PENGENALAN DINI & PENATALAKSANAAN DEMENSIA

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1 PENGENALAN DINI & PENATALAKSANAAN DEMENSIA
Dr dr Anam Sp.S(K) Klinik Memori RS Hasan Sadikin /RS ADVENT Bandung

2 PERAN DOKTER UMUM SANGAT PENTING

3 Ny. Anna Seorang janda pensiunan PNS, 67 tahun, berpendidikan SLTA, tinggal bersama anak laki, menantu dan seorang cucunya .

4 Masalah daya ingat (memori)
Ny. Anna Sejak 3 tahun yl. Ny. Ana sering lupa letak kaca mata, dompet, kunci kamar dan kesulitan mencarinya sendiri. Sebelum berbelanja dia harus membuat catatan karena sering lupa belanjaan dan sering kekurangan uang untuk membayar. Masalah daya ingat (memori)

5 Menurut Anda apakah ini lupa yang masih wajar?

6 Masalah Bahasa Hanya menantunya menyadari hal ini
Dia kadang-kadang sulit menemukan kata yang mau diucapkan & lupa nama teman lamanya. Sesuatu ketika, saat kumpul bersama teman2 merencanakan kegiatan bazar, dia sulit mengikuti pembicaraan walaupun masih bisa jawab dengan benar saat ditanya. Di dalam dirinya ia bingung dan mulai menarik diri. Hanya menantunya menyadari hal ini Masalah Bahasa

7 Depresi, menarik diri & hilang rasa humor
Beberapa bulan kemudian: Dia sangat tersinggung ketika menantunya memberitahu bahwa masakan keasinan. Ny. Ana menjadi mudah tersinggung, sedih, dan sering menangis. Hobbi merangkai bunga berangsur-angsur mulai ditinggalkan dan acara komedi keluarga TV tidak lagi menarik baginya. Depresi, menarik diri & hilang rasa humor

8 Beberapa tahun berlalu
Suatu ketika tetangga telepon panik ke anaknya karena kepulan asap kompor dari rumah yang ditinggal pergi berbelanja oleh Ny. Ana. Karena takut kebakaran, menantu memutuskan untuk berhenti kerja dan mulai membantu di dapur. Tidak mampu mengurus rumah tangga, membahayakan diri sendiri dan lingkungan Beban keluarga

9 Delusi ( Kepercayaan yang salah)
Satu ketika Ana dirawat dirumah sakit karena radang paruh Saat sadar, dia berkata kepada anaknya “Kemaren saya ketemu ayahmu” Anaknya berusaha meyakinkan bahwa ayahnya sudah meninggal 20 tahun yl, namun Ana tetap tidak percaya Dia marah karena merasa menantu tidak pernah jeguknya Delusi ( Kepercayaan yang salah)

10 Waham paranoid (Curiga yg tidak benar)
Setelah pulang dari RS: Ketika istirahat di kamar dia merasa sebagian hiasannya hilang dan mencurigai menantu telah mencurinya Ny. Ana merasa takut kehilangan semua barang miliknya. Waham paranoid (Curiga yg tidak benar)

11 Memori baru lenyap, memori masih utuh
Memori baru yang semakin menurun Memori kejadian baru semakin menurun, memori lama masih baik Ketika teman-teman lama datang kumpul bersama mengenang masa lama, memori lama muncul dan dia merasa senang, ketika teman pulang memori menyelinap pergi dan dia mulai murung kembali Memori baru lenyap, memori masih utuh

12 Tidak mandiri dalam aktivitas keseharian
Saat mandi Air bathtub mengalir hampir penuh mengingatkan dia akan banjir karena tidak bisa mematikan kran. Dia lupa bagaimana cara menggunakan handuk & mengancingkan baju Mandi menjadi suatu yang menakutkan baginya Tidak mandiri dalam aktivitas keseharian

13 Tidak mengenal jalan (disorientasi tempat)
Ny. Ana mau keluar rumah tetapi takut sesat Karena menantu stress dimarahi dan dituduh mencuri, Ny. Ana dikirim ke rumah penitipan orang tua Pagi dia diantar dan sore dijemput oleh menantunya. Ny. Ana masih bisa menyanyi lagu2 lama kesayangannya bersama teman2 di sana. Dia terkadang salah masuk ke WC Pria. Tidak mengenal jalan (disorientasi tempat)

14 3 tahun kemudian ketika tiba waktu dimana beban fisik dan mental terlalu berat buat keluarga Ny. Ana dikirim ke rumah perawatan orang tua. Ny. Ana merasa aman dan nyaman dalam kamar tidunya yg kecil dan terang, W.C dekat dan terlihat dari kamar

15 Tidak mengenal tempat dan orang
Ny. Ana menyenangi acara rutin yang dirancang baginya walaupun tidak bisa ingat kegiatannya Terkadang dia merasa dirinya masih berada di penitipan orang tua Dia senang ketika keluarga datang menjeguknya walaupun terkadang tidak dapat mengenal nama mereka Dia senang keluarga memegang tangan dan memeluknya. Tidak mengenal tempat dan orang

16 Halusinasi dan delusi terus berlansung, oleh dokter diberi obat antipsikotik.
Empat bulan kemudian ibu Anna jatuh dan mengalami patah tulang paha kanan dan menjadi bedridden Di panti wreda

17 Ny. Ana adalah contoh pasien Penyakit Alzheimer
Lupa adalah gejala utama, dan sering pasien sendiri tidak menyadari, tetapi keluarga dekat dapat merasakan perubahan memorinya sejak dini.

18 Pendahuluan Kasus demensia di Indonesia semakin meningkat.
TAHUN 2015 sebanyak 1 juta orang dengan demensia tahun 2030 MENCAPAI 1,8 juta DemeNsia Alzheimer dan demensia vaskuler TERSERING Masa perawatan demensia yang panjang menimbulkan beban kesehatan dan sosioekonomi yang berat kepada pasien, keluarga, masyarakat dan negara secara keseluruhan. Pelayanan medis: Pelayanan Kesehatan Tingkat I, II dan III

19 Demensia menyebabkan:
Beban Sosial dan Ekonomi keluarga, masyarakat dan negara World Alzheimer Report 2010

20 Pengertian sindrom penurunan fungsi intelektual dibanding sebelumnya yang cukup berat sehingga mengganggu aktivitas sosial dan profesional yang tercermin dalam aktivitas hidup keseharian, biasanya ditemukan juga perubahan perilaku dan tidak disebabkan oleh delirium maupun gangguan psikiatri mayor.

21 Etiologi demensia Demensia bukan suatu diagnosis, perlu diteliti penyebab ( >150) Penyakit Alzheimer Degenerasi Lobar Frontotemporal Penyakit Lewy Body Demensia Vaskuler • Infeksi HIV • Penyakit Prion (Creutzfeld-Jacob Disease) • Penyakit Parkinson • Penyakit Huntington Trauma kepala • Penggunaan obat / substansi tertentu • Kondisi medik lain • Etiologi multiple

22 Penyakit Alzheimer penyakit neurodegeneratif yang tersering (60-80%).
KHAS: penurunan progresif memori episodik (Amnesia) dan fungsi kortikal lain (AFASIA, Apraksia, agnosia) (4a) Tanpa Gangguan motorik kecuali pada tahap akhir penyakit. Gangguan perilaku dan ketergantungan dalam aktivitas hidup keseharian menyusul gangguan memori episodik. Terutama usai >65 tahun Diagnosis klinis dapat dibuat dengan akurat pada sebagian besar kasus (90%) diagnosis pasti biopsi otak plak neuritik (deposit β-amiloid40 dan β-amiloid42) serta neurofibrilary tangle (hypertphosphorylated protein tau). biomarka neuroimaging (MRI struktural/fungsional/PET) dan cairan otak (β- amiloid dan protein tau) untuk menambah akurasi diagnosis.

23 Alzheimer’s disease is the most common dementia in clinics

24

25 Neuroimaging Dementia Alzheimer

26 Faktor Risiko Penyakit Alzheimer
Usia lanjut: diatas 65 tahn (10%), 85 tahun (50%) Riwayat keluarga demensia atau Down Sydrome Faktor Genetik: Apolipoprotein E4; Presenilin 1,2 Wanita lebih sering Cedera kepala Hipertensi

27 DEMENSIA VASKULER DV adalah penyakit heterogen dengan patologi vaskuler yang luas termasuk infark tunggal strategi, demensia multi-infark, lesi kortikal iskemik, stroke perdarahan, gangguan hipoperfusi, gangguan hipoksik dan demensia tipe campuran (PA dan stroke / lesi vaskuler) Faktor risiko mayor kardiovaskuler stroke akut CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoensefalopathy),

28 Neuroimaging demensia vaskuler

29 DEMENSIA LEWY BODY DAN DEMENSIA PENYAKIT PARKINSON
15-25% dari kasus otopsi demensia fluktuasi kognisi halusinasi visual yang nyata (vivid) pada awal perjalanan penyakit orang dengan Parkinsonism. jatuh berulang dan sinkope sensitif terhadap neuroleptik PA tumpang tindih temuan patologi antara DLB dan Parkonson dementia DLB cenderung mengalami gangguan fungsi eksekutif dan visuospasial sedangkan performa memori verbalnya relatif baik jika dibanding dengan Parkinson dementia yang terutama mengenai memori verbal.

30 DEMENSIA FRONTOTEMPORAL
early onset dementia/EOD (sebelum umur 65 tahun) Klinis: perburukan progresif perilaku dan atau kognisi tahap dini (3 tahun pertama): perilaku disinhibisi, apati atau inersia, kehilangan simpati/empati, perseverasi, steriotipi atau perlaku kompulsif/ritual, hiperoralitas/perubahan diet gangguan fungsi eksekutif tanpa gangguan memori dan visuospasial pada pemeriksaan neuropsikologi.

31 MRI pada demensia frontotemporal
FvFTD/ bv-FTD Frontal/prefrontal cortex Anterior temporal cortex Semantic Dementia Middle and inferior temporal neocortex Progressive Aphasia Left perisylvian cortex

32 Kriteria diagnosis semua Dementia The National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease tahun 2011 Terdapat gejala kognisi atau perilaku (neuropsikiatri) yang: Mempengaruhi kemampuan untuk berfungsi di pekerjaan atau aktivitas harian + penurunan tingkat fungsi dan performa dibanding sebelumnya + Tidak disebabkan oleh delirium atau gangguan psikiatri mayor Diagnosis melalui suatu gabungan antara (1) anamnesis + tes neuropsikologis

33 Diagnosis Dementia Pemeriksaan Neurobehavior (Gangguan kognisi & non kognisi) Gangguan kognisi gangguan memori, disorientasi, Kemampuan membuat keputusan dan pengertian diri tentang penyakit Keluhan non-kognisi: behavioral neuropsychological symptoms of dementia (BPSD). Depresi, agitasi, Delusi, halusinasi, tindakan agresif dan non-agresif seperti wandering, disinhibisi, sundowning syndrome dan gejala lainnya.

34 Pemeriksaan Fisik Pasien dengan demensia tipe Penyakit Alzheimer: tidak ditemukan kelainan fisik secara umum, dan tidak ditemukan gangguan motorik dan sensoris yang berarti pada tahap awal dan sedang. Pada tahap lanjut dapat ditemukan kekakuan ekstremitas dan kontraktur pasien demensia vaskuler paska stroke: kelumpuhan anggota gerak, kesulitan berjalan, bicara cadel dan gangguan gerak lainnya dengan faktor risiko vaskuler Pasien dengan Penyakit Penyakit Parkinson atau demensia Lewy Body ditandai dengan gejala Parkinsonism seperti tremor, rigiditas, akinesia dan pustural instability dari awal penyakit. Kejang mioklonik dengan demensia: Creutzfeld Jacob Disease, kejang dengan bangkitan parsial dapat ditemukan pada pasien epilepsi maupun epilepsi pasca stroke atau lesi struktural fokal di otak lainnya

35 Pemeriksaan kognisi bedside
Pemeriksaan neuropsikologi singkat untuk pelayanan kesehatan tingkat primer AD8 Clock Drawing Test (CDT) Minimental State Examination (MMSE)

36 AD8-INA No Untuk ditanyakan ke keluarga/pengasuh pasien: Dibanding beberapa tahun sebelumnya, apakah keluarga Anda/ pasien mengalami perubahan seperti yang tercantum dibawah ini? Ya Tidak Tidak tahu 1 Kesulitan dalam membuat keputusan? Misalnya tidak mampu memberi saran dengan benar, tidak mampu mengurus keuangan, membeli hadiah yang tidak layak untuk orang lain, bermasalah dengan pemikiran? 2 Sudah tidak menekuni hobi/ kegiatan yang sebelumnya disenangi? Misalnya merajut, menjahit, berkebun, memasak kue, membaca buku, bermain catur, memainkan alat musik, atau bernyanyi? 3 Mengulang-ulang pertanyaan, cerita atau pernyataan yang sama? 4 Kesulitan belajar menggunakan perkakas & peralatan?, seperti TV, radio, komputer, microwave, remote control, kompor, setrika, blender? 5 Lupa nama bulan atau tahun? 6 Kesulitan mengatur keuangan? Misalnya membayar rekening air/listrik, periksa buku cek, pajak pendapatan, mengambil uang pensiun di bank? 7 Apakah keluarga anda mengalami kesulitan mengingat janji terhadap orang lain? 8 Sehari-harinya mengalami gangguan memori dan pemikiran yang konsisten?. Misalnya lupa meletakkan kaca mata, kunci kendaraan, meletakkan barang tidak sesuai pada tempatnya

37 AD8-INA Penilaian: Ya = nilai 1; Tidak/tidak tahu = 0 Interpretasi
Total skor 0-1: normal Toal Skor > 2: Gangguan kognisi

38 Done in 2011: case control method
InaAD-8 Validity Done in 2011: case control method Sensitivity: 89% Specificity: 94% Area under the ROC curve (UC) 0,941 95% Confidence interval 0.862ti 0.982 Z test 13.147 P value <0.0001 Gafur, Anam, Suryani, presented in Asian Society Against Dementia, Hongkong 2011

39 Mini mental state examination (MMSE)
Item Tes Nilai Max Nilai ORIENTASI 1 Sekarang (tahun), (musim), (bulan), (tanggal), hari apa? 5 2 Kita berada dimana? (negara), (propinsi), (kota), (rumah sakit), (lantai/kamar) REGISTRASI 3 Sebutkan 3 buah nama benda ( Apel, Meja, Koin), tiap benda 1 detik, pasien disuruh mengulangi ketiga nama benda tadi. Nilai 1 untuk tiap nama benda yang benar. Ulangi sampai pasien dapat menyebutkan dengan benar dan catat jumlah pengulangan ATENSI DAN KALKULASI 4 Kurangi 100 dengan 7. Nilai 1 untuk tiap jawaban yang benar. Hentikan setelah 5 jawaban. Atau disuruh mengeja mundur kata “ WAHYU” MENGINGAT KEMBALI (RIKOL) Pasien disuruh menyebut kembali 3 nama benda di atas BAHASA 6 Penamaan: Pasien disuruh menyebutkan nama benda yang ditunjukkan (pensil, buku) 7 Pengulangan: Pasien disuruh mengulang kata-kata:” namun”, “ tanpa”, “ bila” 8 Perintah 3 tingkat: Pasien disuruh melakukan perintah: “Ambil kertas ini dengan tangan anda, lipatlah menjadi dua dan letakkan di lantai”. 9 Membaca: Pasien disuruh membaca dan melakukan perintah “Pejamkanlah mata anda” 10 Menulis: Pasien disuruh menulis dengan spontan 11 Menyalin gambar: Pasien disuruh menggambar bentuk di bawah ini Total  30

40 Interpretasi MMSE Secara umum tanpa memandang usia, pendidikan dan pekerjaan: Nilai 24 – 30 : Normal Nilai : Probable gangguan kognisi Nilai : Definite gangguan kognisi Nilai dipengaruhi oleh usia, pendidikan dan pekerjaan

41 Penanganan dementia : 3 Aspek yang terlibat dementia
Functional Cognition Behavior / non cognitive symptoms

42 Current Management of Dementia (Alzheimer’s Disease)
Increased quality of life for patient and family Manage cognitive symptoms Intervention Pharmacology & Non Pharmacology Manage BPSD Support To patient/family Although there is no current cure for Alzheimer’s disease, both nonpharmacological and pharmacological interventions are needed to optimally treat the cognitive, behavioral and psychological symptoms in patients with the disease. When coordinated with support services, outcomes for the patient, family and caregiver can be improved. Functional

43 Rekomendasi Dosis Penguat Kognisi
Obat Sediaan Dosis Awal Titrasi Contoh jadwal titrasi Inhibitor kolinesterase Donepezil Tablet (5mg, 10mg) 2.5 – 5mg satu kali sehari Naikan hingga 10mg/ hari setelah 4-8 minggu 2.5 mg  5 mg  10mg Rivastigmine Patch (4.6mg/24h, 9.5mg/24h) 4.6mg/24 jam satu kali sehari Naikan hingga 9.5 mg/24 jam setelah 4 minggu 4.6mg/24 jam  9.5mg/24 jam (ditempel di badan) Galantamine Tablet (4mg, 8mg) PR Capsule *(16 mg) 4mg dua kali sehari, sesudah makan Naikan 4 mg dua kali sehari setiap 2-4 minggu, hingga 16 mg per hari 4mg (dua kali sehari) 8mg (dua kali sehari) atau 16 mg PRC (sekali sehari) (2) NMDA antagonists Memantine Tablet (10mg) 5mg sekali sehari Naikan 5 mg tiap 1-2 minggu hingga 10 mg dua kali sehari 5mg (malam)  5mg (pagi dan malam)  5mg (pagi) dan 10mg (malam)  10mg (pagi dan malam)

44 Benefit of Therapy Placebo AChEI +/- Memantine
Improvements in cognition and function are small relative to the overall decline in cognitive/functional status seen in almost all AD patients AChEis can be expected to slow cognitive decline, but less likely to improve status above baseline. “It’s like getting 6-12 months of your memory back.” Rather than being disease-modifying agents, cholinesterase inhibitors and memantine have potential as disease-course-modifying agents. The functional and behavioral benefits extend beyond 6 months, but testing seems to return to where it was prior to drug treatment -This is a progressive condition Symptomatic therapies are those affecting the course of the disease. Their benefits are multidimensional, improving cognition, global assessment, activities of daily living, behavior, and caregiver burden. Symptomatic therapies should defer decline. Clinical trials show that symptomatic therapies produce an initial improvement above baseline.4,5 However, some patients experience observable changes and some experience none. These therapies are believed to produce ~1 point improvement on the Mini-Mental State Examination (MMSE) average, and a decline that is otherwise parallel to a placebo group after a period of delayed progression. Birks J. Cholinesterase Inhibitors for Alzheimer’s Disease (Review). The Cochrane Library 2012 Issue 5.

45 Potential positive effects of antidementia drugs
Slowed/stabilized illness Happier/brighter/more aware/more active Improved/helped memory loss Calmer/less aggressive More independent/taking care of personal needs Showed an interest in things Improved conversation/speech Less confused/better understanding Better quality of life Restored/more confident

46 Common Side Effects Cholinesterase inhibitors (Donepezil, galantamine, rivastigmine) NMDA-receptor antagonist (Memantine) Gastrointestinal: nausea, vomiting, diarrhea, anorexia, loss of appetite Cardiovascular: bradycardia, syncope (attention with sick sinus syndrome, AV-block) Neuromuscular: cramps CNS: insomnia, REM Behavior Disorder (Donepezil) , worsening of depression Urinary: increase voiding Dizziness Headache Constipation Confusion ChEIs The most common reason for discontinuing a ChEI is gastrointestinal disturbances, such as nausea, vomiting and diarrhea that may result in anorexia and weight loss. Cardiovascular side effects include dizziness, syncope and bradycardia Incontinence, leg cramps and sleep disturbances also may occur. Side effects associated with cholinesterase inhibitors occur primarily during the dose-escalation phase of therapy and seem to be transient. If patient is not tolerating a cholinesterase inhibitors, switching to another agent may minimize side effects.

47 Behavioural and psychological symptoms of dementia (BPSD)
Symptoms of disturbed perception, thought content, mood or behaviour that frequently occur in patients with dementia Moderator Summary Behavioural symptoms: usually identified on the basis of observation of the patient, including physical aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviours, sexual disinhibition, hoarding, cursing and shadowing Psychological symptoms: usually and mainly assessed on the basis of interviews with patients and relatives. These symptoms include anxiety, depression, hallucination and delusions. The term BPSD is a collective term for many of the behaviours and psychological symptoms that occur in patients with dementia. Importantly these symptoms are often associated with increased patient and carer stress, reduced activities of daily living and admission to 24-hour care settings. Definition Begreppet BPSD (Behavioural and Psychological Symptoms in Dementia) myntades 1996 som ett samlingsnamn för ett antal vanliga, icke-kognitiva symtom vid demenssjukdom. BPSD beskrivs dels som förändrade beteenden som är belastande för individen och andra människor, dels som psykiska symtom av sådant slag som också kan uppträda hos personer utan demens såsom ångest och hallucinationer. BPSD-begreppet är ifrågasatt. Det saknas en enhetlig definition av fenomenet som är en sammanfogning av olika symtom med olika svårighetsgrad vid olika demensdiagnoser. I dagsläget saknas även ingående kunskap om naturalförlopp hos olika typer av beteendemässiga och psykiska symtom för olika diagnoser. Att BPSD-begreppet trots detta förekommer i dessa behandlingsrekommendationer betingas dels av att termen ändå används frekvent och dels av att många av de studier som ligger till grund för rekommendationerna inte närmare specificerar symtomen. Konfusion (delirium) är en vanlig orsak till BPSD-symtom vid demenssjukdom. Symtom vid konfusion utgörs av olika BPSD-symtom med varierande intensitet. Förloppet vid konfusion är dock typiskt, med snabbt påkommande symtombild som växlar under och mellan dagar. Läkemedel, kroppslig sjukdom eller miljö kan vara utlösande. Behandling av konfusion är specifik och bör riktas mot de identifierade utlösande faktorerna. International Psychogeriatric Association 1996

48 NPI: Neuropsychiatric Inventory
Point and 5 year prevalence of BPSD in the community as measured by NPI NPI: Neuropsychiatric Inventory

49 Pentingnya Penanganan BPSD
Menambah penderitaan, disabilitas pasien Berhubungan dengan progresitas penyakit Penyebab distres pada pasien dan pengasuh Penyebab utama perawatan panti wredha Menambah biaya pengobatan Tetapi dapat ditangani dan diobati Why should we be interested in treating non-cognitive symptoms? Firstly as we have seen they are common. Indeed only a handful of dementia sufferers will have no non-cognitive disturbance during the course of the illness but the individual symtoms will of course vary from patient to patient. Secondly, these symtoms undoubtedly increase patient suffering as well as crarer burden. Carer burden is often greter as a result of behavioural disturbance such as wandering and aggression that cognitive disturbance alone and is a major cause of premature insitutionilisation. The costs of caring for patients with behavioral disturbance is gretaer than non disturbed individuals. Finally we should be interseted in treating these symtoms because thay are largely treatable Frequent, cost for patient, carers and society, institutionalinization, carer, QoL, to much antipsychotics, to long use, to high or to low dosie, side effects and effect, prevention, structure More rapid illness progression, exacerbation of functional and cognitive deficits, increased caregiver stress 700,000 dementia patients in UK Most at moderate to severe stages 90% of these will have one or more behavioural problems Misery for informal carers Precipitate institutionalization Treated on basis of limited evidence base for efficacy and good evidence base for harm While much of the focus of AD management has been directed towards delaying and preventing cognitive decline, it is now recognised that behavioural changes also contribute to the disability associated with AD.1 Furthermore, behavioural symptoms are associated with rapid disease progression,2,3 and are a common cause of distress for patients and carers.4 Consequently, the presence of behavioural symptoms is a major determinant of institutionalisation,5 and increased direct costs of care.6 1. Wynn ZJ, Cummings JL. Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer’s disease. Dement Geriatr Cogn Disord 2004; 17: 100–108. 2. Drevets WC, Rubin EH. Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type. Biol Psychiatry 1989; 25: 39–48. 3. Jeste DV, Wragg RE, Salmon DP, et al. Cognitive deficits of patients with Alzheimer’s disease with and without delusions. Am J Psychiatry 1992; 149: 184–189. 4. Ballard C, Fossey J. Clinical management of dementia. Psychiatry 2007; 7 (2): 88–93. 5. Steele C, Rovner B, Chase GA, et al. Psychiatric symptoms and nursing home placement of patients with Alzheimer’s disease. Am J Psychiatry 1990; 147: 1049–1051. 6. Murman DL, Chen Q, Powell MC, et al. The incremental direct costs associated with behavioural symptoms in AD. Neurology 2002; 59: 1721–1729. Impact of behavioural symptoms on caregivers and patients Caregivers spend from 40–100 hours per week with the patient 90% are affected emotionally (frustrated, drained) 75% report feeling depressed; 66% have significant depression Half say they do not have time for themselves and that the stress affects family relations Many experience a significant loss of income Isolation Wynn & Cummings 2004 Drevets et al Jeste et al 1992 Ballard & Fossey Steele et al1990 Wilcock et al2008

50 Agitation/agression

51 Delusions Incidence: 10-73% Symptoms People are stealing things
House is not one’s home Spouse (or other caregiver) is an impostor Abandonment Infidelity

52 Hallucinations 12% to 49% of total dementia patients
Visual halucination in 30% of dementia patients 80% in DLB (phantom boarder, misindentification syndromes)

53 Sundowning Exacerbation of BPSD in the afternoon or evening.
Agitation and sleep disturbances commonly accompany sundowning. Increases the burden of care on caregivers, as it often occurs when the staffing in institutional settings is at the lowest levels. The circadian, hormonal, physiological, and environmental correlated (Sharer, 2008).

54 Treatment of BPSD - overview
Non-pharmacological Pharmacolocial treatment Anti-dementia agents Cholinesterase inhibitors NMDA receptor antagonist Psychotropics Antidepressants Antipsychotics Seminar: dementia Area: Clinical management of dementia Subject: Module: Module 3: Treating behavioral disturbances Chapter: Pharmacological approaches Topic: Topic 1: Introduction Title of slide: Treatment of BPSD - overview Slideposition:after: general principles treating BPSD Moderator notes: Many clinical guidelines place non-pharmacologic interventions to prevent and treat BPSD at first line. As a second line treatment often anti-dementia agents are recommended and the psychotropics are recommended when nothing else works, due to the potential serious side effects. This is also one possible interpretation of the studies by Callahan et al (2006) and Schneider et al. (2006). Referencies: 1. JAMA 2006;295: Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized controlled trial. Callahan CM, Boustani MA, Unverzagt FW, Austrom MG, Damush TM. Perkins AJ, Fultz BA, Hui SL, Counsell SR, Hendrie HC. CONTEXT: Most older adults with dementia will be cared for by primary care physicians, but the primary care practice environment presents important challenges to providing quality care. OBJECTIVE: To test the effectiveness of a collaborative care model to improve the quality of care for patients with Alzheimer disease. DESIGN, SETTING, AND PATIENTS: Controlled clinical trial of 153 older adults with Alzheimer disease and their caregivers who were randomized by physician to receive collaborative care management (n = 84) or augmented usual care (n = 69) at primary care practices within 2 US university-affiliated health care systems from January 2002 through August Eligible patients (identified via screening or medical record) met diagnostic criteria for Alzheimer disease and had a self-identified caregiver. INTERVENTION: Intervention patients received 1 year of care management by an interdisciplinary team led by an advanced practice nurse working with the patient's family caregiver and integrated within primary care. The team used standard protocols to initiate treatment and identify, monitor, and treat behavioral and psychological symptoms of dementia, stressing nonpharmacological management. MAIN OUTCOME MEASURES: Neuropsychiatric Inventory (NPI) administered at baseline and at 6, 12, and 18 months. Secondary outcomes included the Cornell Scale for Depression in Dementia (CSDD), cognition, activities of daily living, resource use, and caregiver's depression severity. RESULTS: Initiated by caregivers' reports, 89% of intervention patients triggered at least 1 protocol for behavioral and psychological symptoms of dementia with a mean of 4 per patient from a total of 8 possible protocols. Intervention patients were more likely to receive cholinesterase inhibitors (79.8% vs 55.1%; P = .002) and antidepressants (45.2% vs 27.5%; P = .03). Intervention patients had significantly fewer behavioral and psychological symptoms of dementia as measured by the total NPI score at 12 months (mean difference, -5.6; P = .01) and at 18 months (mean difference, -5.4; P = .01). Intervention caregivers also reported significant improvements in distress as measured by the caregiver NPI at 12 months; at 18 months, caregivers showed improvement in depression as measured by the Patient Health Questionnaire-9. No group differences were found on the CSDD, cognition, activities of daily living, or on rates of hospitalization, nursing home placement, or death. CONCLUSIONS: Collaborative care for the treatment of Alzheimer disease resulted in significant improvement in the quality of care and in behavioral and psychological symptoms of dementia among primary care patients and their caregivers. These improvements were achieved without significantly increasing the use of antipsychotics or sedative-hypnotics. 2. N Engl J Med Oct 12;355(15): Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA; CATIE-AD Study Group. BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. Key words: non-pharmacologic, behaviour, environmental, complementary, anti-dementia agents, cholinesterase inhibitors, NMDA receptor antagonist, psychotropics, antipsychotics, mood stabilisers, antidepressants, Callahan, Schneider

55 Reasons for using nonpharmacologic intervention approach to treat inappropriate behaviours
Aims at addressing the psychosocial/environmental underlying cause for the behaviour It avoids the limitations of pharmacologic interventions Side effects Drug-interactions Limited efficacy When medication is efficacious, it masks the real need. There by reducing the already compromised communication by elderly persons and limiting the caregiver’s ability to properly care for him or her To 1.: this is not absolutely true, since mostly the symptom, i.e. vocalization or wandering, is treated, not the underlying cause. At least not in the trials, where everybody get the same treatment, regardless of the underlying cause. To 2a: there are some side effects of . Reorientating patients to their situation through the use of therapies such as reality orientation, which repeatedly require the patient to acknowledge problems, may have the effect of increasing awareness and therefore reducing HRQL. The effect of other therapies aimed at improving cognition such as cognitive stimulation is of interest as a form of intervention potentially benefitting HRQL in mild dementia through improved cognition. Insight – cognition (stage) – QoL, what is the correlation?

56 Non-pharmacological intervention for dementia includes:
Cognitive /emotion-oriented interventions Cognitive training Reminiscence therapy Simulated presence therapy Validation therapy Sensory stimulation interventions Acupuncture, Aromatherapy Light therapy, Massage/touch Music therapy, Snoezelen multisensory stimulation, TENS Behavior management techniques (BMT) Other psychosocial interventions Animal-assisted therapy Exercise Targeting Wondering and agitation

57 Physical & Environment Factors
Assessment – PAID & ABC Physical problem triggered BPSD Activity related BPSD, Intrinsic to the disease D Depression or Delusion De olika demenstillstånden har olika kliniska uttryck och en specifik diagnos är en förutsättning för en adekvat behandling. En del patienter har aldrig fått en demensdiagnos och i ännu mindre grad en specifik demensdiagnos. Det är av största vikt att i varje enskilt fall analysera patientens symtomkonstellation för att kunna optimera behandlingen. BPSD-begreppet som sådant är alltför heterogent för att låta sig behandlas som en enhet. - Anamnes och kartläggning av symtom symtomdebut, frekvens, tid på dygnet, sammanhang, relation till omgivning använd gärna någon sorts protokoll/checklista - Är basala mänskliga behov tillfredsställda? närhet, fysisk kontakt, meningsfull syssla, rörlighet/aktivitet, mag-tarmfunktion, vikt, nutrition, vattenkastning och sömn Hur är den omgivande miljön och interaktionen med personalen? Medicinsk bedömning fysisk och psykisk status, sanering av läkemedel, vb. riktad undersökning (lab-prover, datortomografi, neuropsykologiska bedömning) Nedanstående rekommendationer har som ambition att specificera för vilka symtom en viss behandling kan vara effektiv. Att BPSD-begreppet trots detta förekommer i dessa behandlingsrekommendationer betingas dels av att termen ändå används frekvent och dels av att många av de studier som ligger till grund för rekommendationerna inte närmare specificerar symtomen. Analysis: Dementia diagnosis, Cause Somatic (side effects pain, heart disease, infection etc), Environmental ABC Psychiatric (depression, psychosis, anxiety) ABC: Antecedents, Behaviour, Consequences PAID: Physical, Activity, Intrinsic, Depression and delusions Skattningsskalor: 1. Cohen-Mansfield Agitation Inventory (CMAI) aggressiva och icke aggressiva verbala och fysiska beteenden (slag, vandrande och skrik) 2. The Behavioral Pathologic Rating Scale for Alzheimer’s Disease (BEHAVE-AD) AD-symtom: vanföreställning att bli bestulen, rädsla att bli lämnad ensam, fragmenterad sömn m.fl. 3. The Neuropsychiatric Inventory (NPI) frekvens och grad av beteendemässiga och psykiska symtom vanliga vid AD demenssjukdom skattas Antecedent – Behavior – Consequencies

58 Triggers Pain, discomfort, malnourishment, dehydration, boredom and physical illness – these are very common triggers which are often overlooked Stress, irritability, mood disturbance and suspiciousness Increased levels of distress Early signs may be noticed at certain times of the day and may indicate a specific trigger Abuse or neglect.

59 Substances that may induce psychotic disorders
Antiarrhythmic agents Antineoplastic agents, Antiviral agents, Baclofen ß blockers, Cyclosporine, Dopaminergi dan anticholinergic agents Interferon, Opioids and steroids Reduce the dose of or to eliminate the medication

60 Cholinesterase Inhibitor & MNDA receptor antagonist in treatment of BPSD

61 Efficacy of memantine in moderate to severe AD
The efficacy of memantine (20 mg/day) in the moderate to severe AD population was examined through meta-analysis.1 Based upon data from the six Phase III, 6-month clinical studies (MRZ-9605, MD-01, MD-02, MD-10, MD-12 and 99679), the analysis included patients with a baseline MMSE score <20.1 In total, 1,826 patients were analysed in the moderate to severe AD subgroup (MMSE <20).1 Each domain revealed statistically significant effects in favour of memantine (versus placebo), with mean differences (OC): global status (0.22; p<0.0001), cognition (0.26; p< ), function (0.18; p<0.0007), and behaviour (0.12; p<0.03).1 LOCF data were consistent with OC values.1 Thus, in patients with moderate to severe AD (MMSE <20), memantine produced a statistically significant effect versus placebo in the cognitive, functional, global, and behavioural domains.1 1. Winblad B, Jones RW, Wirth Y, et al. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007; 24: 20–27. Winblad et al. Dement Geriatr Cogn Disord 2007; 24: 20–27

62 Lockhart I A et al. Dement Geriatr Cogn Disord Extra 2011
Meta-analysis for studies reporting use in licensed indication: donepezil, and memantine monotherapy Forest plot of random-effect meta-analysis for studies reporting use in licensed indication: donepezil, mild to moderately severe AD population, and memantine monotherapy, moderate to severe AD population. Note: ChEIs are also used in the placebo control arm; I 2 = Variation in effect attributable to heterogeneity. Dement Geriatr Cogn Dis Extra Jan;1(1): Epub 2011 Jul 20. The efficacy of licensed-indication use of donepezil and memantine monotherapies for treating behavioural and psychological symptoms of dementia in patients with Alzheimer's disease: systematic review and meta-analysis. Lockhart IA, Orme ME, Mitchell SA. Source Pfizer Ltd., Tadworth. Abstract BACKGROUND/AIMS: Behavioural and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) greatly increase caregiver burden. The abilities of donepezil and memantine to manage BPSD within their licensed indications in AD were compared. METHODS: A systematic review, random effects meta-analysis and Bucher indirect comparison were conducted. RESULTS: Six randomised controlled studies (4 donepezil and 2 memantine) reported use within the licensed indication and had Neuropsychiatric Inventory (NPI) data suitable for meta-analysis. BPSD showed significant improvement with donepezil compared with placebo [weighted mean difference (WMD) in NPI -3.51, 95% confidence interval (CI) -5.75, -1.27], whereas this was not the case for memantine (WMD -1.65, 95% CI -4.78, 1.49). WMD in NPI for donepezil versus memantine favoured donepezil but was not statistically significant (-1.86, 95% CI -5.71, 1.99; p = 0.34). CONCLUSION: Within its licensed indication, donepezil is efficacious for the management of BPSD in AD compared with placebo. Lockhart I A et al. Dement Geriatr Cogn Disord Extra 2011

63 A 24-week, double-blind study of donepezil in mod/severe AD
Axura Launchsymposium Stockholm Wilkinson A 24-week, double-blind study of donepezil in mod/severe AD -2.0 Donepezil Placebo -1.5 * -1.0 Clinical improvement NPI change from baseline Week 24 -0.5 0.0 Baseline 0.5 Donepezil has been shownto reduce apathy in people with moderate-severe apathy in AD. Amantadine, modafinil and d-amphetamine has shown mixed results. Clinical decline 1.0 Delusions Hallucinations Elation Irritability Depression Anxiety Apathy Disinhibition Night-time behav Appetite/eating Agitation/aggression Aberr motor behav *p<0.05 vs placebo H. Feldman, et al Neurology 20010

64 Memantine prevents behavioural symptoms in asymptomatic AD patients
Memantine Placebo * Percentage of patients remaining asymptomatic at week 24/28 (LOCF) ** ** Fewer patients develop agitation and aggressiveness with memantine, but we don’t know if stops these behaviours In the pooled analysis of six memantine clinical studies, memantine showed significant advantages over placebo in the proportion of patients without behavioural symptoms at baseline who remained asymptomatic at Week 24/28 in the items agitation/aggression (p=0.002), irritability/lability (p=0.004), and night-time behaviour (p=0.05).1 Therefore, the beneficial effect of memantine in this domain is not limited to those patients with behavioural symptoms at baseline, but can also reduce symptom emergence. 1. Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 2008; 23: 537–545. *p=0.05; **p<0.01 Gauthier et al. Int J Geriatr Psychiatry 2008 64

65 Benzodiazepines in dementia
Frequently used, rarely studied Considerable adverse effects falls confusion oversedation disinhibition If absolutely unavoidable, use short term only Short half-life, hepatic metabolism, no active metabolites are favourable qualities (e.g. lorazepam, temazepam) Moderator Summary Benzodiazepines may be an effective treatment for the most distressing and intractable of symptoms—insomnia. However, tolerance develops, withdrawal is difficult and the side-effect profile renders these compounds highly toxic in all elderly, but more so in the cognitively impaired. Even low-dose lorazepam affects AD patients differently from normal elderly (Sunderland et al 1989). When the effect on sleep has been examined, the data suggest that those with dementia may be more resistant to the insomniac effects of benzodiazepines (McCarten et al 1995). There is little evidence on which to base treatment recommendations. Many avoid wherever possible and, where unavoidable, treat for very short times only with a short-acting drug. User Notes None Found McCarten et al (1995); Sunderland et al (1989)

66 Antipsychotics – is it worth it?
Triples the rate of stroke Doubles mortality Substantially increases falls and fractures Reduces quality of life Rarely discontinued with cumulative adverse effect Weight gain and disruption of blood glucose control: metabolic syndrome Doubles the rate of cognitive decline AP’s are associated with a number of major adverse outcomes and side- effects including sedation, parkinsonism, gait disturbance, dehydration, falls, chest infections, accelerated cognitive decline, stroke and death. Moderator notes: There are now many studies and meta-analyses showing that the antipsychotics are efficacious in treating psychosis and agitation in patients with dementia, at least for short term use (up to three months), but are they effective and is it worth it? The evidence indicates the best results are for treatment of aggression in people with AD, particularly using risperidone. The evidence for the treatment of other symptoms of agitation and psychosis is less clear (Ballard et al 2006). A study by Schneider et al (2006) suggest that olanzapine and risperidone were equally effective though and were superior to placebo and quetiapine in treating behavioural symptoms, but this was limited to a subgroup of patients who tolerated the drugs and did not have side effects like sedation or extrapyramidal symptoms. The vascular complications in patients with dementia have been a hot topic the last years and Schneider et al (2006) summarizes that atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. Several authorities claims though that the available information and RCTs included in systematic reviews described adverse events too incompletely and heterogeneously to allow generation of clear treatment recommendations, and they do not provide sufficient evidence to support recent safety warnings (van Ierslel et al, drugs of ageing 2006). Schneider et al (2006) concludes, however, that adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for treatment of BPSD symptoms. It seems clear that caution should be used, considering that the effects of antipsychotics are modest and further complicated by an increased risk of stroke and other disturbing side effects, which have to be compared with the possible positive effects before prescribing these drugs. There are advantages trying other alternatives (non-pharmacological treatments and anti-dementia drugs) first, especially when thinking of the lack of serious side effects or no side effects at all using the alternatives. Reference 1. International Psychogeriatrics (2005), 17:1, 3––29 FOR DEBATE: SHOULD NOVEL ANTIPSYCHOTICS EVER BE USED TO TREAT THE BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD)? Ballard C et al 2. Nat Rev Neurosci Jun;7(6): Neuroleptic drugs in dementia: benefits and harm Ballard C, Howard R. Neuroleptic (antipsychotic) drugs are often used to treat psychiatric symptoms frequently seen in dementia, but their use is controversial. We present a new meta-analysis to assess the efficacy of these drugs for the treatment of psychiatric symptoms in Alzheimer's disease, and discuss the more limited evidence for their potential benefits in other dementias. We recommend that these treatments be limited to the short-term treatment of psychiatric symptoms associated with serious distress or risk. 3. N Engl J Med Oct 12;355(15): Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA; CATIE-AD Study Group BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. 4. JAMA Oct 19;294(15): Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. Schneider LS, Dagerman KS, Insel P. CONTEXT: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use. OBJECTIVE: To assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia. DATA SOURCES: MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations ( ), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial. STUDY SELECTION: Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors. DATA EXTRACTION: Trials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer. DATA SYNTHESIS: Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], ; P = .02; and risk difference was 0.01; 95% CI, ; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis. CONCLUSIONS: Atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed. 5. Am J Geriatr Psychiatry Mar;14(3): Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Schneider LS, Dagerman K, Insel PS. OBJECTIVE: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease (AD) and other dementia. Several clinical trials have not shown efficacy, and there have been concerns about adverse events. The objective of this study was to assess the evidence for efficacy and adverse events of atypicals for people with dementia. METHODS: MEDLINE, the Cochrane Register of Controlled Trials, meetings, presentations, and information obtained from sponsors were used in this study. Published and unpublished randomized, placebo-controlled, double-blind, parallel-group trials in patients with AD or dementia of atypical antipsychotics marketed in the United States were studied. Clinical and trials characteristics, outcomes, and adverse events were extracted. Data were checked by a second reviewer. Fifteen trials including 16 contrasts of atypical antipsychotics with placebo met selection criteria: aripiprazole (k = 3), olanzapine (k = 5), quetiapine (k = 3), and risperidone (k = 5). A total of 3,353 patients were randomized to drug and 1,757 to placebo. Standard meta-analysis methods were used to summarize outcomes. RESULTS: Quality of the reporting of trials varied. Efficacy on rating scales was observed by meta-analysis for aripiprazole and risperidone, but not for olanzapine. Response rates were frequently not reported. There were smaller effects for less severe dementia, outpatients, and patients selected for psychosis. Approximately one-third dropped out without overall differences between drug and placebo. Adverse events were mainly somnolence and urinary tract infection or incontinence across drugs, and extrapyramidal symptoms or abnormal gait with risperidone or olanzapine. Cognitive test scores worsened with drugs. There was no evidence for increased injury, falls, or syncope. There was a significant risk for cerebrovascular events, especially with risperidone; increased risk for death overall was reported elsewhere. CONCLUSIONS: Small statistical effect sizes on symptom rating scales support the evidence for the efficacy of aripiprazole and risperidone. Incomplete reporting restricts estimates of response rates and clinical significance. Dropouts and adverse events further limit effectiveness. Atypicals should be considered within the context of medical need and the efficacy and safety of alternatives. Individual patient meta-analyses are needed to better assess clinical significance and effectiveness. 6. Drugs Aging. 2005;22(10):845-58 Antipsychotics for behavioural and psychological problems in elderly people with dementia: a systematic review of adverse events. van Iersel MB, Zuidema SU, Koopmans RT, Verhey FR, Olde Rikkert MG. OBJECTIVE: Although antipsychotics are important in the treatment of behavioural and psychological symptoms of dementia (BPSD), they have moderate efficacy and often cause adverse events. Recent safety warnings about increased frequency of cerebrovascular adverse events in elderly patients who use atypical antipsychotics mean that physicians now face a dilemma when weighing the benefits and risks of use of antipsychotics in this patient group. This study systematically reviews the reporting of adverse events of antipsychotics used to treat BPSD in randomised, controlled trials (RCTs). METHODS: We searched the MEDLINE, EMBASE, PsychInfo and CINAHL databases (search period 1980 or 1986-April 2005) and the Cochrane controlled trials register (2005) for RCTs that used intention-to-treat analysis to evaluate the efficacy and harms of antipsychotics used to treat BPSD. Two independent reviewers assessed the reporting of adverse events. RESULTS: Screening of 930 abstracts identified 12 eligible RCTs (2809 patients). Most participants were elderly people (mean age 80 years) with Alzheimer's, vascular or mixed dementia. Studies lasted from 3 to 16 weeks. Adverse events, though common, were described heterogeneously and incompletely. No RCT fulfilled all Consolidated Standards of Reporting Trials requirements for the reporting of harms. Atypical antipsychotics caused fewer extrapyramidal symptoms and less somnolence than typical antipsychotics, but these differences disappeared when dosages were increased. Only one trial reported cerebrovascular adverse events, with a number needed to harm of 14 (95% CI 8, 41). CONCLUSIONS: At lower doses atypical antipsychotics may cause fewer adverse events in the treatment of BPSD, but there is uncertainty about their cerebrovascular safety profile. The RCTs included in this systematic review described adverse events too incompletely and heterogeneously to allow generation of clear treatment recommendations, and they do not provide sufficient evidence to support recent safety warnings. Better reporting on harms in RCTs is needed to enable rational treatment decisions with respect to use of antipsychotics for BPSD. 7. Cochrane Database Syst Rev Jan 25;(1):CD003476 The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Ballard C and Waite J. BACKGROUND: Aggression, agitation or psychosis occur in the majority of people with dementia at some point in the illness. There have been a number of trials of atypical antipsychotics to treat these symptoms over the last five years, and a systematic review is needed to evaluate the evidence in a balanced way. OBJECTIVES: To determine whether evidence supports the use of atypical antipsychotics for the treatment of aggression, agitation and psychosis in people with Alzheimer's disease. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 December 2004 using the terms olanzapine, quetiapine, risperidone, clozapine, amisulpride, sertindole, zotepine, aripiprazole, ziprasidone. This Register contains articles from all major healthcare databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: Randomised, placebo-controlled trials, with concealed allocation, where dementia and psychosis and/or aggression were assessed. DATA COLLECTION AND ANALYSIS: 1. Two reviewers extracted data from included trials2. Data were pooled where possible, and analysed using appropriate statistical methods3. Analysis included patients treated with an atypical antipsychotic, compared with placebo MAIN RESULTS: Sixteen placebo controlled trials have been completed with atypical antipsychotics although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer reviewed journals. No trials of amisulpiride, sertindole or zotepine were identified which met the criteria for inclusion. The included trials led to the following results:1. There was a significant improvement in aggression with risperidone and olanzapine treatment compared to placebo.2. There was a significant improvement in psychosis amongst risperidone treated patients.3. Risperidone and olanzpaine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extra-pyramidal side effects and other important adverse outcomes.4. There was a significant increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated patients.5. The data were insufficient to examine impact upon cognitive function. AUTHORS' CONCLUSIONS: Evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis, but both are associated with serious adverse cerebrovascular events and extra-pyramidal symptoms. Despite the modest efficacy, the significant increase in adverse events confirms that neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is marked risk or severe distress. Although insufficient data were available from the considered trials, a meta-analysis of seventeen placebo controlled trials of atypical neuroleptics for the treatment of behavioural symptoms in people with dementia conducted by the Food and Drug Administration (using data not in the public domain) suggested a significant increase in mortality (OR 1.7). Keywords:antipsychotics, BPSD, side effects, cognitive decline, stroke, mortality, falls, fracture, quallity of life, Ballard, Schneider, van Iersel Ballard et al (2005)

67 Kales H C et al. American Journal of Psychiatry 2012
Risk of Mortality Among Individual Antipsychotics in Patients With Dementia 2011 N= veterans COD: Tromboembolic events: Stroke & pulmonary Cardiac arrhythmia Deaths related to bronchopneumonia, thrombo-embolic events (including stroke and pulmonary embolism), and sudden cardiac arrhythmias are all significantly increased in people with dementia receiving antipsychotic treatment. The Kales et al. study in AM J Psychiatry 2011 Antipsychotics and Mortality in Dementia: a cohort of more than 30,000 veterans with dementia, ages 65 years and older. A key observation is that the highest increase in mortality risk was in the first 120 days, particularly in the first 30 days for haloperidol. One important consideration in implementing the evidence from this study into clinical practice is to balance safety and efficacy. the lowest mortality risk was associated with quetiapine. However, three randomized controlled trials of quetiapine did not demonstrate any effectiveness in the treatment of aggression, agitation, or psychosis. The best evidence of efficacy is for risperidone, with consistent evidence of a modest but significant benefit over 12 weeks in the treatment of both aggression and psychosis. There is also evidence of a similar level of benefit with aripiprazole, olanzapine, and haloperiodol, but only a few studies have examined other agents. Through balancing the mortality data from this study and efficacy data from previous randomized controlled trials, risperidone and olanzapine emerge as the best evidence-based options. Deaths related to bronchopneumonia, thrombo-embolic events (including stroke and pulmonary embolism), and sudden cardiac arrhythmias are all significantly increased in people with dementia receiving antipsychotic treatment. Another major clinical imperative is to deliver treatment and care to proactively reduce the mortality associated with antipsychotics when they are appropriately prescribed. significant incidence of sedation, chest-infection, and dehydration. It is likely that better care of people who are prescribed antipsychotics, for example, by monitoring fluid intake and promoting vigilance for early detection and treatment of chest infections, may offer important potential opportunities to reduce excess mortality. Dementia represents a significant clinical challenge, with an estimated 35.6 million people with dementia in the world, of whom 4.38 million reside in the United States (1, 2). Ninety percent of people with dementia experience behavioral and psychological symptoms of dementia at some point during their illness. Behavioral and psychological symptoms of dementia commonly manifest as agitation, aggression, depression, or psychosis (hallucinations and delusions), which can cause significant distress to the person and their caregiver as well as have a direct effect on the person's quality of life and likelihood of institutionalization. Although the majority of best practice guidelines emphasize the importance of nonpharmacological treatments and judicious short-term use of pharmacological treatment for behavioral and psychological symptoms of dementia, antipsychotic drugs are commonly used as a first-line approach for managing these symptoms. It is therefore a critical issue to understand the clinical efficacy and safety profile of individual antipsychotics to inform guidance on prescribing practice and choice of antipsychotic medication in situations where a prescription is deemed necessary. In this issue of the Journal, the cohort study conducted by Kales et al. (3) provides extremely valuable new knowledge pertinent to these key treatment decisions. A substantial number of trials have focused on the effectiveness of atypical antipsychotics for the treatment of behavioral and psychological symptoms of dementia. In total, 18 placebo-controlled randomized controlled trials conducted over a 6- to 12-week period have been undertaken in people with Alzheimer's disease. The best evidence of efficacy for the treatment of agitation, aggression, and psychosis relates to risperidone. Five trials have indicated a modest but significant improvement in aggression and psychosis, equating to a small treatment effect size (Cohen's d=0.2 at the optimal dose) (4, 5). However, this must be considered in the context of the widely reported side effects of atypical antipsychotics, which include extrapyramidal symptoms, sedation, gait disturbances, and falls. Kales H C et al. American Journal of Psychiatry 2012

68 Behavioral symptoms that do not justify antipsychotics
Wandering Agitated behaviors not dangerous to the resident or others Anxiety Poor self-care Restlessness Nervousness Uncooperativeness Fidgeting Insomnia Unsociability Impaired memory Depression (without psychotic features) Indifference to surroundings Only psychotic symptoms such as severe hallucination, delusion, agitation, aggressive behavior worth use of antipsychotic Despite serious safety concerns and minimal overall effect on symptomatology, antipsychotics are frequently prescribed off-label for BPSD. In 2010, the Centers for Medicare and Medicaid Services (CMS) reported that 39% of U.S. nursing home residents were inappropriately prescribed an antipsychotic without having a clinical indication for treatment. [14] According to CMS guidelines, it is appropriate to consider the use of an antipsychotic to treat delusions, hallucinations, and/or aggression in patients with dementia, but only if these symptoms are dangerous and/or severely distressing to the patient or others. Behaviors such as wandering, hoarding, and apathy are not considered appropriate treatment targets ( Table 2). [15] Additionally, modifiable causes of behavioral problems should always be definitively ruled out prior to beginning treatment with an antipsychotic. Table 3 lists conditions that can cause behavioral problems and/or mimic dementia. [15,16] To thwart the practice of prescribing antipsychotics for the chief purpose of behavior control or sedation, the CMS issued a mandate in 2012—since renewed for 2013—that all nursing homes reduce unnecessary use of antipsychotics by at least 15%. CMS regulation F329 (commonly known as F-Tag 329) defines unnecessary use as excessive dose, excessive duration, inadequate monitoring, lack of clinical indication for use, and presence of adverse events. [15] Table 2.  Inappropriate Antipsychotic Treatment Targets Wandering Nervousness Impaired memory Uncooperativeness without aggression Apathy Poor self-care Mild anxiety Avoidance of social interaction Inattention to surroundings Any verbal expression or behavior not posing a threat to self or others

69 Recommended ¼-1/2 dose of schizophrenic patients
What is the dose of antipsychotic for Delusion, Halucination and Agitation? Recommended ¼-1/2 dose of schizophrenic patients

70 Different Spectrum Side Effect of Atypical Antipsychotics
Seminar: dementia Area: Clinical management of dementia Subject: Module: Module 3: Treating behavioral disturbances Chapter: Pharmacological approaches Topic: Topic 3: Psychosis –> Psychiatric symptoms Title of slide: Side effects of antipsychotics Slide position:After – Atypical neuroleptics Moderator notes: There is a shortage of evidence of which antipsychotic drug to choose, when necessary to treat BPSD in patients with dementia. The side effects are a major obstacle when treating this category of patients. It may be worth considering the different spectrum of the side effects in the different AP’s before prescribing any of these drugs in the individual patient. Moretti R et al. (2006) and others have addressed these problems. Somnolence, sedation and parkinsonism are the most significant side effects in comparison with placebo. Many other are described, as gait problems, postural instability, hypotension, falls, incontinence, anticholinergic influence, cognitive deterioration, weight gain or loss and vascular risks. To the slide: +: Present ++: Present and major effect +++: Present and very important side effects 0: No effect References: Expert Rev Neurother May;6(5):705-10 Atypical neuroleptics as a treatment of agitation and anxiety in Alzheimer's disease: risks or benefits. Moretti R, Torre P, Antonello RM, Pizzolato G. Abstract: Atypical neuroleptics as a treatment of agitation and anxiety in Alzheimer's disease: risks or benefits. Moretti R, Torre P, Antonello RM, Pizzolato G.. Behavioral problems produce excess disability that can be potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they have the potential for significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism and akathisias. On examination of the consequences of adverse events, somnolence, as well as postural instability and postural hypotension, have been noted. All patients with Alzheimer's disease (AD) and other progressive dementias will advance through stages of moderate-to-severe AD unless effective treatments suspend transition from mild deterioration to dementia, or competitive mortality truncates survival. Treatment trials suggest that these patients respond to both disease-modifying (such as inhibitors of cholinesterase and butirrylcholinesterase) and symptomatic (such as neuroleptics) agents. Relatively few studies have been conducted in this patient population, and more information regarding the type of behavioral disturbances exhibited, how best to measure them in this disabled population and their optimum treatment are urgently needed. Keywords: antipsychotics, BPSD, side effects, cognitive decline, stroke, mortality, gait problems, postural instability, hypotension, falls, incontinence, anticholinergic influence, cognitive deterioration, weight gain,weight loss, vascular risks, seizure risk, clozapine, risperidone, olanzapine, quetiapine, restindole, ziprasidone Moretti et al (2006) Patient with DLB may hypersensitive to antipyschotic, if really needed, quetiapin or clozapine are more preferable than others Avoid agent with severe EPS for PDD and DLB patients

71 Discontinuation of antipsychotics
All antipsychotic prescriptions should be reviewed at six and/or 12 weeks. Discontinuation should be default except in extreme circumstances. 70% of people have no worsening of symptoms when antipsychotics are discontinued. The risk of recurrence of behavioural and psychiatric symptoms after discontinuation may be more likely if: previous discontinuation has caused symptoms to return the person currently has severe symptoms. If the person is receiving a low dose proceed directly with discontinuation and monitoring* Risperidone low dose = 0.5mg (500 micrograms) Olanzapine low dose = 2.5mg Quetiapine low dose = 50mg Aripiprazole low dose = 5mg If the person is receiving a higher dose taper the dose over one month Reduce to half dose for two weeks GP review at two weeks Discontinue immediately after a further two weeks

72 Malignant neuroleptic syndrom (DSM IV, APA 2000)
In a patient treated with a neuroleptic agent Symptoms Rigidity Fever And at least two of the following symptoms: Tremor Increased CK (creatine kinase) Autonomic dysfunctions Tachycardia Instable blood pressure Incontinence Diaphoresis is excessive sweating, the state of perspiring prof usely Leucocytosis Dysphagia Impaired consciousness, confusion Mutism +

73 Pharmacotherapy for BPSD
Antipsychotic can only be used after discussing the potential side- effect and risk/benefit ratio with patients and/or caregiver (fall, sedation, CVA, mortality) The side effect and response to treatment should be monitored and antipsychotic should be withdrew when patients are stable.

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77 PPK1/ PPK2

78 Diagnosis banding dementia/BPSD

79 Delirium: A differential diagnosis of BPSD
Patients who have dementia are at higher risk for developing delirium. Diagnosing delirium in a cognitively intact patient is fairly straightforward, with the sudden onset of global impairment that is easy to recognize. Confusion Assessment Method or CAM (Inouye et al., 1990) 1. Acute onset and fluctuating course 2. Inattention 3. Disorganized thinking 4. Altered level of consciousness Diagnosis of delirium if 1+2 satisfied + either 3 or 4

80 Differentiating delirium from dementia may be difficult, but:
Delirium usually presents with: Acute or subacute onset of symptoms Heightened or reduced attention in a patient with preexisting dementia, or, Prominent fluctuations in symptoms; visual hallucinations accompanied by agitation; altered psychomotor activity and occasionally asterixis.

81 Causes of delirium The most common causes are the following:
infection, especially urinary tract infection medication malnutrition / dehydration metabolic illnesses (e.g., certain renal or hepatic diseases) changes / stress in the patient’s environment surgery

82 DIAGNOSIS BANDING DEMENSIA
Gejala Demensia Delirium Depresi Awitan Perlahan Akut Bertahap Durasi Bulan/tahun Jam/hari/minggu Minggu/berapa bulan Perjalanan Bertahap progresif Fluktuasi, memburuk pada malam hari, periode lucid Memburuk pada pagi dan membaik pada malam hari Alertness Normal Fluktuasi Tidak tertarik, sering menjawab tidak tahu Orientasi Biasanya disorientasi waktu dan tempat Selalu terganggu Biasanya normal Memori Terganggu memori baru dan terkadang memori jangka panjang Gangguan memori baru Memori baru mungkin terganggu, memori lama utuh Pikiran Lambat dan perseveratif Sering beda dari kenyataan Lambat, preokupasi, sedih dan putus asa Persepsi Sering normal, halusinasi visual 30-40% Halusinasi visual dan auditori sering 20% dengan mood congruent halusination Emosi Apatetik, labil dan iritabel Iritabel, agresif atau ketakutan Mendatar, sedih, tidak responsif. Mungkin iritabel Tidur Terganggu, wandering atau konfusi malam Konfusi malam Terbangun pagi dini Lainnya Penyakit fisik lain jelas Gangguan mood sebelumnya atau riwayat keluarga

83 Potentially Reversible dementia
Hypothyroidism Pernicious anemia Chronic Subdural Hematoma CNS infections: TB, Cryptococcal, viral,HIV, syphilis Tumors Normal pressure hydrocephalus Drug intoxication Heavy metal poisoning

84 Natural history of Alzheimer’s disease and current stage-specific interventions
Control of risk factors Normal Aging Cognitive training Amnestic M C I Antidepressants ChEI ChEI Memantine Diagnosis of AD Severity of the disease Memantine +/- ChEI Atypical neuroleptics Loss of some functional independence Memantine +/- ChEI Atypical neuroleptics Behavioral symptoms Nursing home Palliative care Placement Death Time (years) Modified from Jelic & Winblad, 2004

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