benefit in patients
experiencing maximal or waning effects from levodopa.
Amantadine is commonly introduced at a dose of 100 mg per day and slowly increased to an initial maintenance dose of
100 mg 2 or 3 times daily. The most concerning potential side effects of amantadine are confusion and hallucinations.
Common side effects include nausea, headache, dizziness, and insomnia. Less frequently reported side effects include
anxiety and irritability, ataxia, livedo reticularis, peripheral edema, and orthostatic hypotension.
In a small, double-blind crossover study, amantadine was found to ameliorate pathologic gambling associated with
Parkinson disease.[53] However, in a large cross-sectional study, amantadine was associated with a higher prevalence of
impulse control disorders, including gambling.[54] Thus, further research is needed to understand the role of amantadine
as a treatment or cause of impulse control disorders in patients with Parkinson disease.
Symptomatic Therapy, Advanced Disease

Motor fluctuations
Patients initially experience stable, sustained benefit through the day in response to levodopa. However, after several
months to years, many patients notice that the benefit from immediate-release (IR) levodopa/carbidopa wears off after 4-5
hours. Over time, this shortened duration of response becomes more fleeting, and clinical status fluctuates more and
more closely in concert with peripheral levodopa concentration. Ultimately, benefit lasts only about 2 hours. The time
when medication is providing benefit for bradykinesia, rigidity, and tremor is called "on" time, and the time when
medication is not providing benefit is called "off" time.
Treating motor fluctuations in the absence of peak-dose dyskinesia is relatively easy. Several different strategies, either
alone or in combination, can be used to provide more sustained dopaminergic therapy. Possible strategies include the
following:
Adding a dopamine agonist, catechol-O -methyltransferase (COMT) inhibitor, or monoamine oxidase (MAO)-B
inhibitor
Dosing levodopa more frequently
Increasing the levodopa dose
Adding intermittent levodopa inhaled doses
Switching from immediate-release (IR) to sustained-release (CR) levodopa/carbidopa or

levodopa/carbidopa/entacapone
Continuous intrajejunal infusion of a carbidopa/levodopa enteral suspension[55]
In January 2015, the FDA approved a carbidopa/levodopa enteral suspension (Duopa) that is infused into the jejunum by a
portable pump. The efficacy of the enteral suspension to decrease off-time and increase on-time was shown in a
multicenter, international study. From baseline to 12 weeks, mean off-time decreased by 4.04 hours for 35 patients
allocated to the levodopa/carbidopa intestinal group compared with a decrease of 2.14 hours for 31 patients allocated to
immediate-release oral levodopa/carbidopa (p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11
hours in the intestinal gel group and 2.24 hours in the immediate-release oral group (p=0.0059).[55]
Safinamide (Xadago), a MAO-B inhibitor, was approved by the FDA in March 2017 as add-on treatment for patients with
Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. It is the first new
chemical entity approved in the United States in more than 10 years. Approval was based on 2 phase-III trials that
included nearly 1200 patients who had PD with motor fluctuations. Results showed that safinamide as add-on treatment
to levodopa/carbidopa provided a significant reduction in off-time and a significant increase in on-time without troublesome
dyskinesia in patients experiencing motor fluctuations.[56, 57]
Levodopa inhaled (Inbrija), a dopamine agonist, was approved in December 2018 for intermittent treatment of "off"
episodes in patients who are already treated with oral carbidopa/levodopa. The inhaled dosage form bypasses the
digestive system, thereby providing a quick onset of action as soon as 10 minutes. Approval was based on the phase 3
SPAN-PD trial (N = 339). The change at week 12 in UPDRS III score was -9.83 for patients receiving the 84-mg dose
compared with -5.91 for the group taking placebo (P = 0.009).[132]
Unless limited by the emergence of peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy
should be increased until off-time is eliminated. Once-daily formulations of the dopamine agonists ropinirole and
pramipexole are now available. These medications appear to provide efficacy and safety similar to the IR formulations that
are administered 3 times daily.[58]
Diskinesia
By several months to years after the introduction of levodopa, many patients develop peak-dose dyskinesia consisting of
choreiform, which is twisting/turning movements that occur when levodopa-derived dopamine levels are peaking. At this
point, increasing dopamine stimulation is likely to worsen peak-dose dyskinesias, and decreasing dopamine stimulation
may worsen Parkinson disease motor signs and increase off time. The therapeutic window lies above the threshold
required to improve symptoms (on threshold) and below the threshold for peak-dose dyskinesia (dyskinesia threshold).
The therapeutic window narrows over time because of a progressive decrease in the threshold for peak-dose dyskinesia.
Although many patients prefer mild dyskinesia to off time, the clinician should recognize that dyskinesias can be
sufficiently severe to be troublesome to the patient, either by interfering with activities or because of discomfort. Asking
patients how they feel during both off time and time with dyskinesia is important in titrating medication optimally. Having
patients fill out a diary may be helpful; the diary should be divided into half-hour time periods on which the patient denotes
whether they are off; on without dyskinesia; on with non-troublesome dyskinesia; or on with troublesome dyskinesia (see
the following image). The goal of medical management is to minimize off time and time on with troublesome dyskinesia.
Stated another way, the goal is to maximize on time without troublesome dyskinesia.
Parkinson disease diary. The patient or caregiver should place 1 check mark in each half-hour time slot to indicate the
patient's predominant response during most of that period. The goal of therapeutic management is to minimize off time
and on time with troublesome dyskinesia. Copyright Robert Hauser, 1996. Used with permission.
Treatment of motor fluctuations with dyskinesia
The treatment of patients with both motor fluctuations and troublesome peak-dose dyskinesia can be difficult. The goal of
treatment in this situation is to provide as much functional time throughout the day as possible. This is accomplished by
maximizing on time without troublesome dyskinesia. An attempt is made to reduce both off time and time with
troublesome or disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may increase off time, and an
increase in dopaminergic therapy may worsen peak-dose dyskinesia.
For patients on the levodopa/carbidopa CR formulation, switching to levodopa/carbidopa IR often provides a more
consistent and predictable dosing cycle and allows finer titration. In general, smaller levodopa doses are administered
more frequently. A dose should be sought that is sufficient to provide benefit without causing troublesome dyskinesia. The
time to wearing-off then determines the appropriate interdose interval. The extreme of this strategy is using liquid
levodopa, a solution with which the dose can be titrated finely and administered every hour.
COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -methyldopa (3-OMD), thereby prolonging the
levodopa half-life and making more levodopa available for transport across the blood-brain barrier over a longer period.
Because of the potential risk of hepatotoxicity with tolcapone (Tasmar), liver function test monitoring is required, and this
medication should be used only in patients who are experiencing motor fluctuations on levodopa that cannot be
adequately controlled with other medications. If dyskinesia occurs, the levodopa dose should be reduced. In patients who
already have dyskinesia, the levodopa dose often is reduced by 30-50% at the time tolcapone is introduced.
Entacapone (Comtan) is a COMT inhibitor that does not cause hepatotoxicity; liver function tests are not required with
this medication. Levodopa/carbidopa/entacapone (Stalevo) is currently available as a drug combination for Parkinson
disease.
Similarly, dopamine agonists can be added to levodopa to try to smooth the response. If the patient has both fluctuations
and dyskinesias on levodopa, adding a dopamine agonist is likely to decrease the disease severity and could delay
dyskinesias and motor fluctuations; then, an attempt can be made to lower the levodopa dose.
The FDA approved amantadine (Gocovri) extended-release (ER) capsules for the treatment of dyskinesia in Parkinson
disease patients receiving levodopa-based therapy, with or without concomitant dopaminergic medications. Amantadine
ER, previously known as ADS-5102, is the first drug FDA-approved for this indication.
The safety and efficacy of amantadine ER was seen in two Phase 3 controlled trials in Parkinson disease patients with
dyskinesia. In the Easy LID trial, amantadine ER-treated patients had statistically significant and clinically relevant
reductions in dyskinesia as per the Unified Dyskinesia Rating Scale (UDysRS) total score vs. placebo at Week 12 (37%
vs. 12%). In the Easy LID 2 trial, amantadine ER-treated patients had a 46% reduction in UDysRS compared with 16% in
the placebo arm. For both studies, treatment with amantadine ER increased functional time daily (ON time without
troublesome dyskinesia) for patients at Week 12 (3.6 hours and 4.0 hours, respectively) vs. placebo (0.8 hour and 2.1
hours, respectively).[59, 60]
This should be considered for patients who have clinically relevant dyskinesia and who appear likely to be able to tolerate
this medication. Results from the 3-month, parallel-group, washout AMANDYSK (AMANtadine for DYSKinesia) study
showed that amantadine treatment maintained its antidyskinetic effect over several years in patients with Parkinson
disease and levodopa-induced dyskinesia.[61, 62]
The principal side effects of amantadine are hallucinations and confusion, so the drug is usually not appropriate for
patients with preexisting cognitive dysfunction.
For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication
manipulation, surgery is considered.
Getaran
Levodopa/carbidopa, dopamine agonists, and anticholinergics each provide good benefit for tremor in approximately 50-
60% of patients. If a patient is experiencing troublesome tremor and if symptoms are not controlled adequately with one
medication, another should be tried. If the tremor is not controlled adequately with medication, surgical therapy may be
considered at any time during the disease.
Bradykinesia
A study published in Neurology found that laser shoes can improve freezing episodes in patients with PD. The shoes are
specially designed to emit a laser beam on the ground ahead, providing a visual cue to the patient and a target to aim for.
In the study, the shoes cut freezing episodes and their overall duration by 49.5% when patients were off medication and
37.7% when patients were on medication.[63]
Putative Neuroprotective Therapy

Neuroprotective therapies are defined as those that slow underlying loss of neurons. Currently, no proven neuroprotective
therapies exist for Parkinson disease. If a neuroprotective therapy were available for Parkinson disease, it would be
administered from the time of diagnosis onward. At the current time, the greatest interest in possible neuroprotection
resides with the monoamine oxidase (MAO)-B inhibitors, selegiline, and rasagiline. Other agents of interest include
creatine and isradipine. Clinical trials have not provided support for neuroprotective effects for vitamin E or coenzyme Q10.
Selegiline
Selegiline (Eldepryl, Zelapar) is an irreversible inhibitor of MAO-B. In humans, brain dopamine is metabolized by MAO-B,
and the blockade of this enzyme will reduce the metabolism of dopamine. Selegiline was shown conclusively to delay the
need for levodopa therapy in early Parkinson disease, in the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of
Parkinsonism) study.[64, 65] The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay
progression of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/day)
or placebo and tocopherol (2000 IU/day) or placebo. Patients who received selegiline, with placebo or with tocopherol,
experienced a significant delay in the need for levodopa therapy. Patients who received placebo required levodopa at a
projected median of 15 months from enrollment, whereas those who received selegiline required levodopa
ataprojectedmedianof24monthsafterenrollment.Tocopherolhadnoeffectonprogression of disability.[64, 65]
Because selegiline was observed to provide a small but statistically significant symptomatic (early) benefit, it is not
possible to determine whether a neuroprotective effect contributed to the delay in need for levodopa in the DATATOP
study.[64, 65]
In another study, patients with early Parkinson disease who received selegiline over a 7-year period experienced less
clinical progression and required less levodopa than patients receiving placebo.[66] In this study, patients with early
Parkinson disease were randomized to selegiline or placebo, and levodopa was added as needed. After 5 years, patients
who were treated with placebo had Unified Parkinson Disease Rating Scale (UPDRS) scores that were 35% higher
(worse) than those treated with selegiline, even as they were receiving 19% higher doses of levodopa.[66] This is a
striking finding, considering that as monotherapy in early disease, selegiline provides only modest symptomatic
improvement.
Selegiline is the medication that first garnered wide interest as a possible neuroprotective agent for Parkinson disease.
Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons
independent of MAO-B inhibition. Selegiline was reported to protect dopamine cells in mice from MPTP (1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine) toxicity, even when the agent was administered after a delay sufficient to allow the
oxidation of MPTP to MPP+ (1-methyl-4-phenylpyridinium),[67] an effect that cannot be attributed to MAO-B inhibition.
In cell-culture systems, selegiline's neuroprotective effect is mediated by new protein synthesis. Selegiline induces
transcriptional events that result in increased synthesis of antioxidant and antiapoptotic proteins. Evidence indicates that
one of selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection. It is possible that selegiline's
amphetamine metabolites may interfere with its neuroprotective actions.
Rasagilin
Rasagiline (Azilect) is also an MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models.
Possible disease-modifying effects of rasagiline were studied in 2 large, delayed-start studies. In such studies, subjects
are randomized to treatment with active study medication or to placebo followed by active study medication. This creates
2 phases within the study. In phase I, one group is on placebo, and the other is on active study medication; in phase II,
both groups are receiving active study medication. If phase II is long enough to allow full wash-in of symptomatic effects,
any differences between the groups at the end of the study should be due to enduring benefits (ie, disease modification)
that accrue only to the group that received active study medication during phase I.
Stated another way, in a delayed-start design, half of the subjects in the study take the trial drug from day 1 and the other
half take placebo. However, halfway through the study, the placebo group is switched from placebo to the trial drug. If the
drug is truly beneficial in slowing progression of the disease, those that started the trial on placebo should never catch up,
in terms of disease progression, to those who were given the trial drug from the beginning of the study.
ADAGIO and TEMPO studies
In October 2011, the US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory
Committee voted against approval of an indication for disease-modifying effects for rasagiline. The advisory committee
determined that the 2 delayed-start rasagiline studies did not provide compelling evidence that rasagiline slows
progression of Parkinson disease. These trials were the ADAGIO (Attenuation of Disease progression with Azilect Given
Once-daily)[68, 69] and TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients)[70, 71] studies,
which are discussed below.
In the TEMPO study, patients were randomized to treatment with rasagiline 1 mg/day for 12 months; rasagiline 2 mg/day
for 12 months; or placebo for 6 months, followed by rasagiline 2 mg/day for 6 months.[70] Rasagiline administered at a
dosage of 1 or 2 mg/day for the first 6 months resulted in improved Unified Parkinson Disease Rating Scale (UPDRS)
scores relative to placebo; there was also a higher proportion of patients with treatment responses in the active treatment
groups than in the placebo group.[70] In addition, both of the rasagiline groups showed significant differences, compared
with the placebo group, in the motor and activities of daily living (ADL) subscales of the UPDRS and in the Parkinson
Disease Quality of Life (PDQUALIF) scale.[70]
Over the 12 months of the TEMPO study, patients who were initially treated with placebo had a greater progression in
clinical symptomatology as assessed by UPDRS scores than did patients who were treated with rasagiline for the full 12
months. This finding suggested that there was an effect over and above a simple symptomatic effect and potentially
consistent with a disease-modifying effect.[72] When the TEMPO investigators looked at the long-term (6.5-year follow-up
period) outcome of early rasagiline therapy relative to late therapy in early Parkinson disease, patients in the early
rasagiline treatment group—who received the drug from the beginning of the TEMPO study—had significantly less
worsening of their total UPDRS scores than patients in the delayed-start group, even as investigators added other
antiparkinson medications as needed.[71]
In the large and rigorous delayed-start study called ADAGIO, patients with early Parkinson disease were randomized to
rasagiline 1 mg/day for 18 months; rasagiline 2 mg/day for 18 months; placebo for 9 months, followed by rasagiline 1
mg/day for 9 months; or placebo for 9 months, followed by rasagiline 2 mg/day for 9 months. Results demonstrated that
rasagiline at 1 or 2 mg/day was associated with a slower rate of worsening in the active drug groups, relative to the
placebo groups.[69] Over 18 months, rasagiline 1 mg/day started early resulted in less worsening in mean total UPDRS
score than when it was started late. However, for the groups that received rasagiline 2 mg/day, there was no difference at
18 months between the early-start and delayed-start groups.[69]
Based on their findings, the ADAGIO investigators concluded that early treatment with rasagiline at a dose of 1 mg/day
provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a
dose of 2 mg/day did not.[69] They speculated that the effect of the 2-mg dose on symptoms may have masked any
disease-modifying effects in patients with mild Parkinson disease; they also noted that it was possible that results with 1
mg/day were false positive, rather than the results with 2 mg/day being false negative.[69]
Thus, there remains interest as to whether selegiline and rasagiline improve long-term outcome for Parkinson disease
patients, but this is not definitively proven, and the mechanism is unclear.
Levodopa
Clinical trial data suggest that levodopa therapy in early Parkinson disease can potentially slow progression or has a
prolonged effect on the symptoms of the disease.[73] However, neuroimaging studies also indicate that loss of
nigrostriatal dopamine nerve terminals may be accelerated or the dopamine terminals may be modified with use of
levodopa.[73] In a study by Parkkinen et al that evaluated whether chronic levodopa use accelerates pathologic cerebral
processes in parkinsonism, the investigators did not find such a progression based on nigral neuronal count and Lewy
body pathology.[74] Nonetheless, the lowest dose that is necessary to maintain good function should be used to avoid
motor complications.[23] Additional research is needed to determine whether levodopa accelerates, slows, or has no
effect on disease progression.
Agonis dopamin
Dopamine agonists have been used to provide symptomatic relief in early Parkinson disease. In vivo experiments have
demonstrated that the ergot and nonergot dopamine agonists protect cultured cells from death due to oxidative damage.
Clinical data in patients with early Parkinson disease provide neuroimaging results that suggest a possible
neuroprotective effect.[73, 75] Various studies have been conducted with ropinirole and pramipexole; however, definitive
neuroprotection cannot be confirmed on the basis of these studies.[76, 77]
Stimulasi Otak Jauh

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease for the following
reasons:
It does not involve destruction of brain tissue
It is reversible
It can be adjusted as the disease progresses or adverse events occur
Prosedur bilateral dapat dilakukan tanpa peningkatan efek samping yang signifikan
Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of Parkinson disease
largely because long-term complications of levodopa therapy result in significant disability over time. A better
understanding of basal ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and
electrophysiologic recording have allowed surgical procedures to be performed more accurately and with lower morbidity.
Surgery for movement disorders previously involved predominantly destructive lesioning of abnormally hyperactive deep
brain nuclei; however, the observation that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the
thalamus eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible
alternative to lesioning procedures.
Continued refinement of the knowledge of basal ganglia circuitry and Parkinson disease pathophysiology has narrowed
the focus of movement disorder surgery to 3 key gray-matter structures: the thalamus, the globus pallidus, and the
subthalamic nucleus (STN). Currently, the STN is the most commonly targeted site for Parkinson disease. (See the
following image.)
Bagian sagital, 12 mm lateral garis tengah, menunjukkan inti subthalamic (STN) (lavender).
STN adalah salah satu target bedah yang disukai untuk stimulasi otak dalam untuk mengobati gejala penyakit Parkinson
lanjut.
DBS surgery includes subthalamic nucleus (STN) stimulation, globus pallidus interna (GPi) stimulation, and thalamic
deep brain stimulation (see the following images). The UK National Collaborating Centre for Chronic Conditions notes the
following indications for STN and GPi in patients with Parkinson disease[23] :
The presence of motor complications refractory to medical therapy
The absence of significant comorbidities in a biologically fit individual
The absence of significant mental health problems (eg, depression, dementia)
Response to levodopa
A key to patient selection is that appropriate patients still experience a good response to levodopa, but that response
cannot be adequately maintained through the day or is complicated by excessive dyskinesia.
The deep brain stimulating lead is equipped with 4 electrode contacts, each of which may be used, alone or in
combination, for therapeutic stimulation.
Implantation of the deep brain stimulation (DBS) lead.
Insertion of an electrode during deep brain stimulation for Parkinson disease.
Thalamic DBS has been used in patients with predominantly severe and disabling tremor.[23] However, this surgery is
now rarely used in patients with Parkinson disease, because it has been shown that other symptoms continue to
progress, causing significant disability that is not controlled by thalamic DBS.
Recent landmark studies have demonstrated the effectiveness of STN and GPi DBS for appropriate Parkinson disease
patients.[78] In a randomized, controlled trial of 255 patients enrolled in the Veterans Affairs (VA) Cooperative Studies
Program (CSP) trial for patients with advanced Parkinson disease, bilateral DBS (STN and GPi) was more effective than
best medical therapy in improving on time without troublesome dyskinesia, motor function, and quality of life at 6 months;
however, DBS was associated with an increased risk of serious adverse events.[79] In the same study, when the 2-year
outcomes of 147 patients who received STN DBS and 152 patients who received GPi DBS were compared, motor function
and adverse events were not significantly different between the 2 sites.[80] However, those who received STN DBS had a
greater reduction in dopaminergic medications, and individuals who received GPi DBS had significantly less depression.
[80]
Investigators from the EARLYSTIM Study Group reported that relative to medical therapy alone, STN DBS in conjunction
with medical therapy offers benefits earlier in the course of PD, before the appearance of severe disabling motor
complications.[81, 82] Moreover, subthalamic stimulation plus medical therapy was superior to medical therapy alone on
several key measures of quality of life and motor function. However, 54.8% of the patients in the DBS group suffered
serious adverse events, compared to 44.1% of those in the medical-therapy group[81, 82] ; 17.7% of patients suffered
serious adverse events related to surgical implantation or the neurostimulation device.
A study by Foltynie assessed 79 consecutive patients who underwent bilateral subthalamic nucleus DBS at the National
Hospital for Neurology and Neurosurgery using an MRI-guided surgical technique without microelectrode recording.[83] At
a median follow-up period of 12-14 months, a mean improvement of 27.7 points (standard deviation, 13.8) was noted in the
off-medication motor part of the Unified Parkinson Disease Rating Scale (UPDRS III), equivalent to a mean improvement of
52%. Significant improvements in dyskinesia duration, disability, and pain were noted. This suggests that in well-selected
patients with Parkinson disease, image-guided STN DBS without microelectrode recording can lead to substantial
improvements in motor disability and improvements in quality of life, with very low morbidity.
A randomized trial by Moreau et al assessed the effectiveness of the drug methylphenidate in improving gait disorders
and freezing of gait in patients with advanced Parkinson disease without dementia who also received subthalamic nucleus
stimulation (STN). Eighty-one patients from 13 movement disorders departments in France were randomly assigned to
methylphenidate or placebo for 90 days. Compared with patients in the placebo group, patients in the methylphenidate
group used fewer steps at 90 days. These results suggest methylphenidate may improve gait hypokinesia and freezing
although further study is needed to determine long-term risks.[84]
There is evidence that long-term motor improvement from STN DBS is sustained overall. However, axial signs
progressively decline over time and contribute to a waning of the initial benefit of this procedure.[85]
Although not specifically approved by the Food and Drug Administration (FDA) for pain, STN DBS may be effective in
improving specific types of pain related to Parkinson disease,[86, 87] such as musculoskeletal pain[86, 88] and dystonic
pain. However, there is a risk of postoperative deterioration of somatic pain exacerbated by Parkinson disease and
radicular/peripheral neuropathic pain due to lumbar spine diseases. Patients with central pain have had a poor response
to STN DBS.[86]
STN DBS may result in either a favorable or an unfavorable outcome in patients with Parkinson disease and impulse
control and related disorders.[89] Although there may be resolution or improvement of impulse control disorders following
STN DBS, the procedure may also induce, exacerbate, reveal, or have no effect on these conditions.[89]
In 2017, the FDA approved the Vercise DBS system to treat symptoms of Parkinson disease. The device is a
rechargeable implantable pulse generator with a potential battery life of 15 years. It has been available in Europe since
2012.[90]
(See Deep Brain Stimulation forParkinson Disease for a more extensive discussion of deep brain stimulation in this
setting, including mechanisms of action, advantages and disadvantages, and stages of the procedure.)
Neuroablative Lesion Surgeries

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease.
Lesion surgeries for Parkinson disease have largely been replaced by deep brain stimulation (DBS). During neuroablation,
a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to
heat the lesioning electrode tip to the prescribed temperature in a controlled fashion.
Thalamotomy and pallidotomy
Thalamotomy involves destruction of a part of the thalamus, generally the ventralis intermedius (VIM), to relieve tremor.
The VIM nucleus is considered the best target for tremor suppression, with excellent short- and long-term tremor
suppression in 80-90% of patients with Parkinson disease. Thalamotomy has little effect on bradykinesia, rigidity, motor
fluctuations, or dyskinesia. When rigidity and akinesia are prominent, other targets, including the globus pallidus interna
(GPi) and subthalamic nucleus (STN), are preferred.
Svenillson and Leksell described ventral posterior pallidotomy in the 1960s[91] ; however, their report was largely
overlooked. The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called medial
pallidotomy effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the
posteroventral and lateral GPi, resulting in sustained improvement in as many as 96% of patients. In 1992, Laitinen et al
reported reduced tremor, rigidity, akinesia, and levodopa-induced dyskinesia in 38 patients treated with pallidotomy,
prompting a reappraisal of the procedure performed with more modern techniques.[92]
Pallidotomy involves destruction of a part of the GPi. Pallidotomy studies have demonstrated significant improvements in
each of the cardinal symptoms of Parkinson disease (tremor, rigidity, bradykinesia), as well as a significant reduction in
dyskinesia.
The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual
field. This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi.
The risk of visual-field deficit is reduced greatly by accurate delineation of the ventral GPi border by microelectrode
recording. Less frequent complications (< 5%) include injury to the internal capsule, facial paresis, and intracerebral
hemorrhage (1-2%). Abnormalities of speech, swallowing, and cognition may also be observed.
Bilateral pallidotomy is not recommended because complications are relatively common and include speech difficulties,
dysphagia, and cognitive impairment.
Subthalamotomy
Hyperactivity of the excitatory STN projections to the GPi is a crucial physiologic feature of Parkinson disease.
Subthalamotomy involves destruction of a part of the STN. Although lesioning the STN usually has been avoided because
of the concern about producing hemiballismus, results obtained by experimental lesions of the STN in animals and
humans suggest that subthalamotomy may be performed safely and may reverse parkinsonism dramatically.
Subthalamotomy studies have shown significant improvements in the cardinal features of Parkinson disease, as well as
the reduction of motor fluctuations and dyskinesia.
Evaluasi Praoperatif
Good surgical outcomes begin with careful patient selection and end with attentive, detail-oriented postoperative care. The
authors believe that this level of care is best provided by a multidisciplinary team that includes a movement disorder
neurologist, a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a
neuropsychologist. Additional support from neuroradiology and rehabilitation medicine is essential.
First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important
for successful subthalamic nucleus (STN) deep brain stimulation (DBS), because a number of factors determine positive
surgical outcome.[93, 94] These can be summarized as follows:
A diagnosis of Parkinson disease
Positive response to levodopa
Absence of atypical parkinsonian features
Advanced disease, virtually unmanageable with dopaminergic medications
Relatively young age; however, advanced age (>75 years) is not an absolute contraindication to surgery (if a patient
otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially,
surgery should be offered)
No significant cognitive impairment
Absence of active psychiatric disease
Good social support and access to programming
Potential surgical candidates are then evaluated by the neurosurgeon, who determines whether the patient is indeed a
surgical candidate and decides which procedure(s) would benefit the patient most. Close collaboration between the
neurologist and the neurosurgeon aids the decision-making process, minimizing patient confusion and stress. If the
neurologist and neurosurgeon agree that the patient is a good surgical candidate, further workup includes the following:
Brain magnetic resonance imaging (MRI) to rule out comorbid conditions and to assess the degree of brain
atrophy; significant atrophy may increase the risk of perioperative hemorrhage
Detailed neuropsychological testing to rule out cognitive impairment, which can be worsened by the surgical
procedure
A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active
psychiatric disease and screen for relevant past psychiatric history that may pose a contraindication to surgery (eg,
major depression, suicidality).
A fluorodopa positron emission tomography (PET) scan may be performed in the unusual circumstance of diagnostic
uncertainty. A medical evaluation is performed to determine the patient's general fitness for surgery.
Surgery is reserved for patients with disabling motor fluctuations and dyskinesia or disabling tremor that cannot be
adequately controlled with medications. Key points to consider are as follows:
Ablative surgery such as thalamotomy, pallidotomy, and subthalamotomy have largely been replaced by DBS
Thalamic DBS is offered to the minority of patients with Parkinson disease who have predominant and disabling
tremor (more commonly, this procedure is performed on patients with disabling essential tremor)
Bilateral STN DBS (or globus pallidus interna [GPi] DBS) is offered to patients with advanced Parkinson disease
with disabling motor fluctuations and/or dyskinesia or disabling tremor that cannot be adequately controlled by
medications; outcomes have been shown to be similar after STN and GPi DBS
Before surgery, the patient should be informed that these procedures do not cure Parkinson disease and that
progression is expected
Neural Transplantation
Neural transplantation is a potential treatment for Parkinson disease, because the most significant neuronal degeneration
is site and type specific (ie, dopaminergic); the target area is well defined (ie, striatum); postsynaptic receptors are
relatively intact; and the neurons provide tonic stimulation of the receptors and appear to serve a modulatory function.
Transplantation of autologous adrenal medullary cells and fetal porcine cells has not been found to be effective in double-
blind studies and has been abandoned. Although open-label studies of fetal dopaminergic cell transplantation yielded
promising results, 3 randomized, double-blind, sham-surgery–controlled studies found no net benefit. In addition, some
patients receiving these transplants developed a potentially disabling form of dyskinesia that persisted even after
withdrawal of levodopa. Features such as gait dysfunction, freezing, falling, and dementia are likely due to
nondopaminergic pathology and hence are unlikely to respond to dopaminergic grafts.[95]
Lewy body–like inclusions have been found in grafted nigral neurons in long-term transplant recipients; these inclusions
stained positively for alpha-synuclein and ubiquitin and had reduced immunostaining for dopamine transporter, suggesting
that Parkinson disease may affect grafted cells.[14]
Human retinal pigment epithelial cells produce levodopa, and retinal pigment epithelial cells in gelatin microcarriers have
been implanted into the putamen in preliminary studies. A phase II double-blind, randomized, multicenter, sham-surgery–
controlled study of this technique has been completed.[96, 97] Parkinson disease patients received no benefit from this
procedure compared to sham surgery. In addition, in one case study, postmortem examination in a patient who died 6
months after surgical implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells.[98]
Terapi gen
Several studies have demonstrated the safety of gene therapy as a treatment for Parkinson disease, and larger studies
have been initiated to examine the efficacy of this procedure. Three investigational strategies that use gene transfer for
targeted protein expression are as follows[99] :
Improving dopamine availability to the striatum using more continuous delivery,
Reducing STN activity with local induction of gamma-aminobutryic acid (GABA) expression
Protection/restoration of nigrostriatal neuronal function with trophic factor expression
A double-blind, phase II, randomized, controlled trial of gene delivery of the trophic factor neurturin via an adeno-
associated type-2 vector (AAV2) in Parkinson patients aged 30-75 years suggested mild efficacy. Further studies are
ongoing.[100]
Management of Psychiatric Comorbidities

Demensia
Although no specific therapy exists for dementia, the American Academy of Neurology evaluated the evidence regarding
the use of cholinesterase inhibitors in Parkinson disease dementia.[101] Based on their review, they suggested that
rivastigmine (Exelon) and donepezil (Aricept) are probably effective in treating Parkinson disease dementia.
Anticholinergic drugs used for the treatment of motor symptoms of Parkinson disease may exacerbate memory
impairment. When possible, avoid these medications.
Depresi
Depression is one of the most common nonmotor symptoms of Parkinson disease, occurring in approximately 35% of
patients.[102, 103] This condition is more common in patients with Parkinson disease than in the general elderly
population and in those with chronic conditions such as osteoarthritis. Depression in Parkinson disease has a profound
impact on quality of life and is associated with reduced function, cognitive impairment, and increased caregiver stress.
A systematic review of prevalence studies of depression in Parkinson disease found that 17% of patients present with
major depression, 22% with minor depression, and 13% with dysthymia[104] Moreover, multiple studies have found that a
history of depression is a risk factor for the subsequent development of Parkinson disease.[105]
Imaging, cerebrospinal fluid, and autopsy studies indicate that depression in Parkinson disease is associated with
dysfunction of basal ganglia dopaminergic circuits that project to the frontal lobes, as well as noradrenergic limbic and
brainstem structures.[103] Whether serotonin (5-HT) dysfunction plays a role in depression in PD is unclear.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used medications to treat depression in
Parkinson disease in clinical practice. However, several randomized controlled trials, systematic reviews, and meta-
analyses have suggested that SSRIs may be no more effective than placebo in this situation.[47, 103, 106]
Positive results in randomized clinical trials have been demonstrated for nortriptyline (a tricyclic antidepressant [TCA] with
serotoninergic and adrenergic activity), desipramine (a predominantly noradrenergic reuptake inhibitor TCA), venlafaxine (a
serotonin-noradrenaline uptake inhibitor), citalopram (an SSRI), and paroxetine (an SSRI).[103] For example, in Parkinson
disease patients that were diagnosed with depressive disorder or operationally-defined subsyndromal depression,
venlafaxine extended release or paroxetine significantly reduced scores on the Hamilton Rating Scale for Depression
compared to placebo. Both venlafaxine and paroxetine were well tolerated and did not worsen motor function.[107]
There is a suggestion that noradrenergic or dual action (noradrenergic/serotoninergic) antidepressants may be more
effective for treating depression in Parkinson disease than SSRIs. However, whether this is an artifact of clinical-trials
methodology is not yet clear, and more research is necessary.
Antiparkinsonian medications can also exert an antidepressant effect. In a large, randomized trial, pramipexole (mean
daily dose, 2.18 mg) significantly reduced depression scores relative to placebo.[108] The monoamine oxidase (MAO)-B
inhibitor selegiline was also demonstrated to provide an antidepressant effect in patients with early Parkinson disease
who were not clinically depressed.[109]
Preliminary studies suggest that repetitive transcranial magnetic stimulation (rTMS) may be effective for depression in
Parkinson disease, but more research is required. Electroconvulsive therapy (ECT) can be considered for refractory
moderate to severe depression.
Psychotic symptoms (hallucinations or delusions)
Antiparkinsonian drugs can trigger psychosis in patients with Parkinson disease. In Parkinson disease patients with
psychosis, antiparkinsonian medications other than levodopa should be withdrawn in an effort to resolve psychosis while
maintaining motor control with levodopa. In individuals with only mild hallucinations that are well tolerated, active
antipsychotic treatment may not be necessary.
Pimavanserin (Nuplazid) was approved in April 2016 for treatment of hallucinations and delusions associated with
Parkinson disease psychosis. It is the first drug to be approved for this condition. It is a selective serotonin inverse
agonists (SSIA). It not only preferentially targets 5-HT2A receptors, but also avoids activity at dopamine and other
receptors commonly targeted by antipsychotics. Efficacy was shown in a 6-week clinical trial (n=199), where it was
shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without
worsening the primary motor Parkinson disease symptoms (p=0.001).[110]
Use of some other typical antipsychotics can exacerbate motor symptoms of Parkinson disease and should be avoided.
[23]
Quetiapine is the atypical neuroleptic agent most commonly used by movement-disorder experts, because it rarely
exacerbates motor symptoms and blood monitoring is not required. However, its efficacy has not been confirmed in
clinical trials. Quetiapine is used in Parkinson disease at doses much lower than those used in schizophrenia. It is
usually introduced at a dose of 25 mg at bedtime and can be increased to 50 mg or more at bedtime as necessary.
Clozapine can also be used, but blood monitoring is required due to its potential for agranulocytosis and other severe side
effects.[23, 111] For this reason, clozapine is usually reserved for patients who are not adequately controlled with
quetiapine. Other atypical neuroleptics generally have more potential to worsen Parkinson disease motor symptoms than
quetiapine and clozapine.
Kegelisahan
The 2010 American Academy of Neurology (AAN) practice parameter on the treatment of nonmotor symptoms in
Parkinson disease found insufficient evidence to support or refute the treatment of anxiety in Parkinson disease with
levodopa.[48] However, SSRIs and venlafaxine (Effexor, Effexor XR) may be beneficial. Buspirone is well tolerated but has
not been studied in this population. Benzodiazepines can be considered, but adverse effects such as cognitive
impairment, somnolence, and balance problems may be concerning. Behavior modification techniques can play an
important role in the treatment of anxiety.[112]
Impulse behaviors
Cognitive-behavioral therapy (CBT) can help control impulse behaviors in PD. In a study of 45 patients with idiopathic PD
and associated impulse control behaviors that had not responded to standard treatment, CBT significantly improved
symptom severity, neuropsychiatric disturbances, and depression and anxiety levels. Of the 45 patients, 17 were
randomly assigned to a 6-month wait list for CBT along with standard medical care and 28 were randomized to CBT
starting immediately. Among the 28 patients in the treatment group, 58% completed all 12 sessions of CBT and 88%
completed at least 6. Three-quarters of those receiving the treatment had improved symptom severity compared with only
about a third of those who did not receive the therapy.[113, 114]
In a placebo-controlled pilot study of 50 patients with idiopathic PD who developed impulse control disorder (ICD)
symptoms while receiving dopamine agonist treatment, Papay and colleagues found that the opioid antagonist naltrexone
improved ICD symptoms, as measured on a PD-specific rating scale.[115, 116]
Naltrexone was administered at 50 mg daily for 4 weeks and then increased to 100 mg daily for 4 weeks in
nonresponders. The difference in response rate on the Clinical Global Impression-Change (CGI-C) scale between the
naltrexone (54.5%) and placebo (34.8%) groups was not significant (P = 0.23). Estimated changes on the patient-
completed Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) from
baseline to week 8, however, significantly favored naltrexone: a change of 14.9 points for naltrexone vs 7.5 points for
placebo (P = 0.04). Nausea and headache were the most common side effects of naltrexone treatment.[115, 116]
Gangguan tidur
Benzodiazepines can be helpful in the treatment of rapid eye movement (REM) sleep behavior disorder (RBD), and
obstructive sleep apnea (OSA) can be treated with positive airway pressure with either continuous pressure or bilevel
pressure. Sleep hygiene techniques include avoiding stimulants/fluids near bedtime, avoiding heavy late-night meals, and
following a regular sleep schedule.[112, 117] It is advised that patients with Parkinson disease and sudden-onset sleep
avoid driving and take precautions against potential occupational hazards.[23]
The 2010 AAN practice parameter found insufficient evidence to support or refute beneficial effects from the treatment of
RBD in Parkinson disease. Other sleep disorders may benefit from treatment. Levodopa/carbidopa should be considered
to treat periodic limb movements of sleep. Modafinil may improve patients' subjective perceptions of excessive daytime
somnolence (EDS), and methylphenidate may be considered in patients with fatigue.[48]
Exercise and Physical Therapy

Exercise therapy in patients with Parkinson disease using a variety of physiotherapy interventions may play a role in
improving gait, balance and flexibility, aerobic capacity, initiation of movement, and functional independence. Studies
generally have suggested improvement in functional outcomes, but the observed benefits were small in magnitude and
were not sustained following discontinuation of the exercise.[77]
A systematic review of 33 randomized trials involving 1518 patients evaluated various physiotherapy interventions,
including general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. There were significant
improvements for walking speed, walking endurance and step length, mobility (the Timed Up & Go test), and balance.
Unified Parkinson's Disease Rating Scale (UPDRS) scores were also improved with physiotherapy. There was no benefit
observed for falls or patient-rated quality of life, and there was no evidence that one type of physiotherapy was superior to
others.[118]
There has been a resurgence of interest in the potential benefit of exercise in Parkinson disease, including a possible
neuroprotective effect.[119] Vigorous exercise in mid-life is associated with a reduced risk of subsequent Parkinson
disease. In animal models, vigorous exercise provides a protective effect against a variety of toxins that cause
parkinsonism. In addition, in healthy people, serum brain-derived neurotrophic factor (BDNF) increases after exercise, in
proportion to the intensity of the activity. In Parkinson disease, BDNF levels in the substantia nigra are reduced, and in
animal models of Parkinson disease, BDNF provides a neuroprotective effect. This is an area of active research.
Terapi berbicara
The laryngeal manifestations of Parkinson disease often lead to decreased participation in the activities of daily living
because of an inability to communicate effectively. During the course of the disease, 45-89% of patients report speech
problems, and more than 30% find speech problems to be the most debilitating part of the disease.
Medications and surgery cannot effectively treat the laryngeal manifestations of Parkinson disease. For this reason,
speech therapy plays a key role in the disease's vocal treatment regimen. Speech therapy is effective in treating the
laryngeal manifestations of Parkinson disease, but despite the significant number of patients with vocal symptoms, only
an estimated 3-4% of patients with Parkinson disease undergo speech therapy.
The Lee Silverman Voice Treatment (LSVT) is a program designed to increase vocal intensity in patients with Parkinson
disease. The treatment focuses on a simple set of tasks that are practiced intensively, 4 sessions per week during a 4-
week period, resulting in maximization of phonatory and respiratory functions. The goal of LSVT is to improve vocal
performance for 6-24 months without interval intervention. LSVT focuses on maximizing vocal effort ("think loud, think
shout") and maximizing sensory perception of vocal effort and loudness by therapists. Therapists who quantify results
give constant feedback to patients during sessions and encourage patients to self-monitor and internally calibrate their
loudness. After LSVT, patients with Parkinson disease speak at a normal volume and with a healthy voice quality despite
the need to "think loud, think shout."
In studies with a 2-year follow-up, patients who received LSVT maintained or improved vocal intensity compared with
pretreatment levels. Glottal incompetence and swallowing ability both improved after LSVT, without any significant change
in supraglottal hyperfunction. Preliminary positron emission tomography (PET) scans after LSVT training in patients with
Parkinson disease show reduced activity in the globus pallidus, an effect similar to pallidotomy. LSVT may also stimulate
coordination of motor output beyond the phonatory system in the form of increased orofacial expression.
Other therapies have been suggested for the treatment of the vocal symptoms in Parkinson disease, but most data so far
support LSVT as the most promising therapy for Parkinson disease laryngeal symptoms. Alternative methods of
delivering therapy that do not involve 16 face-to-face sessions with a therapist are currently being studied. These methods
incorporate webcam delivery of LSVT (eLOUD) and software programs that patients can perform at home. These
technologically enhanced methods, when used to replace half of the face-to-face sessions, have documented outcomes
that are equivalent to classic LSVT. The hope is that such alternatives will be implemented to allow a less transportation-
intensive therapy course for the patient and to allow follow-up review of the LSVT techniques as needed.
A systematic review of clinical trials of speech and language therapy in Parkinson disease identified 3 randomized
controlled trials that included 61 patients. The authors concluded that although improvements were noted, they were not
able to conclusively confirm or refute the benefit of speech and language therapy in Parkinson disease due to the small
number of patients in these trials, methodologic limitations, and possible publication bias.[120]
Dietary Considerations
Proper nutritional support is essential for patients with Parkinson disease, including adequate dietary fiber to prevent the
common problem of constipation. Patients recently diagnosed with Parkinson disease are often confused regarding
dietary protein, because they receive conflicting information.
Levodopa is absorbed via a large neutral amino acid active carrier system and therefore competes with dietary proteins for
absorption; this effect is generally relatively small and is not clinically important for most patients, especially those with
early or moderate disease. However, as the disease progresses and patients become more and more sensitive to
maintaining relatively narrow therapeutic serum concentrations of levodopa, this effect can become clinically relevant.
These patients usually have significant motor fluctuations. Some report that when they are "on" and they eat a meal
including protein, they turn "off." Others find that if they eat a protein meal, their next levodopa dose does not kick in.
These patients may benefit from a low protein or a protein redistributed diet.
In a low-protein diet, the total daily protein intake is spread more or less equally over the day. In a protein-redistributed
diet, individuals only consume food very low in protein during the day and then eat a high-protein meal in the evening.
Unfortunately, these diets are difficult to follow; dietary consultation may be beneficial for patients in whom such diets are
considered.
For patients with early and moderate Parkinson disease, the considerations are quite different. As with patients with more
advanced Parkinson disease, patients with early and moderate Parkinson disease will get the most complete and
consistent absorption of levodopa by taking their levodopa doses a half hour or more before meals or 1 hour or more after
meals. However, most patients with early or moderate disease will not notice a difference in clinical benefit, whether they
take their levodopa with meals or apart from meals.
Even if there is some reduction in clinical benefit when levodopa is taken with meals, this can be mitigated by increasing
the levodopa dose, if necessary. In patients with early disease, the primary concern regarding levodopa is typically
nausea, which is less likely to occur if they take their levodopa dose at the completion of meals. Therefore, in early
Parkinson disease, it is common to instruct patients to take their levodopa after meals to reduce the likelihood of nausea
as the dose is titrated to clinical effect.
Some studies have shown mild motor benefit with Mucuna pruriens (cowhage, velvet bean), which contain levodopa, and
Vicia faba (broad or fava bean) may have short-term benefits.[77] However, additional studies are needed.
Vitamin E and coenzyme Q10 have not been shown to have a neuroprotective effect in Parkinson disease,[64, 121] and
they are not currently recommended as dietary supplements for this condition.
Konsultasi
Generally, patients with Parkinson disease are best treated and monitored by a neurologist or movement disorder
specialist. Depending on the patient, consultations may include the following:
Ahli Bedah Saraf
Psikiater
Ahli Urologi
Fisiotris
Ahli ilmu gizi
Ahli THT
Ahli gastroenterologi
Terapi bicara
Neurosurgical consultation may be appropriate in patients with tremor, dyskinesias, motor fluctuations, or dystonia
refractory to medical treatment. However, patients with dementia or significant psychiatric or behavioral problems are not
candidates for current neurosurgical treatments for Parkinson disease.
Psychiatric consultation may be required to control mood disorders and psychiatric symptoms, especially in patients with
refractory depression or psychosis.
A urologist is consulted for evaluation and treatment of urinary frequency, urgency, incontinence, or erectile dysfunction.
A physiatrist, physical therapist, or occupational therapist may be able to improve the patient's ability to perform activities
of daily living, reduce pain, and avoid fractures and compression neuropathies from falls. Botulinum injections for limb
dystonia can be very helpful and are administered by specially trained physiatrists or neurologists.
A nutritionist can help ensure adequate energy intake, particularly when low-protein diets are needed to avoid adverse
effects of levodopa.
An otolaryngologist can offer vocal fold bulking procedures in the form of vocal fold injection or Gore-Tex thyroplasty as a
possibility in treating refractory true vocal fold bowing. Bilateral injections to medialize the vocal fold can offer
improvement, unless the patient is already aphonic due to advanced disease. Bilateral collagen, gel, fat, and
hydroxyapatite injections have been used for this purpose.[122] Articulatory problems can persist, and the result of
surgery can be disappointing.
A gastroenterologist and a speech therapist may be needed to evaluate dysphagia, a common complication in patients
with more advanced Parkinson disease. Excessive sialorrhea can be treated with botulinum toxin injections into the
salivary glands, usually administered by neurologists or otolaryngologists. In some patients, a gastrostomy may be
needed to maintain adequate nutrition.
Pemantauan Jangka Panjang

Patients with Parkinson disease must have regular follow-up care to ensure adequate treatment of motor and behavioral
abnormalities. Once patients are stable on a medication regimen, provide follow-up care at least every 3-6 months, and
periodically adjust medication dosages as necessary. Patients also need to be monitored for adverse events, including
somnolence, sudden-onset sleep, impulse control disorders, and psychosis. In addition, patients should be evaluated and
treated for emergence of clinically relevant nonmotor symptoms, including dementia, psychosis, sleep disorders, and
mood disorders.
Future Treatments for Parkinson Disease

Future treatments for Parkinson disease are covered in Future Treatments for Parkinson's Disease: Surfing the PD
Pipeline. This article provides a discussion of new therapies in clinical development that may alleviate motor features or
slow disease progression, including A2a antagonists, levodopa formulations, other antiparkinsonian medications,
antidyskinesia medications, and gene therapy.[123]
Pedoman
Ringkasan Pedoman
American Academy of Neurology (AAN)
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations
included the following[48] :
Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction
Polyethylene glycol may be considered to treat constipation
Modafinil should be considered for patients who subjectively experience excessive daytime somnolence
For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters
that are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for
poor sleep quality
Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but
there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that
of restless-legs syndrome
Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)
Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence,
anxiety, and RMD
Obat
Medication Summary
The cornerstone of symptomatic treatment for Parkinson disease (PD) is dopamine replacement therapy. The criterion
standard of symptomatic therapy is levodopa (L-dopa), the metabolic precursor of dopamine, in combination with
carbidopa, a peripheral decarboxylase inhibitor (PDI). This combination provides the greatest symptomatic benefit with the
fewest short-term adverse effects.
Dopamine agonists such as pramipexole and ropinirole can be used as monotherapy to improve symptoms in early
disease or as adjuncts to levodopa in patients whose response to levodopa is deteriorating and in those who are
experiencing fluctuations in their response to levodopa.
Monoamine oxidase (MAO)-B inhibitors (eg, rasagiline, safinamide, selegiline) provide symptomatic benefit as
monotherapy in early disease and as adjuncts to levodopa in patients experiencing motor fluctuations.
Catechol-O -methyl transferase (COMT) inhibitors inhibitors such as entacapone and tolcapone may be used to increase
the peripheral half-life of levodopa, thereby delivering more levodopa to the brain over a longer time.
Anticholinergic medications can be used for the treatment of resting tremor. However, they are not particularly effective for
bradykinesia, rigidity, gait disturbance, or other features of advanced Parkinson disease; and cognitive side effects are
common. Therefore anticholinergics are usually reserved for the treatment of tremor that is not adequately controlled with
dopaminergic medications.
Pimavanserin is the first medication approved by the FDA for hallucinations and delusions associated with PD. It is a
selective serotonin inverse agonists (SSIA) which preferentially targets 5-HT2A receptors and avoids activity at dopamine
and other receptors commonly targeted by antipsychotics.
Dopamine Agonists
Class Summary
Dopamine agonists are effective as monotherapy in early PD and as adjuncts to levodopa/PDI (peripheral decarboxylase
inhibitor) in moderate to advanced disease. Dopamine agonists directly stimulate postsynaptic dopamine receptors to
provide antiparkinsonian benefit. All available dopamine agonists stimulate D2 receptors, an action that is thought to be
clinically beneficial. The role of other dopamine receptors is currently unclear.
Dopamine agonists are effective to treat motor features of early PD, and they cause less development of motor
fluctuations and dyskinesia than levodopa. For patients with motor fluctuations on levodopa/PDI, the addition of a
dopamine agonist reduces off time, improves motor function, and allows lower levodopa doses.
Carbidopa/levodopa (Sinemet, Sinemet CR, Rytary, Duopa)

Carbidopa/levodopa is approved for the treatment of symptoms of idiopathic PD, postencephalitic parkinsonism, and
symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide and/or manganese
intoxication. Levodopa, combined with a peripheral decarboxylase inhibitor (PDI) such as carbidopa, is the criterion
standard of symptomatic treatment for PD; it provides the greatest antiparkinsonian efficacy in moderate to advanced
disease with the fewest acute adverse effects. When administered alone, levodopa causes a high incidence of nausea
and vomiting due to the formation of dopamine in the peripheral circulation. Carbidopa inhibits the decarboxylation of
levodopa to dopamine in the peripheral circulation thereby reducing nausea and allowing for greater levodopa distribution
into the CNS. Carbidopa does not cross the blood-brain barrier.
Sustained-release capsules (Rytary) may improve drug delivery for patients unable to swallow effectively. The capsule
may be either swallowed whole or opened and sprinkled on a small amount of applesauce for immediate consumption.
An enteral suspension (Duopa) is administered by a portable pump into the jejunum over a 16-hr period to improve on-time
and decrease off-time in patients with motor fluctuations with advanced Parkinson disease.
Levodopa inhaled (Inbrija)

Powder for inhalation is systemically absorbed via lungs, and therefore bypasses GI absorption, which may be variable in
patients with PD. Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is converted to
dopamine in the brain. It is indicated for intermittent treatment of "off" episodes in patients with Parkinson disease who
are taking oral carbidopa/levodopa.
Apomorphine (Apokyn)
Apomorphine is a nonergoline dopamine agonist indicated for the acute, intermittent treatment of hypomobility "off"
episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced PD. It is administered
by a subcutaneous injection. Although the exact mechanism by which apomorphine exerts its therapeutic effects in PD is
unknown, it is thought to occur via activation of postsynaptic D2 receptors in the striatum.
Pramipexole (Mirapex, Mirapex ER)
Pramipexole is approved as monotherapy in early disease and as adjunctive therapy to levodopa/PDI in more advanced
stages. The mechanism of action of pramipexole as a treatment for PD is unknown, although it is believed to be related to
its ability to stimulate D2 dopamine receptors in the striatum. It is available as an immediate-release and an extended-
release tablet.
Ropinirole (Requip and Requip XL)

Ropinirole is approved as monotherapy in early disease and as adjunctive therapy to levodopa/PDI in more advanced
disease. Ropinirole is a nonergot dopamine agonist that has high relative in vitro specificity and full intrinsic activity at the
D2 subfamily of dopamine receptors; it binds with higher affinity to D3 than to D2 or D4 receptor subtypes. The
mechanism of action of ropinirole is stimulation of dopamine D2 receptors in striatum. It is available as an immediate-
release and an extended-release tablet.
Amantadine (Gocovri)
Amantadine is approved for the treatment of idiopathic PD, postencephalitic parkinsonism, and symptomatic
parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication. The extended-release
capsule is indicated for dyskinesia in patients with PD. Amantadine is available as a syrup, tablet, capsule, and an
extended-release capsule. The exact mechanism of amantadine for the treatment of PD and dyskinesia associated with
PD is unknown. Amantadine is a weak, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.
Rotigotine (Neupro)
Dopamine agonist stimulating D3, D2, and D1 receptors. Improvement in Parkinson-related symptoms thought to be its
ability to stimulate D2 receptors within the caudate putamen in the brain. Indicated for the treatment of the signs and
symptoms of idiopathic Parkinson disease (PD). Dosage ranges differ for early-stage PD and advanced-stage PD.
Available as transdermal patch that provides continuous delivery for 24 h
Antikolinergik
Class Summary
Anticholinergics are commonly used as symptomatic treatment of PD, both as monotherapy and as part of combination
therapy. Anticholinergic agents provide benefit for tremor in approximately 50% of patients but do not substantially
improve bradykinesia or rigidity. If one anticholinergic does not work, try another.
Trihexyphenidyl
Trihexyphenidyl is indicated as an adjunct for all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic).
It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa.
It is a synthetic tertiary amine anticholinergic agent. It has a direct antispasmodic action on smooth muscle and has
weak mydriatic, antisecretory, and positive chronotropic activities. In addition to suppressing central cholinergic activity,
trihexyphenidyl may also inhibit reuptake and storage of dopamine at central dopamine receptors, thereby prolonging the
action of dopamine. It is commonly used in combination with other antiparkinsonian agents. Generally, anticholinergic
agents can help control tremor but are less effective for treating bradykinesia or rigidity.
Benztropine mesylate (Cogentin)

Benztropine mesylate is approved for use as an adjunct in the therapy of all forms of PD. It partially blocks striatal
cholinergic receptors, and by blocking muscarinic cholinergic receptors in the CNS, benztropine reduces the excessive
cholinergic activity present in parkinsonism and related states. It can also block dopamine reuptake and storage in CNS
cells. In general, anticholinergic agents can help control tremor but are less effective for treating bradykinesia or rigidity.
MAO-B inhibitors
Class Summary
MAO-B inhibitors inhibit the activity of MAO-B oxidases that are responsible for inactivating dopamine.
Selegiline (Eldepryl, Zelapar)

Selegiline is approved as adjunctive therapy to levodopa/carbidopa in patients who exhibit deterioration in response to that
therapy. For patients who are experiencing motor fluctuations on levodopa/carbidopa, the addition of selegiline reduces off
time, improves motor function, and allows levodopa dose reductions. If a patient experiences an increase in troublesome
dyskinesia, reduce the levodopa dose. Selegiline blocks the breakdown of dopamine and extends the duration of action of
each dose of levodopa.
Rasagiline (Azilect)
Rasagiline is indicated for the treatment of the signs and symptoms of idiopathic PD as initial monotherapy and as
adjunctive therapy to levodopa. Rasagiline is an irreversible MAO-B inhibitor that blocks dopamine degradation. Rasagiline
at a dosage of 1 mg once daily is given as monotherapy. When it is given as adjunctive therapy, an initial dose of 0.5 mg
once daily is administered. Dosage adjustments are required if clinical response is not seen.
Safinamide (Xadago)
Safinamide inhibits MAO-B activity, by blocking the catabolism of dopamine. It is indicated as add-on treatment for
patients with Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes.
Acetylcholinesterase Inhibitors, Central
Class Summary
Pathologic changes in dementia associated with PD involve cholinergic neuronal pathways that project from the basal
forebrain to the cerebral cortex and hippocampus. These pathways may be involved in memory, attention, learning, and
other cognitive processes. Acetylcholinesterase inhibitors may exert their therapeutic effect by enhancing cholinergic
function through inhibition of acetylcholinesterase.
Donepezil (Aricept)
Donepezil is a reversible inhibitor of ACh and exerts its beneficial effects by enhancing cholinergic function. It is indicated
for the treatment for dementia of the Alzheimer type.
Rivastigmine (Exelon)
Rivastigmine is indicated for the treatment of mild to moderate dementia associated with PD. In addition, it is also
approved for the treatment of mild to moderate dementia of the Alzheimer type.
Rivastigmine is a selective, competitive, and reversible acetylcholinesterase (ACh) inhibitor. It may reversibly inhibit
cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in CNS and
thereby enhance cholinergic function. The effect may lessen as the disease process advances and fewer cholinergic
neurons remain functionally intact. It is available as a capsule and an extended-release transdermal.
Galantamine (Razadyne, Razadyne ER)

Galantamine is a competitive and reversible inhibitor of ACh. It is approved for the treatment of mild to moderate dementia
of the Alzheimer type.
NMDA Antagonists
Class Summary
Persistent activation of CNS N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been
hypothesized to contribute to the symptomatology of dementia. Agents such as memantine, which is an NMDA receptor
antagonist, can prevent activation of the NMDA receptors.
Memantine (Namenda, Namenda XR)

Memantine is approved for the treatment of moderate to severe dementia in Alzheimer disease. Initial dosage is 5 mg
once daily for immediate-release tablets and 7 mg once daily for extended-release tablets. Dosage titration may be
required based on clinical response.
Memantine is postulated to exert its therapeutic effect through its action as a low- to moderate-affinity, uncompetitive
NMDA receptor antagonist. Blockade of NMDA receptors by memantine slows the intracellular calcium accumulation and
helps prevent further nerve damage.
COMT Inhibitors
Class Summary
Catechol-O -methyl transferase (COMT) inhibitors inhibit the peripheral metabolism of levodopa, making more levodopa
available for transport across the blood-brain barrier over a longer time. For patients with motor fluctuations on
levodopa/carbidopa, the addition of a COMT inhibitor decreases off time, improves motor function, and allows lower
levodopa doses.
Tolcapone (Tasmar)
Tolcapone is an adjunct to levodopa/carbidopa therapy in PD in patients who are experiencing motor fluctuations.
Because of the risk of hepatotoxicity, tolcapone is reserved for patients who have not responded adequately to, or are not
appropriate candidates for, other adjunctive medications. If improvement is not apparent within 3 weeks, this medication
should be withdrawn.
Tolcapone is a selective and reversible inhibitor of COMT. In the presence of a decarboxylase inhibitor such as carbidopa,
COMT is the major degradation pathway for levodopa. By inhibiting COMT, there are more sustained plasma levels of
levodopa, as well as enhanced central dopaminergic activity.
Entacapone (Comtan)
Entacapone is approved as an adjunct to levodopa/carbidopa for patients who are experiencing signs and symptoms of
end-of-dose "wearing-off." The mechanism of action of entacapone is related to its ability to inhibit COMT and alter
plasma pharmacokinetics of levodopa. When given in conjunction with levodopa and an aromatic amino acid
decarboxylase inhibitor (eg, carbidopa), plasma levels of levodopa are more sustained than after administration of
levodopa and an aromatic amino acid decarboxylase inhibitor alone. These sustained plasma levels of levodopa may
result in more constant dopaminergic stimulation in the brain. This may lead to greater effects on signs and symptoms of
PD, as well as increased levodopa adverse effects (which sometimes require a levodopa dose decrease).
Carbidopa, levodopa, and entacapone (Stalevo)

Carbidopa/levodopa/entacapone is indicated for the treatment of PD to substitute (with equivalent strengths of each of the
3 components) for immediate-release carbidopa/levodopa and entacapone previously administered as individual products.
It is also used to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience
the signs and symptoms of end-of-dose "wearing-off" (only for patients taking a total daily dose of levodopa of 600 mg or
less and not experiencing dyskinesias).
Carbidopa inhibits dopa decarboxylation, thereby allowing more complete levodopa distribution to the CNS. Levodopa is a
dopamine precursor capable of crossing the blood-brain barrier, thereby increasing CNS dopamine following conversion.
Entacapone inhibits COMT, another enzyme that metabolizes levodopa. COMT inhibition increases and sustains levodopa
plasma levels, enabling more blood-brain barrier penetration.
Selective Serotonin Inverse Agonists (SSIA)
Class Summary
SSIAs preferentially target 5-HT2A receptors, but does not affect activity of dopamine and other receptors commonly
targeted by antipsychotics.
Pimavanserin (Nuplazid)
Pimavanserin is an SSIA which preferentially targets 5-HT2A receptors and avoids activity at dopamine and other
receptors commonly targeted by antipsychotics. It is indicated for hallucinations and delusions associated with PD.
pertanyaan
Ikhtisar
Which major neurological findings are characteristic of Parkinson disease (PD)?
Why is it important to recognize both motor and nonmotor symptoms in patients with suspected Parkinson disease
(PD)?
What are the initial clinical symptoms of Parkinson disease (PD)?
What are the initial motor signs of Parkinson disease (PD)?
What are the diagnostic criteria for Parkinson disease (PD)?
What is the goal of medical management of Parkinson disease (PD)?
Which medications are used to control symptoms of Parkinson disease (PD)?
Which medications are used to control the nonmotor symptoms of Parkinson disease (PD)?
What is deep brain stimulation for Parkinson disease (PD)?
What causes Parkinson disease (PD)?
What are the three motor signs of Parkinson disease (PD)?
What causes of tremor should be considered in the differential diagnoses of Parkinson disease (PD)?
How is a diagnosis confirmed in patients with a typical Parkinson disease (PD) presentation?
When are imaging studies considered in the diagnosis of Parkinson disease (PD)?
Which medications are used to control the motor symptoms of Parkinson disease (PD)?
What part of the brain is affected by Parkinson disease (PD)?
What are the neuropathologic findings of Parkinson disease (PD)?
How does Parkinson disease (PD) affect the basal ganglia motor circuit?
What is the etiology of Parkinson disease (PD)?
Which environmental risk factors may increase the risk of developing Parkinson disease (PD)?
Does exposure to pesticides, herbicides, or other pollutants increase the risk of developing Parkinson disease (PD)?
Does high caffeine intake or smoking increase the risk of developing Parkinson disease (PD)?
Does 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause Parkinson disease (PD)?
What is the oxidation hypothesis of the etiology of Parkinson disease (PD)?
What is the role of genetic factors in the development of Parkinson disease (PD)?
Which gene mutations may be related to Parkinson disease (PD)?
Which genetic mechanisms are thought to cause Parkinson disease (PD)?
What is the role of alpha-synuclein in the pathogenesis of Parkinson disease (PD)?
What is the relationship between melanoma and Parkinson disease (PD)?
What is the incidence of Parkinson disease (PD)?
How does the incidence of Parkinson disease (PD) change with age, and are men and women equally affected?
What is the impact of levodopa treatment on the prognosis and mortality rate of Parkinson disease (PD)?
What factors are predictive of the rate of progression of Parkinson disease (PD)?
What educational information should be given to patients with Parkinson disease (PD)?
Presentasi
What are the initial physical findings of Parkinson disease (PD)?
Which nonmotor symptoms precede the motor signs of Parkinson disease (PD)?
What are the initial clinical symptoms of Parkinson disease (PD)?
What is the typical presentation of tremors due to Parkinson disease (PD)?
What is bradykinesia in patients with Parkinson disease (PD)?
What are the characteristics of facial bradykinesia in patients with Parkinson disease (PD)?
What are the characteristics of truncal bradykinesia in patients with Parkinson disease (PD)?
How does bradykinesia manifest in activities of daily life in patients with Parkinson disease (PD)?
What is cogwheel rigidity in patients with Parkinson disease (PD)?
How does dystonia present in patients with Parkinson disease (PD)?
What are the cardinal signs of Parkinson disease (PD)?
How is resting tremor assessed in a physical exam in patients with Parkinson Disease (PD)?
How is rigidity assessed in a physical exam in patients with Parkinson disease (PD)?
How is bradykinesia assessed in a physical exam in patients with Parkinson disease (PD)?
How is postural instability assessed in patients with Parkinson disease (PD)?
Which speech tendencies should be assessed in patients with Parkinson disease (PD)?
What are manifestations of dysphagia in patients with Parkinson disease (PD)?
How is laryngeal dysfunction assessed in patients with Parkinson disease (PD)?
What are characterizations of the Parkinson disease (PD) larynx?
What is the prevalence of vocal tremor in patients with Parkinson disease (PD)?
Is autonomic dysfunction common in patients with Parkinson disease (PD)?
Does prominent autonomic dysfunction suggest an alternative diagnosis to Parkinson disease (PD)?
Which cardiopulmonary impairments may be caused by Parkinson disease (PD)?
How is Parkinson disease (PD) severity assessed and staged?
How is depression assessed in patients with Parkinson disease (PD)?
Which assessment is most effective in screening for mild cognitive impairment or dementia in patients with Parkinson
disease (PD)?
What is the prevalence of dementia in patients with Parkinson disease (PD)?
When in the course Parkinson disease (PD) does dementia or other cognitive impairment typically occur?
What are atypical parkinsonisms (Parkinson-plus syndromes)?
What is the prognosis of atypical parkinsonisms (Parkinson-plus syndromes)?
DDX
How is essential tremor differentiated from Parkinson disease (PD)?
Which secondary causes of parkinsonism (Parkinson-plus syndromes) should be considered in the differential diagnoses
of Parkinson disease (PD)?
Does Parkinson disease (PD) increase the risk of osteoporosis and osteopenia?
Does Parkinson disease (PD) increase the risk of bone fracture?
What features differentiate an atypical parkinsonism (Parkinson-plus syndromes) from Parkinson disease (PD)?
How is Lewy body disease characterized in patients with parkinsonism?
When should Wilson disease be considered in patients with parkinsonism?
What are the differential diagnoses for Parkinson Disease?
Bekerja
Which lab studies are useful in the diagnosis of Parkinson disease (PD)?
Are any lab tests or imaging studies required for the diagnosis of Parkinson disease (PD)?
What tests may be indicated in patients with an unusual presentation of Parkinson disease (PD)?
How is Wilson disease screened for in the evaluation of patients with suspected Parkinson disease (PD)?
How is the clinical diagnosis of Parkinson disease (PD) confirmed?
Why is there a high diagnosis error rate between Parkinson disease (PD) and other movement disorders?
When is MRI indicated in the evaluation of patients with suspected Parkinson disease (PD)?
What is the role of PET scanning and SPECT in the evaluation of patients with Parkinson disease (PD)?
What are the usual histologic findings in Parkinson disease (PD)?
What histologic findings i Lewy bodies in patients with Parkinson disease (PD)?
What were the results of the Parkinson's Progression Markers Initiative (PPMI)?
When is lumbar puncture considered in the evaluation of patients with suspected Parkinson disease (PD)?
When should dopa-responsive dystonia be considered in the evaluation of Parkinson disease (PD)?
Pengobatan
What is the goal of medical management of Parkinson disease (PD)?
Are there neuroprotective (disease modifying) treatment options for Parkinson disease (PD)?
What is the role of levodopa in the management of Parkinson disease (PD)?
What is the role of monoamine oxidase (MAO)-B inhibitors in the management of Parkinson disease (PD)?
What is the role of dopamine agonists (ropinirole, pramipexole) in the treatment of Parkinson disease (PD)?
How long are medications effective in controlling the motor signs of Parkinson disease (PD)?
What is neuroprotective (disease modifying) therapy in the context of Parkinson disease (PD)?
How does the management of Parkinson disease (PD) differ in younger patients?
What are the indications for surgery in patients with Parkinson disease (PD)?
How are the nonmotor symptoms of Parkinson disease (PD) categorized?
What are the American Academy of Neurology (AAN) guidelines for the treatment of nonmotor symptoms of Parkinson
disease (PD)?
Which medications are commonly used to control motor symptoms in early Parkinson disease (PD)?
What are the long-term risks of levodopa for the management of Parkinson disease (PD)?
What is the benefit of combining carbidopa with levodopa in the management of Parkinson disease (PD)?
What are the available preparations of levodopa/carbidopa?
How is the combination of levodopa, carbidopa, and entacapone used in the management of Parkinson disease (PD)?
What is the recommended dosage for levodopa and a dopa decarboxylase inhibitor in the management of Parkinson
disease (PD)?
What are the benefits of using MAO-B inhibitors (selegiline and rasagiline) in the treatment of Parkinson disease (PD)?
When are selegiline and rasagiline indicated in the treatment of Parkinson disease (PD)?
How effective are dopamine agonists in the treatment of Parkinson disease (PD)?
Should dopamine agonists be used in the treatment of Parkinson disease (PD) in patients older than 65 years?
What dosage is recommended for the introduction of a dopamine agonist in the treatment of Parkinson disease (PD)?
What are the adverse effects of dopamine agonists?
When are anticholinergic medications indicated in the treatment of Parkinson disease (PD)?
How effective are anticholinergic agents in the treatment of Parkinson disease (PD)?
What are the possible adverse effects of anticholinergic agents in patients with Parkinson disease (PD)?
What are the recommended dosages of anticholinergic agents in the treatment of Parkinson disease (PD)?
What is amantadine's mechanism of action in controlling parkinsonian activity?
What is the recommended dosage for amantadine in the treatment of Parkinson disease (PD)?
What are the potential adverse effects of amantadine?
Does amantadine increase or decrease impulse control disorders in patients with Parkinson disease (PD)?
Which drugs reduce dyskinesis in patients with Parkinson disease (PD)?
Does the benefit of levodopa for the management of Parkinson disease (PD) decrease over time?
What options are available to provide more sustained dopaminergic therapy in patients with Parkinson disease (PD)?
How effective is carbidopa/levodopa enteral suspension (Duopa) in increasing the benefit of levodopa in the treatment of
Parkinson disease (PD)?
How effective is safinamide (Xadago) in in increasing the benefit of levodopa in the management of Parkinson disease
(PD)?
When should dopaminergic therapy be increased to eliminate off-time in patients with Parkinson disease (PD)?
What is peak-dose dyskinesia in patients with Parkinson disease (PD)?
Is it safe to continue increasing dosage of levodopa if the patient develops dyskinesia?
What is the goal of treating patients with Parkinson disease (PD) who experience both motor fluctuation and peak-dose
dyskinesia?
What is the benefit of switching from levodopa/carbidopa CR to levodopa/carbidopa IR in the treatment of Parkinson
disease (PD)?
What is the role of COMT inhibitors in the treatment of Parkinson disease (PD)?
Are dopamine agonists beneficial in the management of Parkinson disease (PD) patients with both motor fluctuation and
peak-dose dyskinesia?
What are the potential adverse effects of amantadine?
Are there any surgical options for patients with Parkinson disease (PD) who have both motor fluctuations and dyskinesia?
What are the treatment options for tremor in patients with Parkinson disease (PD)?
What is the role of laser shoes in reducing freezing episodes among patients with Parkinson disease (PD)?
Are any neuroprotective therapies available for Parkinson disease (PD)?
Does selegiline (Eldepryl, Zelapar) have neuroprotective effects in patients with Parkinson disease (PD)?
Does rasagiline (Azilect) have neuroprotective effects in patients with Parkinson disease (PD)?
What were the results of the TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients) study?
What were the results of the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily) study?
What are the potential neuroprotective effects of levodopa therapy in early Parkinson disease (PD)?
What are the potential neuroprotective effects of dopamine agonists in Parkinson disease (PD)?
Why is deep brain stimulation (DBS) the surgical procedure of choice for Parkinson disease (PD)?
Which gray-matter structures are involved in deep brain stimulation (DBS) surgery for Parkinson disease (PD)?
What are the indications for deep brain stimulation (DBS) surgery in patients with Parkinson disease (PD)?
How are patients with Parkinson disease (PD) selected for deep brain stimulation (DBS)?
Is thalamic deep brain stimulation (DBS) indicated for patients with Parkinson disease (PD)?
How effective is subthalamic nucleus (STN) stimulation and globus pallidus interna (GPi) deep brain stimulation (DBS) in
the management of Parkinson disease (PD)?
How effective is bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease
(PD)?
Is methylphenidate effective in improving gait disorders in patients with advanced Parkinson disease (PD)?
What is the long-term effectiveness of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson
disease (PD)?
Is subthalamic nucleus (STN) deep brain stimulation (DBS) effective for treating pain related to Parkinson disease (PD)?
Does subthalamic nucleus (STN) deep brain stimulation (DBS) increase or decrease impulse control disorders in patients
with Parkinson disease (PD)?
When are lesion surgeries indicated in the treatment of Parkinson disease (PD)?
Is thalamotomy effective in the treatment of Parkinson disease (PD)?
Is pallidotomy effective in the treatment of Parkinson disease (PD)?
What are the potential adverse effects of pallidotomy?
Is bilateral pallidotomy recommended in patients with Parkinson disease (PD)?
Is subthalamotomy effective in the treatment of Parkinson disease (PD)?
Which specialists should provide care for a patient undergoing surgical procedures for the treatment of Parkinson disease
(PD)?
What is the patient evaluation and selection process for individuals with Parkinson disease (PD) considering subthalamic
nucleus (STN) deep brain stimulation (DBS)?
After patient selection, what is the process for determining the correct surgical procedure for management of Parkinson
disease (PD)?
What is the role of a psychiatrist in the preoperative evaluation of a patient with Parkinson disease (PD)?
When is a fluorodopa positron emission tomography (PET) scan indicated in the preoperative evaluation of patients with
When is surgery indicated in the treatment of Parkinson disease (PD)?
How is neural transplantation used in the treatment of Parkinson disease (PD)?
What are the effects of neural transplantation in patients with Parkinson disease (PD)?
Is gene therapy safe and effective in the treatment of Parkinson disease (PD)?
How is dementia managed in patients with Parkinson disease (PD)?
What is the prevalence of depression in patients with Parkinson disease (PD)?
How is depression treated in patients with Parkinson disease (PD)?
Can medications for Parkinson disease (PD) trigger psychosis?
How is psychosis treated in patients with Parkinson disease (PD)?
How is anxiety treated in patients with Parkinson disease (PD)?
How are impulse behaviors treated in patients with Parkinson disease (PD)?
How are sleep disturbances treated in patients with Parkinson disease (PD)?
How effective is exercise and physical therapy in patients with Parkinson disease (PD)?
What is the prevalence of speech problems in patients with Parkinson disease (PD)?
What is the role of speech therapy in the treatment of Parkinson disease (PD)?
What is the Lee Silverman Voice Treatment (LSVT) program for Parkinson disease (PD)?
How effective is the Lee Silverman Voice Treatment (LSVT) program in improving laryngeal symptoms in patients with
Are there effective alternative therapies to the Lee Silverman Voice Treatment (LSVT) program?
Are speech and language therapy effective in the treatment of Parkinson disease (PD)?
Why is dietary fiber recommended for patients with Parkinson disease (PD)?
What is the effect of dietary protein on levodopa in patients with Parkinson disease (PD)?
How is levodopa-induced nausea avoided in patients with Parkinson disease (PD)?
Are there dietary options that are beneficial in the management of Parkinson disease (PD)?
Do vitamin E and coenzyme Q10 have a neuroprotective effect in patients with Parkinson disease (PD)?
What consultations may be indicated for patients with Parkinson disease (PD)?
When is a neurosurgical consultation indicated in patients with Parkinson disease (PD)?
When is a psychiatric consultation indicated in patients with Parkinson disease (PD)?
When is consultation with a urologist indicated in patients with Parkinson disease (PD)?
What is the benefit of consultation with a physiatrist, physical therapist, or occupational therapist in patients with
What is the benefit of consultation with a nutritionist in patients with Parkinson disease (PD)?
What is the benefit of an otolaryngologist consultation for patients with Parkinson disease (PD)?
How are dysphagia, excessive sialorrhea, or nutrition issues managed in patients with Parkinson disease (PD)?
How often should patients with Parkinson disease (PD) be monitored?
What types of treatments may be available in the future for Parkinson disease (PD)?
Pedoman
What are the AAN treatment guidelines for nonmotor symptoms of Parkinson disease (PD)?
Obat-obatan
Which medications are used in the treatment of Parkinson disease (PD)?
Which medications in the drug class Dopamine Agonists are used in the treatment of Parkinson Disease?
Which medications in the drug class Anticholinergic are used in the treatment of Parkinson Disease?
Which medications in the drug class MAO-B inhibitors are used in the treatment of Parkinson Disease?
Which medications in the drug class Acetylcholinesterase Inhibitors, Central are used in the treatment of Parkinson
Disease?
Which medications in the drug class NMDA Antagonists are used in the treatment of Parkinson Disease?
Which medications in the drug class COMT Inhibitors are used in the treatment of Parkinson Disease?
Which medications in the drug class Selective Serotonin Inverse Agonists (SSIA) are used in the treatment of Parkinson
Disease?
Informasi Kontributor dan Pengungkapan
Penulis
Robert A Hauser, MD, MBA Profesor Neurologi, Farmakologi dan Fisiologi Molekuler, Direktur, USF Parkinson's Disease
and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Byrd Institute, Chair Clinical,
Program Interdisipliner Tertentu dalam Neuroscience, University of South Florida College Kedokteran
Robert A Hauser, MD, MBA is a member of the following medical societies: American Academy of Neurology, American
Medical Association, American Society of Neuroimaging, International Parkinson and Movement Disorder Society
Pengungkapan: Menerima biaya konsultasi dari Cerecor untuk konsultasi; Menerima biaya konsultasi dari L&M
Healthcare untuk konsultasi; Menerima biaya konsultasi dari Klinik Cleveland untuk konsultasi; Menerima biaya
konsultasi dari Heptares untuk konsultasi; Menerima biaya konsultasi dari Gerrson Lehrman Group untuk konsultasi;
Menerima biaya konsultasi dari Indus untuk konsultasi; Menerima biaya konsultasi dari University of Houston untuk
konsultasi; Menerima biaya konsultasi dari AbbVie untuk konsultasi; Menerima biaya konsultasi dari Adama.
Penulis pendamping
Kelly E Lyons, PhD, Profesor Riset Neurologi, Direktur Penelitian dan Pendidikan, Pusat Gangguan Penyakit dan
Pergerakan Parkinson, Pusat Medis Universitas Kansas
Kelly E Lyons, PhD is a member of the following medical societies: American Academy of Neurology, International
Parkinson and Movement Disorder Society
Pengungkapan: Menerima honor dari Novartis untuk berbicara dan mengajar; Menerima honor dari Teva Neuroscience
untuk berbicara dan mengajar; Menerima honor dari St Jude Medical untuk keanggotaan dewan.
Theresa A McClain, RN, MSN, ARNP-BC Praktisi dan Investigator Perawat Terdaftar Lanjutan, Pusat Gangguan
Penyakit dan Pergerakan Parkinson, Fakultas Kedokteran Universitas Florida Selatan
Theresa A McClain, RN, MSN, ARNP-BC is a member of the following medical societies: Sigma Theta Tau International
Pengungkapan: Menerima biaya konsultasi dari Teva untuk konsultasi; Menerima biaya konsultasi dari Schering Plough
untuk konsultasi; Menerima biaya konsultasi dari Biotie untuk konsultasi; Menerima biaya konsultasi dari Novartis untuk
konsultasi.
Rajesh Pahwa, MD Profesor Neurologi, Direktur, Parkinson Disease and Movement Disorder Center, Departemen
Neurologi, University of Kansas Medical Center
Rajesh Pahwa, MD is a member of the following medical societies: American Academy of Neurology, International
Parkinson and Movement Disorder Society
Pengungkapan: Tidak ada yang perlu diungkapkan.
Kepala editor
Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and
Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American
Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical
Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai, Greenwich,
Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a
speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova,
Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.
Ucapan Terima Kasih
Ron L Alterman, MD Associate Professor of Neurosurgery, Mount Sinai School of Medicine; Ahli Bedah Konsultasi,
Departemen Bedah Saraf, Fakultas Kedokteran Mount Sinai, Rumah Sakit Elmhurst, dan Pusat Medis Angkatan Darat
Walter Reed
Ron L Alterman, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of
Neurological Surgeons, Congress of Neurological Surgeons, Medical Society of the State of New York, and New York
County Medical Society
Heather S Anderson, MD Assistant Professor, Staff Neurologist, Department of Neurology, Alzheimer and Memory
Center, University of Kansas Medical Center
Heather S Anderson, MD is a member of the following medical societies: American Academy of Neurology
Jeff Blackmer, MD, FRCP(C) Associate Professor, Medical Director, Neurospinal Service, Division of Physical Medicine
and Rehabilitation, The Rehabilitation Centre, University of Ottawa Faculty of Medicine; Direktur Eksekutif, Kantor Etika,
Asosiasi Medis Kanada
Jeff Blackmer, MD, FRCP(C) is a member of the following medical societies: American Paraplegia Society, Canadian
Association of Physical Medicine and Rehabilitation, Canadian Medical Association, and Royal College of Physicians
and Surgeons of Canada
Thomas L Carroll, MD Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Tufts University
School of Medicine and Director, The Center for Voice and Swallowing, Tufts Medical Center
Thomas L Carroll, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Otolaryngology-Head and Neck Surgery, American Bronchoesophagological Association, American Laryngological
Association, and American Medical Association
Pengungkapan: Merz aesthetics inc. Biaya konsultasi Berbicara dan mengajar
Richard J Caselli, MD Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Ketua, Departemen
Neurologi, Klinik Mayo Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American
Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological
Association, and Sigma Xi
Arif I Dalvi, MD Director, Movement Disorders Center, NorthShore University HealthSystem, Clinical Associate Professor
of Neurology, University of Chicago Pritzker Medical School
Arif I Dalvi, MD is a member of the following medical societies: European Neurological Society and Movement Disorders
Society
Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders,
Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of
Neurology, American College of Physicians, and Movement Disorders Society
Stephen T Gancher, MD Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University
Stephen T Gancher, MD is a member of the following medical societies: American Academy of Neurology, American
Neurological Association, and Movement Disorders Society
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA Professor of Neurology, University of Central Florida College of
Medicine; Direktur Neurologi Kognitif, Direktur Program Stroke, Rumah Sakit Urusan Veteran James A Haley
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA is a member of the following medical societies: American
Academy of Neurology, American Headache Society, American Heart Association, and American Society of
Neuroimaging
Daniel H Jacobs MD, FAAN, Associate Professor of Neurology, University of Florida College of Medicine; Direktur
Layanan Stroke, Pusat Medis Regional Orlando
Daniel H Jacobs is a member of the following medical societies: American Academy of Neurology, American Society of
Neurorehabilitation, and Society for Neuroscience
Pengungkapan: Teva Pharmaceutical Grant / Consulting dana penelitian; Hibah Biogen Idex / dana penelitian Kontraktor
independen; Serono EMD Royalty Berbicara dan mengajar; Pfizer Royalty Berbicara dan mengajar; Berlex Royalty
Berbicara dan mengajar
Robert M Kellman, MD Professor and Chair, Department of Otolaryngology and Communication Sciences, State
University of New York Upstate Medical University
Robert M Kellman, MD is a member of the following medical societies: American Academy of Facial Plastic and
Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons,
American Medical Association, American Neurotology Society, American Rhinologic Society, American Society for Head
and Neck Surgery, Medical Society of the State of New York, and Triological Society
Pengungkapan: Keanggotaan panel Ulasan GE Healthcare Honoraria; Revent Medical Honoraria Review panel
Milton J Klein, DO, MBA Consulting Physiatrist, Heritage Valley Health System-Sewickley Hospital and Ohio Valley
General Hospital
Milton J Klein, DO, MBA is a member of the following medical societies: American Academy of Disability Evaluating
Physicians, American Academy of Medical Acupuncture, American Academy of Osteopathy, American Academy of
Physical Medicine and Rehabilitation, American Medical Association, American Osteopathic Association, American
Osteopathic College of Physical Medicine and Rehabilitation, American Pain Society, and Pennsylvania Medical Society
Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School
of Medicine
Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and
Developmental Medicine and American Academy of Physical Medicine and Rehabilitation
Jose G Merino, MD Medical Director, Suburban Hospital Stroke Program
Jose G Merino, MD is a member of the following medical societies: American Heart Association and American Stroke
Association
Arlen D Meyers, MD, MBA Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado
School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and
Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck
Society
Pengungkapan: Konsultasi biaya Covidien Corp Consulting; US Tobacco Corporation Hadiah tidak terbatas Tidak
Diketahui; Konsultasi kepentingan kepemilikan Axis Three Corporation; Omni Biosciences, Kepemilikan, Konsultasi
kepentingan; Kepemilikan kepentingan Dewan Sentegra Kepemilikan; Konsultasi kepentingan Kepemilikan Syndicom;
Konsultasi Oxlo; Posisi Manajemen kepentingan Kepemilikan Medvoy; Cerescan Imaging Honoraria Consulting; GYRUS
ACMI Honoraria Consulting
Lorraine Ramig, PhD Professor, Department of Speech Language Hearing Sciences, University of Colorado at Boulder;
Ilmuwan Senior, Pusat Nasional untuk Suara dan Bicara (NCVS); Ajun Profesor, Departemen Biobehavior, Columbia
University Teacher's College
Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for Education, Associate Residency Training
Director in General Psychiatry, Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry, Indiana
University School of Medicine; Psikiater Ketergantungan, Cener Kesehatan Mental Midtown di Wishard Health Services
Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction Psychiatry,
American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of
Physician Executives, American Medical Association, American Neuropsychiatric Association, American Psychiatric
Association, and Association for Convulsive Therapy
Pengungkapan: Eli Lilly & Co. Hibah / dana penelitian Lainnya
Roy Sucholeiki, MD Director, Comprehensive Seizure and Epilepsy Program, The Neurosciences Institute at Central
DuPage Hospital
Roy Sucholeiki, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy
Society, and American Neuropsychiatric Association
Margaret M Swanberg, DO Assistant Professor of Neurology, Uniformed Services University; Kepala Layanan
Neurobehavior, Walter Reed Army Medical Center; Asisten Kepala, Departemen Neurologi, Walter Reed Army Medical
Center
Margaret M Swanberg, DO is a member of the following medical societies: American Academy of Neurology and
American Neuropsychiatric Association
Michele Tagliati, MD Associate Professor, Department of Neurology, Mount Sinai School of Medicine; Kepala Divisi
Gangguan Gerakan, Pusat Medis Mount Sinai
Michele Tagliati, MD is a member of the following medical societies: American Academy of Neurology, American Medical
Association, and Movement Disorders Society
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Pemimpin Redaksi, Referensi Obat Medscape
Pengungkapan: Pekerjaan Gaji Medscape
B Viswanatha, MBBS, MS, DLO Professor of Otolaryngology (ENT), Chief of ENT III Unit, Sri Venkateshwara ENT
Institute, Victoria Hospital, Bangalore Medical College and Research Institute; Penguji PG dan UG, Universitas Manipal,
India dan Universitas Annamalai, India
B Viswanatha, MBBS, MS, DLO is a member of the following medical societies: Association of Otolaryngologists of
India, Indian Medical Association, and Indian Society of Otology
Referensi
1. Hauser RA, Grosset DG. [(123) I] FP-CIT (DaTscan) Pencitraan Otak SPECT pada Pasien dengan Sindrom Parkinson yang
Diduga. J Neuroimaging. 2011 Mar 16. [Medline].
2. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiologi dan etiologi penyakit Parkinson: tinjauan bukti. Eur J
Epidemiol. 2011 26 Juni. Sup 1: S1-58. [Medline].
3. Anderson P. Lebih Banyak Bukti Mengaitkan Pestisida, Pelarut, Dengan Parkinson. Berita Medis Medscape. Available at
http://www.medscape.com/viewarticle/804834. Accessed: June 11, 2013.
4. Pezzoli G, Cereda E. Paparan terhadap pestisida atau pelarut dan risiko penyakit Parkinson. Neurologi. 2013 28 Mei 80 (22):
2035-41. [Medline].
5. Liu R, Guo X, Park Y, Huang X, Sinha R, Freedman ND, dkk. Asupan Kafein, Merokok, dan Risiko Penyakit Parkinson pada
Pria dan Wanita. Am J Epidemiol. 2012 Apr 13. [Medline].
6. Ballard PA, Tetrud JW, Langston JW. Parkinsonisme manusia permanen karena 1-metil-4-fenil-1,2,3,6-tetrahidropiridin
(MPTP): tujuh kasus. Neurologi. 1985 Jul. 35 (7): 949-56. [Medline].
7. Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P, Mayeux R, dkk. Penyakit Parkinson pada kembar: studi etiologi.
JAMA. 1999 Jan 27. 281 (4): 341-6. [Medline].
8. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, dkk. Mutasi pada gen alpha-synuclein diidentifikasi
dalam keluarga dengan penyakit Parkinson. Ilmu. 1997 Jun 27. 276 (5321): 2045-7. [Medline].
9. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, dkk. Mutasi Ala30Pro dalam gen yang mengkode alpha-
synuclein pada penyakit Parkinson. Nat Genet. 1998 18 Februari (2): 106-8. [Medline].
10. Bekris LM, Mata IF, Zabetian CP. Genetika penyakit Parkinson. J Geriatr Psychiatry Neurol. 2010 23 Desember (4): 228-42.
[Medline]. [Full Text].
11. Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Ross BM, dkk. Frekuensi mutasi yang diketahui pada
penyakit Parkinson onset dini: implikasi untuk konseling genetik: konsorsium risiko untuk onset dini studi penyakit
Parkinson. Arch Neurol. 2010 Sep 67 (9): 1116-22. [Medline].
12. Samanta J, Hauser RA. Duodenal levodopa infusion untuk pengobatan penyakit Parkinson. Apoteker Ahli Opin. 2007 8 April
(5): 657-64. [Medline].
13. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L. Peran patologis a-synuclein dalam gangguan neurologis.
Lancet Neurol. 2011 10 November (11): 1015-25. [Medline].
14. Kordower JH, Chu Y, Hauser RA, TB Freeman, Olanow CW. Lewy seperti patologi tubuh dalam transplantasi nigral embrionik
jangka panjang pada penyakit Parkinson. Nat Med. 2008 Mei 14 (5): 504-6. [Medline].
15. Dalvin LA, GM Damento, Yawn BP, Abbott BA, Hodge DO, Pulido JS. Penyakit Parkinson dan Melanoma: Mengkonfirmasi dan
Memeriksa Kembali Asosiasi. Mayo Clin Proc. 2017 Jul. 92 (7): 1070-1079. [Medline].
16. Mulcahy, N. Melanoma, Parkinson: See One, Waspadai Yang Lain. Berita Medis Medscape. Available at
http://www.medscape.com/viewarticle/883195. 19 Juli 2017; Diakses: 26 Juli 2017.
17. Constantinescu R, Elm J, Auinger P, Sharma S, Agustinus EF, Khadim L, dkk. Melanoma ganas pada penyakit Parkinson
yang diobati dini: uji coba NET-PD. Mov Disord. 2014 29 Februari (2): 263-5. [Medline].
18. De Pablo-Fernandez E, Goldacre R, Pakpoor J, Noyce AJ, Warner TT. Asosiasi antara diabetes dan penyakit Parkinson
berikutnya: Sebuah studi kohort dengan catatan keterkaitan. Neurologi. 2018 Jun 13. [Medline].
19. Muangpaisan W, Mathews A, Hori H, Seidel D. Sebuah tinjauan sistematis dari prevalensi dan insiden penyakit Parkinson di
seluruh dunia. J Med Assoc Thailand. 2011 Juni 94 (6): 749-55. [Medline].
20. Grimes DA, Lang AE. Pengobatan penyakit Parkinson dini. Can J Neurol Sci. 1999 26 Agustus Sup 2: S39-44. [Medline].
21. Thobois S, Delamarre-Damier F, Derkinderen P. Pengobatan disfungsi motorik pada penyakit Parkinson: tinjauan umum.
Klinik Neurol Neurosurg. 2005 Juni 107 (4): 269-81. [Medline].
22. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Parameter Praktik: diagnosis dan prognosis
penyakit Parkinson onset baru (tinjauan berbasis bukti): laporan Sub-komite Standar Kualitas dari American Academy of
Neurology. Neurologi. 2006 Apr 11. 66 (7): 968-75. [Medline].
23. Pusat Kolaborasi Nasional untuk Kondisi Kronis. Penyakit Parkinson: Pedoman klinis nasional untuk diagnosis dan
manajemen dalam perawatan primer dan sekunder. London, Inggris: Royal College of Physicians; 2006
24. Hughes S. Pertimbangkan Gejala Nonmotor untuk Diagnosis Parkinson? Berita Medis Medscape. January 18, 2013.
Available at http://www.medscape.com/viewarticle/777874. Diakses: 22 Januari 2013.
25. Khoo TK, AJ Yarnall, Duncan GW, Coleman S, O'Brien JT, Brooks DJ, dkk. Spektrum gejala nonmotor pada penyakit
Parkinson awal. Neurologi. 2013 Jan 15. 80 (3): 276-81. [Medline].
26. Simuni T, Sethi K. Manifestasi nonmotor dari penyakit Parkinson. Ann Neurol. 2008 Desember 64 Suplemen 2: S65-80.
[Medline].
27. Sato Y, Iwamoto J, Honda Y. Fraktur Vertebra yang Diinduksi Kekurangan Vitamin D Dapat Menyebabkan Postur Bungkuk
pada Penyakit Parkinson. Am J Phys Med Rehabilitasi. 2011 Jan 5. [Medline].
28. Brin MF, Velickovic M, Remig LO. Disfonia karena penyakit Parkinson; perspektif manajemen farmakologis, bedah, dan
perilaku. Vocal Rehabilitation in Medical Speech-Language Pathology. Austin: Pro-Ed; 2004. 209-69.
29. Perez KS, Ramig LO, Smith ME, Dromey C. Parkinson laring: temuan tremor dan videostroboskopik. J Voice. 1996 10
Desember (4): 354-61. [Medline].
30. Ray Chaudhuri K, Rojo JM, Schapira AH, Brooks DJ, Stocchi F, Odin P, dkk. Sebuah proposal untuk penilaian komprehensif
keparahan penyakit Parkinson menggabungkan penilaian motorik dan non-motorik: memenuhi kebutuhan yang tidak
terpenuhi. PLoS Satu. 2013. 8 (2): e57221. [Medline]. [Full Text].
31. Johnson K. Nonmotor Gejala PD Meningkatkan Penilaian Keparahan Penyakit. Medscape [serial online]. Available at
http://www.medscape.com/viewarticle/812182. Diakses: 13 Oktober 2013.
32. Simpai S, Nazem S, Siderowf AD, Duda JE, Xie SX, Stern MB. Validitas MoCA dan MMSE dalam deteksi MCI dan demensia
pada penyakit Parkinson. Neurologi. 2009 24 November 73 (21): 1738-45. [Medline]. [Full Text].
33. Weintraub D, Comella CL, penyakit Horn S. Parkinson - Bagian 3: Gejala neuropsikiatri. Am J Manag Care. 2008 14 Maret (2
Suppl): S59-69. [Medline].
34. Reid WG, MA Hely, Morris JG, Loy C, Halliday GM. Demensia pada penyakit Parkinson: studi neuropsikologis 20 tahun
(Sydney Multicentre Study). J Neurol Neurosurg Psychiatry. 2011 Sep 82 (9): 1033-7. [Medline].
35. Parkinson's Terikat dengan Risiko Tinggi Osteoporosis dan Osteopenia. Medscape. Apr 3 2014. [Full Text].
36. Torsney KM, Noyce AJ, Doherty KM, dkk. Kesehatan tulang pada penyakit Parkinson: tinjauan sistematis dan meta-analisis. J
Neurol Neurosurg Psychiatry. 2014 Mar 21. [Medline].
37. Tolosa E, Gaig C, Santamaría J, Compta Y. Diagnosis dan fase premotor penyakit Parkinson. Neurologi. 2009 17 Februari.
72 (7 Suppl): S12-20. [Medline].
38. King J. Agen kontras baru memungkinkan diagnosis dini pada Parkinson. Berita Medis Medscape. June 18, 2013. [Full Text].
39. Seibyl J, Jennings D, Grachev I, Coffey C, Marek K. Akurasi DaTscan ™ (injeksi ioflupane I 123) dalam diagnosis sindrom
parkinsonian dini (PS) [abstrak 191]. Dipresentasikan pada: Pertemuan Tahunan 2013 Masyarakat Kedokteran Nuklir dan
Pencitraan Molekuler (SNMMI); 10 Juni 2013; Vancouver, British Columbia, Kanada.
40. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Tahapan dalam pengembangan patologi terkait penyakit
Parkinson. Res Jaringan Sel. 2004 Oktober 318 (1): 121-34. [Medline].
41. Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, Coffey CS, dkk. Asosiasi Cairan Serebrospinal ß-Amiloid 1-42, T-
tau, P-tau181, dan Kadar a-Synuclein Dengan Fitur Klinis Pasien N naif Obat Dengan Penyakit Parkinson Awal. JAMA Neurol.
2013 Aug 26. [Medline].
42. Jeffrey S. Biomarker untuk Diagnostik Parkinson, Prognostik. Medscape [serial online]. Available at
http://www.medscape.com/viewarticle/810262. Diakses: 9 September 2013.
43. Grosset D, Taurah L, Burn DJ, MacMahon D, Forbes A, Turner K, dkk. Sebuah studi observasional longitudinal multisenter
tentang perubahan dalam status kesehatan yang dilaporkan sendiri pada orang dengan penyakit Parkinson tidak diobati
saat didiagnosis. J Neurol Neurosurg Psychiatry. 2007 Mei. 78 (5): 465-9. [Medline]. [Full Text].
44. Caslake R, Macleod A, Ives N, Stowe R, Counsell C. Monoamine oxidase B inhibitor dibandingkan agen dopaminergik
lainnya pada penyakit Parkinson awal. Cochrane Database Syst Rev. 2009. (4):CD006661. [Medline].
45. Antonini A, Cilia R. Efek merugikan perilaku perawatan dopaminergik pada penyakit Parkinson: insidensi, dasar
neurobiologis, manajemen dan pencegahan. Drug Saf. 2009. 32 (6): 475-88. [Medline].
46. Bayulkem K, Lopez G. Pendekatan klinis untuk fluktuasi sensorik nonmotor pada penyakit Parkinson. J Neurol Sci. 2011
November 15. 310 (1-2): 82-5. [Medline].
47. Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, dkk. Parameter Praktik: evaluasi dan pengobatan
depresi, psikosis, dan demensia pada penyakit Parkinson (tinjauan berbasis bukti): laporan Sub-komite Standar Kualitas
dari American Academy of Neurology. Neurologi. 2006 Apr 11. 66 (7): 996-1002. [Medline].
48. [Pedoman] Zesiewicz TA, Sullivan KL, Arnulf I, et al. Parameter Praktik: pengobatan gejala nonmotor penyakit Parkinson:
laporan Sub-komite Standar Kualitas dari American Academy of Neurology. Neurologi. 2010 Mar 16. 74 (11): 924-31.
[Medline].
49. Stocchi F, Rascol O, Kieburtz K, dkk. Memulai terapi levodopa / carbidopa dengan dan tanpa entacapone pada penyakit
Parkinson awal: studi STRIDE-PD. Ann Neurol. 2010 Jul 68 (1): 18-27. [Medline].
50. Hauser RA, McDermott MP, Messing S. Faktor yang terkait dengan perkembangan fluktuasi motorik dan diskinesia pada
penyakit Parkinson. Arch Neurol. 2006 Desember 63 (12): 1756-60. [Medline].
51. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. Sebuah studi lima tahun tentang kejadian diskinesia
pada pasien dengan penyakit Parkinson awal yang dirawat dengan ropinirole atau levodopa. 056 Kelompok Studi. N Engl J
Med. 2000 Mei 18. 342 (20): 1484-91. [Medline].
52. Constantinescu R, Romer M, McDermott MP, Kamp C, Kieburtz K. Dampak pramipexole pada timbulnya diskinesia terkait
levodopa. Mov Disord. 2007 Juli 15. 22 (9): 1317-9. [Medline].
53. Thomas A, Bonanni L, Gambi F, Di Iorio A, Onofrj M. Judi patologis pada penyakit Parkinson dikurangi oleh amantadine. Ann
Neurol. Sep 2010. 68 (3): 400-4.
54. Weintraub D, Sohr M, Potenza MN, Siderowf AD, Stacy M, Voon V, dkk. Penggunaan amantadine terkait dengan gangguan
kontrol impuls pada penyakit Parkinson dalam studi cross-sectional. Ann Neurol. 2010 Desember 68 (6): 963-8. [Medline].
55. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, dkk. Infus intrajejunal terus menerus dari gel usus
levodopa-carbidopa untuk pasien dengan penyakit Parkinson lanjut: studi acak, terkontrol, double-blind, dummy ganda.
Lancet Neurol. 2014 13 Februari (2): 141-9. [Medline].
56. Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, dkk. Penilaian Keamanan dan Kemanjuran Safinamide
sebagai Ajudan Levodopa pada Pasien dengan Penyakit Parkinson dan Fluktuasi Motor: Uji Klinis Acak. JAMA Neurol. 2017
1 Februari. 74 (2): 216-224. [Medline].
57. Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, dkk. Percobaan acak tambahan safinamide pada
levodopa pada penyakit Parkinson dengan fluktuasi motor. Mov Disord. 2014 29 Februari (2): 229-37. [Medline]. [Full Text].
58. Schapira AH, Barone P, Hauser RA, Mizuno Y, Rascol O, Busse M, dkk. Diperpanjang-rilis pramipexole pada penyakit
Parkinson lanjut: uji coba terkontrol secara acak. Neurologi. 2011 23 Agustus. 77 (8): 767-74. [Medline].
59. Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, et al. ADS-5102 (Amantadine) Extended-Release
Capsules untuk Dyskinesia yang diinduksi Levodopa pada Penyakit Parkinson (Studi EASE LID): Sebuah Uji Klinis Acak.
JAMA Neurol. 2017 Agustus 1. 74 (8): 941-949. [Medline]. [Full Text].
60. Hauser RA, Pahwa R, Tanner CM, Oertel W, Isaacson SH, Johnson R, et al. ADS-5102 (Amantadine) Extended-Release
Capsules untuk Disadesia yang diinduksi Levodopa pada Penyakit Parkinson (Studi EASE LID 2): Hasil Sementara dari
Studi Keselamatan Label Terbuka. J Parkinsons Dis. 2017. 7 (3): 511-522. [Medline]. [Full Text].
61. Ory-Magne F, Corvol JC, Azulay JP, dkk, atas nama Jaringan CIC NS-Park. Penarikan amantadine pada pasien diskinetik
dengan penyakit Parkinson: Uji coba AMANDYSK. Neurologi. 2013 Dec 26. [Medline].
62. Brooks M. Amantadine memiliki manfaat jangka panjang pada diskinesia yang diinduksi levodopa. Berita Medis Medscape.
January 8, 2014. [Full Text].
63. Barthel C, Nonnekes J, van Helvert M, Haan R, Janssen A, Delval A, dkk. Sepatu laser: Perangkat rawat jalan baru untuk
meringankan pembekuan gaya berjalan pada penyakit Parkinson. Neurologi. 2017 Dec 20. [Medline].
64. Efek tokoferol dan deprenil pada perkembangan kecacatan pada penyakit Parkinson awal. Kelompok Studi Parkinson. N
Engl J Med. 1993 21 Januari 328 (3): 176-83. [Medline].
65. Shults CW. Efek selegilin (deprenyl) pada perkembangan kecacatan pada penyakit Parkinson dini. Parkinson Study Group.
Acta Neurol Scand Suppl. 1993. 146: 36-42. [Medline].
66. Palhagen S, Heinonen E, Hagglund J, Kaugesaar T, Maki-Ikola O, Palm R. Selegiline memperlambat perkembangan gejala
penyakit Parkinson. Neurologi. 2006 25 April 66 (8): 1200-6. [Medline].
67. Tatton WG, Greenwood CE. Penyelamatan neuron yang sekarat: tindakan baru untuk deprenil dalam parkinsonisme MPTP. J
Neurosci Res. 1991 30 Desember (4): 666-72. [Medline].
68. Olanow C, Rascol O. Early Rasagaline treatment slows UPDRS decline in the ADAGIO delayed start study. Poster work in
progress (WIP-11). 12th Congress of European Federation of Neurological Societies. 23 September 2008.
69. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A. Sebuah uji coba rasagilin double-blind yang tertunda untuk
penyakit Parkinson. N Engl J Med. 2009 Sep 24. 361 (13): 1268-78. [Medline].
70. Percobaan terkontrol rasagilin pada penyakit Parkinson awal: Studi TEMPO. Arch Neurol. 2002 Desember 59 (12): 1937-43.
[Medline].
71. Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ. Hasil jangka panjang dari pengobatan rasagilin awal
dibandingkan yang tertunda pada penyakit Parkinson dini. Mov Disord. 2009 Mar 15. 24 (4): 564-73. [Medline].
72. Penelitian rasagilin yang terkontrol, acak, dan tertunda mulai pada penyakit Parkinson dini. Arch Neurol. 2004 April 61 (4):
561-6. [Medline].
73. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, dkk. Levodopa dan perkembangan penyakit Parkinson. N Engl J
Med. 2004 Desember 9. 351 (24): 2498-508. [Medline].
74. Parkkinen L, O'Sullivan SS, Kuoppamäki M, Collins C, Kallis C, Holton JL, dkk. Apakah levodopa mempercepat proses
patologis di otak penyakit Parkinson? Neurologi. 2011 Okt 11. 77 (15): 1420-6. [Medline].
75. Pencitraan otak transporter dopamin untuk menilai efek pramipexole vs levodopa pada perkembangan penyakit Parkinson.
JAMA. 2002 April 3. 287 (13): 1653-61. [Medline].
76. Schapira AH, Olanow CW. Perlindungan saraf pada penyakit Parkinson: misteri, mitos, dan kesalahpahaman. JAMA. 2004 21
Januari 291 (3): 358-64. [Medline].
77. Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ. Parameter Praktik: strategi perlindungan saraf
dan terapi alternatif untuk penyakit Parkinson (tinjauan berbasis bukti): laporan Sub-komite Standar Kualitas dari American
Academy of Neurology. Neurologi. 2006 Apr 11. 66 (7): 976-82. [Medline].
78. Shemisa K, Hass CJ, Foote KD, Okun MS, Wu SS, Jacobson CE 4th, dkk. Operasi stimulasi otak dalam unilateral pada
penyakit Parkinson meningkatkan gejala ipsilateral terlepas dari lateralitas. Parkinsonism Relat Disord. 2011 17 Desember
(10): 745-8. [Medline].
79. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr. Stimulasi otak dalam bilateral vs terapi medis terbaik untuk
pasien dengan penyakit Parkinson lanjut: uji coba terkontrol secara acak. JAMA. 2009 Januari 7. 301 (1): 63-73. [Medline].
[Full Text].
80. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, dkk. Stimulasi otak dalam Pallidal versus subthalamic untuk penyakit
Parkinson. N Engl J Med. 2010 Juni 3. 362 (22): 2077-91. [Medline].
81. Brooks M. Neurostimulation memiliki manfaat pada penyakit Parkinson dini. Berita Medis Medscape. February 15, 2013. [Full
Text].
82. Schuepbach WM, Rau J, et al, untuk Kelompok Studi EARLYSTIM. Neurostimulasi untuk penyakit Parkinson dengan
komplikasi motorik dini. N Engl J Med. 2013 14 Februari. 368 (7): 610-22. [Medline].
83. Foltynie T, Zrinzo L, Martinez-Torres I, Tripoliti E, Petersen E, Holl E, dkk. STN DBS yang dipandu MRI pada penyakit Parkinson
tanpa rekaman elektroda mikro: kemanjuran dan keamanan. J Neurol Neurosurg Psychiatry. 2011 Apr. 82 (4): 358-63.
[Medline].
84. Moreau C, Delval A, Defebvre L, Dujardin K, Duhamel A, Petyt G, et al. Methylphenidate untuk gaya berjalan hipokinesia dan
pembekuan pada pasien dengan penyakit Parkinson yang menjalani stimulasi subthalamic: percobaan multisenter, paralel,
acak, terkontrol plasebo. Lancet Neurol. 2012 11 Juli (7): 589-596. [Medline].
85. Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Hasil sepuluh tahun stimulasi subthalamic pada penyakit
Parkinson: evaluasi buta. Arch Neurol. 2011 Desember 68 (12): 1550-6. [Medline].
86. Oshima H, Katayama Y, T Morishita, K Sumi, T Otaka, Kobayashi K, dkk. Stimulasi nukleus subthalamic untuk melemahkan
rasa sakit yang berhubungan dengan penyakit Parkinson. J Neurosurg. 2012 Jan 116 (1): 99-106. [Medline].
87. Kim HJ, Jeon BS, Paek SH. Efek stimulasi otak dalam pada rasa sakit pada penyakit Parkinson. J Neurol Sci. 2011
88. Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. Manfaat stimulasi otak dalam subthalamic untuk nyeri pada penyakit Parkinson:
studi lanjutan 2 tahun. Bedah Saraf. 2012 Januari 70 (1): 18-23; diskusi 23-4. [Medline].
89. Broen M, Duit A, Visser-Vandewalle V, Temel Y, Winogrodzka A. Kontrol impuls dan gangguan terkait pada pasien penyakit
Parkinson yang diobati dengan stimulasi inti nukleus subthalamic bilateral: sebuah ulasan. Parkinsonism Relat Disord.
2011 17 Juli (6): 413-7. [Medline].
90. Timmermann L, Jain R, Chen L, T Brucke, Seijo F, San Martin ES, dkk. 134 VANTAGE Trial: Hasil Tiga-Tahun dari Prospek,
Triicenter Trial Mengevaluasi Stimulasi Otak Jauh Dengan Sistem Multi-Sumber Baru, Sistem Isi Ulang Arus Konstan pada
Penyakit Parkinson. Bedah Saraf. 2016 Agustus 63 Suppl 1: 155. [Medline].
91. Svennilson E, Torvik A, Lowe R, Leksell L. Pengobatan parkinsonisme dengan termol stereotatik di wilayah pallidal. Evaluasi
klinis 81 kasus. Acta Psychiatr Scand. 1960. 35: 358-77. [Medline].
92. Laitinen LV, Bergenheim AT, Hariz MI. Pallidotomy posteroventral Leksell dalam pengobatan penyakit Parkinson. J
Neurosurg. 1992 Januari 76 (1): 53-61. [Medline].
93. Lang AE, Widner H. Stimulasi otak dalam untuk penyakit Parkinson: seleksi dan evaluasi pasien. Mov Disord. 2002. 17 Suppl
3: S94-101. [Medline].
94. Okun MS, Fernandez HH, Pedraza O, Misra M, KE Lyons, Pahwa R. Pengembangan dan validasi awal alat skrining untuk
kandidat bedah penyakit Parkinson. Neurologi. 2004 13 Juli. 63 (1): 161-3. [Medline].
95. Olanow CW, Kordower JH, Lang AE, Obeso JA. Transplantasi dopaminergik untuk penyakit Parkinson: status saat ini dan
prospek masa depan. Ann Neurol. 2009 November 66 (5): 591-6. [Medline].
96. Silberstein P, Bittar RG, Boyle R, Cook R, Coyne T, O'Sullivan D. Stimulasi otak dalam untuk penyakit Parkinson: pedoman
rujukan Australia. J Clin Neurosci. 2009 16 Agustus (8): 1001-8. [Medline].
97. Stover NP, Watts RL. Spheramine untuk pengobatan penyakit Parkinson. Neurotherapeutics. 2008 5 April (2): 252-9.
[Medline].
98. Farag ES, Vinters HV, Bronstein J. Temuan patologis dalam implantasi sel epitel pigmen retina untuk penyakit Parkinson.
Neurologi. 2009 6 Oktober. 73 (14): 1095-102. [Medline]. [Full Text].
99. Witt J, Marks WJ Jr. Pembaruan pada terapi gen pada penyakit Parkinson. Curr Neurol Neurosci Rep. 2011 Aug. 11(4):362-
70. [Medline].
100. Lewitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, et al. Terapi gen AAV2-GAD untuk penyakit
Parkinson lanjut: uji coba acak ganda yang dikontrol secara acak. Lancet Neurol. 2011 10 April (4): 309-19. [Medline].
101. Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, dkk. Parameter Praktik: evaluasi dan pengobatan
depresi, psikosis, dan demensia pada penyakit Parkinson (tinjauan berbasis bukti): laporan Sub-komite Standar Kualitas
dari American Academy of Neurology. Neurologi. 2006 Apr 11. 66 (7): 996-1002. [Medline].
102. Frisina PG, Borod JC, Foldi NS, Tenenbaum HR. Depresi pada penyakit Parkinson: Risiko kesehatan, etiologi, dan pilihan
pengobatan. Neuropsychiatr Dis Treat. 2008 4 Februari (1): 81-91. [Medline]. [Full Text].
103. Barbas NR. Gambaran kognitif, afektif, dan psikiatris dari penyakit Parkinson. Klinik Geriatr Med. 2006 22 November (4): 773-
96, v-vi. [Medline].
104. Truong DD, Bhidayasiri R, Wolters E. Manajemen gejala non-motorik pada penyakit Parkinson lanjut. J Neurol Sci. 2008 Mar
15. 266 (1-2): 216-28. [Medline].
105. Ziemssen T, Reichmann H. Disfungsi non-motorik pada penyakit Parkinson. Parkinsonism Relat Disord. 2007 13 Agustus
(6): 323-32. [Medline].
106. Hassan A, Bower JH, Kumar N, Matsumoto JY, Fealey RD, Josephs KA, dkk. Perilaku patologis yang dipicu agonis-dopamin:
Surveilans di klinik PD menunjukkan frekuensi tinggi. Parkinsonism Relat Disord. 2011 Mei. 17 (4): 260-4. [Medline].
107. Richard IH, MP McDermott, Kurlan R, Lyness JM, Como PG, Pearson N, dkk. Percobaan antidepresan acak, tersamar ganda,
terkontrol plasebo pada penyakit Parkinson. Neurologi. 2012 Apr 17. 78 (16): 1229-1236. [Medline].
108. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, dkk. Pramipexole untuk pengobatan gejala depresi pada
pasien dengan penyakit Parkinson: uji coba acak, tersamar ganda, terkontrol plasebo. Lancet Neurol. 2010 9 Juni (6): 573-
80. [Medline].
109. Allain H, Pollak P, Neukirch HC. Efek simtomatik selegilin pada pasien Parkinsonian de novo. Uji Coba Multisenter Selegiline
Prancis. Mov Disord. 1993. 8 Suppl 1: S36-40. [Medline].
110. Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, et al. Pimavanserin for patients with Parkinson's
disease psychosis: a randomised, placebo-controlled phase 3 trial. Lanset. 2014 Feb 8. 383 (9916):533-40. [Medline].
111. Pengobatan penyakit Parkinson. Gangguan psikologis: mencapai keseimbangan untuk mengoptimalkan perawatan
antiparkinson. Prescrire Int. 2011 20 Oktober (120): 242-5. [Medline].
112. Ferreri F, Agbokou C, Gauthier S. Pengakuan dan pengelolaan komplikasi neuropsikiatrik pada penyakit Parkinson. CMAJ.
2006 Des 5. 175 (12): 1545-52. [Medline].
113. Okai D, Askey-Jones S, Samuel M, O'Sullivan SS, Chaudhuri KR, Martin A, et al. Uji coba CBT untuk perilaku kontrol impuls
yang mempengaruhi pasien Parkinson dan pengasuh mereka. Neurologi. 2013 Feb 26. 80 (9): 792-799. [Medline]. [Full Text].
114. Anderson P. Cognitive Therapy Mengontrol Perilaku Impuls pada Parkinson. Available at
http://www.medscape.com/viewarticle/779914. Diakses: 21 Maret 2013.
115. Brooks M. Naltrexone untuk Gangguan Kontrol Impuls pada Parkinson's ?. Berita Medis Medscape. Available at
http://www.medscape.com/viewarticle/829633. Diakses: 9 Agustus 2014.
116. Papay K, Xie SX, Stern M, Hurtig H, Siderowf A, Duda JE, dkk. Naltrexone untuk gangguan kontrol impuls pada penyakit
Parkinson: Sebuah studi terkontrol plasebo. Neurologi. 2014 Jul 18. [Medline].
117. Friedman JH, Millman RP. Gangguan tidur dan penyakit Parkinson. CNS Spectr. 2008 13 Maret (3 Suppl 4): 12-7. [Medline].
118. Tomlinson CL, Patel S, Meek C, Clarke CE, Stowe R, Shah L, et al. Fisioterapi versus plasebo atau tidak ada intervensi pada
penyakit Parkinson. Database Cochrane dari Tinjauan Sistematis. Februari 2012
119. Ahlskog JE. Apakah olahraga berat memiliki efek neuroprotektif pada penyakit Parkinson? Neurologi. 2011 Jul 19. 77 (3):
288-94. [Medline]. [Full Text].
120. CP kawanan, Tomlinson CL, Deane KHO, Brady MC, Smith CH, Sackley C, dkk. Terapi bicara dan bahasa versus plasebo
atau tidak ada intervensi untuk masalah bicara pada penyakit Parkinson. Cochrane Database Syst Rev. 2011 Apr 11.
CD002812.
121. Fahn S. Sebuah percobaan percobaan alfa-tokoferol dosis tinggi dan askorbat pada penyakit Parkinson awal. Ann Neurol.
1992. 32 Suppl: S128-32. [Medline].
122. Berke GS, Gerratt B, Kreiman J, Jackson K. Pengobatan Parkinson hipofonia dengan augmentasi kolagen perkutan.
Laringoskop. 1999 Agustus 109 (8): 1295-9. [Medline].
123. Kim HJ, Jeon BS, Paek SH. Efek stimulasi otak dalam pada rasa sakit pada penyakit Parkinson. J Neurol Sci. 2011
124. Hauser RA. Perawatan di masa depan untuk penyakit Parkinson: menjelajahi pipa PD. Int J Neurosci. 2011. 121 Suppl 2: 53-
62. [Medline].
125. WC Koller. Levodopa dalam pengobatan penyakit Parkinson. Neurologi. 2000. 55 (11 Suppl 4): S2-7; diskusi S8-12.
[Medline].
126. Marks WJ Jr, Bartus RT, Siffert J, dkk. Pengiriman gen AAV2-neurturin untuk penyakit Parkinson: uji coba tersamar ganda,
acak, dan terkontrol. Lancet Neurol. 2010 9 Desember (12): 1164-72. [Medline].
127. Urusan Pengaturan PBR. AZILECT dari Teva mendapat persetujuan FDA untuk mengobati semua tahap penyakit Parkinson.
June 10, 2014. Available at http://regulatoryaffairs.pharmaceutical-business-review.com/news/tevas-azilect-gets-fda-
approval-to-treat-all-stages-of-parkinsons-disease-100614-4289261. Diakses: 16 Juni 2014.
128. [Guideline] Jaringan Panduan Lintas Agama Skotlandia (SIGN). Diagnosis and pharmacological management of
Parkinson's disease. A national clinical guideline. Edinburgh (Skotlandia): Scottish Guidelines Network (SIGN) Skotlandia;
2010 Januari 61 hal. (SIGN publikasi; no. 113). [Full Text].
129. Shult CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S. Efek koenzim Q10 pada penyakit Parkinson awal: bukti
perlambatan penurunan fungsional. Arch Neurol. 2002 Oktober 59 (10): 1541-50. [Medline].
130. Teva Pharmaceutical Industries Ltd. FDA menyetujui label diperluas untuk AZILECT untuk perawatan di semua tahap
penyakit Parkinson [siaran pers]. June 9, 2014. Available at http://ir.tevapharm.com/phoenix.zhtml?c=73925&p=irol-
newsArticle&ID=1938203&highlight=. Diakses: 16 Juni 2014.
131. Siapa AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, dkk. Perkembangan penyakit Parkinson yang lebih lambat
dengan ropinirole versus levodopa: Studi REAL-PET. Ann Neurol. 2003 Juli 54 (1): 93-101. [Medline].
132. LeWitt PA, Hauser RA, Pahwa R, Isaacson SH, Fernandez HH, Lew M, et al. Keamanan dan kemanjuran CVT-301 (levodopa
inhalasi bubuk) pada fungsi motorik selama periode off pada pasien dengan penyakit Parkinson: uji coba fase 3 acak,
tersamar ganda, terkontrol plasebo. Neurologi Lancet. 2019 01 Feb; 18 (2): 145-154.

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Mereka mengandung alpha-synuclein terpolimerisasi;

oleh karena itu, penyakit Parkinson adalah sinukleinopati.

Tahapan dalam pengembangan patologi terkait penyakit Parkinson (PD) (path.).

Res Jaringan Sel.

2004 Okt; 318 (1): 121-34.

Tanda dan gejala

Gejala klinis awal penyakit Parkinson meliputi:

Penurunan ketangkasan yang halus

Lengan ayun yang berkurang di sisi yang terlibat pertama

Ekspresi wajah berkurang

Mengurangi indra penciuman

Perasaan umum tentang kelemahan, malaise, atau lassitude

Depresi atau anhedonia

Keterlambatan dalam berpikir

Tanda-tanda motorik meliputi:

Ketidakstabilan postural (gangguan keseimbangan) adalah fenomena yang terlambat

Lihat Presentasi Klinis untuk lebih detail.

Diagnosis klinis membutuhkan 2 dari 3 tanda kardinal:

Lihat Workup untuk lebih detail.

Terapi obat simtomatik

Levodopa / carbidopa: Standar emas untuk pengobatan simtomatik

Perawatan untuk gejala nonmotor

Sildenafil citrate (Viagra): Untuk disfungsi ereksi

Polietilen glikol: Untuk sembelit

Modafinil: Untuk mengantuk siang yang berlebihan

Methylphenidate: Untuk kelelahan (potensial untuk penyalahgunaan dan kecanduan)

Stimulasi otak dalam

Prosedur bedah pilihan untuk penyakit Parkinson

Tidak melibatkan penghancuran jaringan otak

Dapat disesuaikan saat penyakit berkembang atau terjadi efek samping

Lihat Pengobatan dan Obat untuk lebih detail.

Iodine-123-berlabel fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-nortroptane (FP-CIT I123) (Ioflupane, DaTscan)

Untuk ilustrasi inti subthalamic, lihat gambar di bawah ini.

Hilangnya neuron dopaminergik berpigmen dari substantia nigra pars compacta

Kehadiran tubuh Lewy dan Lewy neurites

Sirkuit motor pada penyakit Parkinson

Dalam: Watts RL, Koller WC, eds.

Gangguan Gerakan: Prinsip dan Praktik Neurologis.

New York: McGraw-Hill, 1997: 240.

Hak Cipta, McGraw-Hill Companies, Inc. Digunakan dengan izin.

Dalam: Watts RL, Koller WC, eds.

Gangguan Gerakan: Prinsip dan Praktik Neurologis.

New York: McGraw-Hill, 1997: 241.

Digunakan dengan izin baik.

Hak Cipta, McGraw-Hill Companies, Inc.

Interferensi MPTP dengan fungsi mitokondria

Beberapa individu diidentifikasi mengembangkan parkinson setelah injeksi 1-metil-4-fenil-1,2,3,6-tetrahidropiridin (MPTP).

Perubahan dan agregasi konformasi alfa-synuclein

Air liur berlebihan

Gejala klinis awal pada penyakit Parkinson meliputi:

Lengan ayun yang berkurang di sisi yang terlibat pertama

Ekspresi wajah berkurang

Mengurangi indra penciuman

Perasaan umum tentang kelemahan, malaise, atau lassitude

Depresi atau anhedonia

Keterlambatan dalam berpikir

Ketidakstabilan postur tubuh

Ketidakstabilan postur tubuh

Disfungsi laring dan disfagia

Jatuh saat presentasi atau awal penyakit

Respons buruk terhadap levodopa

Simetri saat onset penyakit

Perkembangan penyakit yang cepat