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Overview of Treatment of Advancing Parkinsons Disease Karen M. Thomas, DO Diplomate, ABPN Associate Professor of Clinical Neurology, EVMS Director, Movement.

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Presentation on theme: "Overview of Treatment of Advancing Parkinsons Disease Karen M. Thomas, DO Diplomate, ABPN Associate Professor of Clinical Neurology, EVMS Director, Movement."— Presentation transcript:

1 Overview of Treatment of Advancing Parkinsons Disease Karen M. Thomas, DO Diplomate, ABPN Associate Professor of Clinical Neurology, EVMS Director, Movement Disorders Program Sentara Neurology Specialists Virginia Beach, VA

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3 WHAT IS PARKINSONS DISEASE? CLASSIC DEFINITION: A NEURODEGENERATIVE SYNDROME WITH THE HALLMARK FEATURES OF MOTOR IMPAIRMENT CAUSING: CLASSIC DEFINITION: A NEURODEGENERATIVE SYNDROME WITH THE HALLMARK FEATURES OF MOTOR IMPAIRMENT CAUSING: –BRADYKINESIA (slowness of movement) –TREMOR (resting > action) –RIGIDITY (stiffness) –POSTURAL INSTABILITY (impairment of postural / balance reflexes) DIAGNOSIS IS BASED ON FINDING THESE CARDINAL FEATURES (X 200 YEARS!!) ON CLINICAL EXAMINATION AND A SUPPORTIVE HISTORY DIAGNOSIS IS BASED ON FINDING THESE CARDINAL FEATURES (X 200 YEARS!!) ON CLINICAL EXAMINATION AND A SUPPORTIVE HISTORY EVOLVING CONCEPTS: EVOLVING CONCEPTS: –MANY OTHER FEATURES OCCUR, SEVERAL PREDATE THE MOTOR SYMPTOMS BY YEARS –PRESENTATION HIGHLY VARIABLE ACROSS PD POPULATION –NUMEROUS GENETIC ASPECTS NOW IDENTIFIED –MORE THAN JUST A DOPAMINE DISORDER

4 Epidemiology AGE RELATED AGE RELATED ~1 - 2% of age 65 and older ~30 % of PD in 50 and under age group ~10% of PD in 40 and under age group INCIDENCE /PREVALENCE INCREASES WITH AGE INCIDENCE /PREVALENCE INCREASES WITH AGE FOUND THROUGHOUT THE WORLD FOUND THROUGHOUT THE WORLD 1 – 1.5 MILLION IN U.S. 1 – 1.5 MILLION IN U.S. 60,000 new cases diagnosed each year 60,000 new cases diagnosed each year

5 Etiolotgy ETIOLOGY IS UNKNOWN ETIOLOGY IS UNKNOWN RISK FACTORS SUSPECTED: RISK FACTORS SUSPECTED: –GENETICS + RURAL LIVING / FARMING RURAL LIVING / FARMING PESTICIDE EXPOSURE PESTICIDE EXPOSURE HEAVY METAL EXPOSURE HEAVY METAL EXPOSURE NONSMOKER NONSMOKER EARLY MENOPAUSE OR OTHER HORMONAL CONTRIBUTIONS EARLY MENOPAUSE OR OTHER HORMONAL CONTRIBUTIONS –EVOLVING CONCEPTS: AT-RISK GENES WITH RECOGNITION OF ROLE OF GENE & ITS INTERACTION WITH ENVIRONMENTAL FACTORS AT-RISK GENES WITH RECOGNITION OF ROLE OF GENE & ITS INTERACTION WITH ENVIRONMENTAL FACTORS –Protein alteration –Cell clearing dysfunction –Chemical transport dysfunction –Different genes in different populations

6 Pathology FORMATION OF LEWY BODIES AND OTHER ACCUMULATIONS (AD PATHOLOGY, TAU) LOSS OF CELLS AND NEUROTRANSMITTERS SUCH AS DOPAMINE DOPAMINERGIC CELLS ARE LOST IN THE SUBSTANTIA NIGRA / BASAL GANGLIA AND OTHER AREAS, WHICH CAUSES MOTOR SYMPTOMS PROCESS OF CELL AND NEUROCHEMICAL LOSS CONTINUES THROUGHOUT DISEASE AND IS BELIEVED TO BE A PROCESS OF CELLULAR SPREAD THAT CAUSE CHANGES TO OCCUR IN MANY AREAS INCLUDING BG, BASAL FOREBRAIN (ACh), DORSAL MOTOR NUCLEUS X, MESOPONTINE, HYPOTHALAMIC, UPPER BRAINSTEM (5HT), LC (NE)

7 Lewy Bodies are filamentous cytoplasmic inclusions that are considered the pathological hallmark of PD and contain aggregated proteins including synuclein and ubiquitin MECHANISMS CONSIDERED: REDUCED PROTEOSOMAL ACTIVITY (IMPAIRED CLEARING OF DAMAGED PROTEINS) MITOCHONDRIAL DYSFUNCTION (INHIBITION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN) OXIDATIVE STRESS INFLAMMATION (PD BRAINS HAVE MARKED GLIAL ACTIVATION)

8 Nigral – Striatal Changes =Motor Symptoms PET scan showing striatal fluorodopa uptake of a normal brain versus PD Gross pathology of the mid brain showing a normal brain versus PD Normal Parkinsons disease Substantia nigra Brooks 1993 Marsden 1994 Lang & Lozano 1998

9 Braak stages I–IV in idiopathic Parkinsons disease. In stage I olfactory and medullary areas (black). The two processes converge in stage III (red) on the medial temporal lobes and then spread widely into the neocortex. Braak et al. 2004, Cell Tissue Res Stage 3 Symptomatic motor features Braak Staging based on LB Pathology

10 Current Hypothesis of PD Timeline CN X = motor component of cranial nerve X; RF = reticular formation; CN = central subnucleus of the amygdala;Meynerts n = basal nucleus of Meynert; PPN = pedunculopontine tegmental nucleus; TEC = transentorhinal cortex; CA2 = second section of the Ammons horn Hawkes CH, et al. Parkinsonism Relat Disord. 2010;16(2): Braak stage Clinical Onset 20 year prodrome 20 year disease stage Symptoms: Hyposmia Constipation Bladder disorder -20y Sleep disorder, Obesity, Depression -10y I Unilateral Tremor, Rigidity, Akinesia 0 II Bilateral disease III Poor balance +10y IV Falls, Dependency, Cognitive decline V Chair/bed- bound Dementia +20y Hoehn & Yahr stage Pathology: Enteric plexus; Olfactory bulb; CN X Coeruleus, Caudal raphe & magnocellular RF Substantia nigra; Amygdala (CN) Meynerts n; PPN Temporal lobe: TEC, CA-2 plexus; Intralaminar thalamic Nuclei Prefrontal cortex: tertiary sensory association areas Secondary, then primary motor & sensory areas Sympathetic nervous system

11 CLASSIFICATION / RECOGNITION OF PD EVOLVING CONCEPTS: –SEVERAL DISEASES OR DIFFERENT PRESENTATIONS OF SAME DISEASE? –TREMOR- PREDOMINANT –PIGD –PDD –AKINETIC –YOPD PRECLINICAL: PRECLINICAL: –PARS (Parkinsons At Risk Syndrome) – genetic at risk –Biomarker (ytd)+, but – symptoms PREMOTOR: PREMOTOR: –SUBTLE AND VARIOUS FEATURES OCCUR FOR YEARS MOTOR: MOTOR: –CLASSIC MOTOR FEATURES OCCUR ADVANCING DISEASE: ADVANCING DISEASE: –COGNITIVE CHANGES –SWALLOWING CHANGES –ADVANCED POSTURAL INSTABILITY –NON-MOTOR ISSUES –MEDICATION COMPLICATIONS PD or PD Plus TYPICAL VS ATYPICAL

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13 TOTAL APPROACH TO TREATMENT TOTALTREATMENT MEDICATIONEXERCISE NUTRITION HYDRATION SLEEPACTIVITIESMOOD

14 Medication Treatments In early PD, any medication chosen will likely provide some benefit In early PD, any medication chosen will likely provide some benefit However: the treatment path chosen early may change the course of symptoms later However: the treatment path chosen early may change the course of symptoms later Things to consider before choosing treatment: Things to consider before choosing treatment: –Age of patient –Baseline Functionality –Social and Family activities –Cognitive Baseline –Degree of impairment from current symptoms INITIAL MEDICATION: INITIAL MEDICATION: YOUNGER PT AT RISK OF LEVODOPA COMPLICATIONS, START WITH SOMETHING ELSE YOUNGER PT AT RISK OF LEVODOPA COMPLICATIONS, START WITH SOMETHING ELSE OLDER PT AT RISK OF SIDE EFFECTS FROM MOST MEDS, START LEVODOPA OLDER PT AT RISK OF SIDE EFFECTS FROM MOST MEDS, START LEVODOPA

15 ADVANCING DISEASE TREATMENT ADDITIONAL MEDS, MULTIDRUG TX ADDITIONAL MEDS, MULTIDRUG TX SAME MEDS, MORE FREQUENT, SMALL ADJUSTMENTS SAME MEDS, MORE FREQUENT, SMALL ADJUSTMENTS –LESS of WHAT & MORE of HOW TIMING BECOMES IMPORTANT TIMING BECOMES IMPORTANT MORE RISK OF SIDE EFFECTS MORE RISK OF SIDE EFFECTS SENSITIVITY TO PLASMA LEVELS SENSITIVITY TO PLASMA LEVELS RECEPTOR CHANGES RECEPTOR CHANGES MORE PROMINENT NON-MOTOR / NON- DOPAMINERGIC SYMPTOMS MORE PROMINENT NON-MOTOR / NON- DOPAMINERGIC SYMPTOMS

16 Levodopa L-3,4- dihydroxyphenylalanine L-3,4- dihydroxyphenylalanine Metabolic precursor to dopamine Metabolic precursor to dopamine Approved by FDA in 1970 Approved by FDA in 1970 Combined with dopa decarboxylase inhibitor in 1973 Combined with dopa decarboxylase inhibitor in 1973 Carbidopa/Levodopa, Sinemet, Sinemet CR, Parcopa, Stalevo Carbidopa/Levodopa, Sinemet, Sinemet CR, Parcopa, Stalevo Remains superior in tx of motor symptoms Remains superior in tx of motor symptoms Associated with development of motor complications of therapy within 5 years of initiation in 40%- 50% of pts (Marsden 1994 / (DATATOP study data, Ahlskog et al, 2001)) Associated with development of motor complications of therapy within 5 years of initiation in 40%- 50% of pts (Marsden 1994 / (DATATOP study data, Ahlskog et al, 2001)) Motor complications can cause significant disability and impact QoL (Marras et al 2003) Motor complications can cause significant disability and impact QoL (Marras et al 2003) Dopamine Dysregulation Syndrome Dopamine Dysregulation Syndrome

17 L-dopa-Associated Motor Complications MOTOR COMPLICATIONS INCLUDE : Single wearing off times Single wearing off times End-of –dose wearing off End-of –dose wearing off Delayed-on / no-on Delayed-on / no-on Unpredictable off times Unpredictable off times Peak-dose dyskinesia/dystonia Peak-dose dyskinesia/dystonia Off-dose dystonia/dyskinesia Off-dose dystonia/dyskinesia Diphasic dyskinesia Diphasic dyskinesia Peripheral causes: Peripheral causes: –delayed gastric emptying –dietary protein competes for aa carriers in the gut that also transport l-dopa –short plasma half-life Central causes: –pulsatile delivery to striatal receptors, dysregulation of striatal MSNs (Chase et al 1993) –alteration of DA receptors (through alteration in signal transduction that regulate gene expression (Canales et al 2000) –impaired storage capacity Therefore, optimal delivery technique of L-dopa still remains elusive Therefore, optimal delivery technique of L-dopa still remains elusive

18 With permission from R. Hauser In Advanced Parkinsons Disease, Brain Dopamine Levels Reflect Plasma Levodopa Levels 41 Mouradian et al 1990 Olanow et al 2000 Stocchi et al 2002

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20 Dopamine Agonists Much longer T1/2 than levodopa Much longer T1/2 than levodopa Delay development of motor fluctuations in de-novo patients Delay development of motor fluctuations in de-novo patients –Ropinirole 056 (dyskinesia 20% vs 45%), CALM-PD (dyskinesia 25% vs 54%), PELMOPET Effective as monotherapy but less potent in treating motor symptoms than levodopa is Effective as monotherapy but less potent in treating motor symptoms than levodopa is Initially developed as adjunctive to L-dopa so had established role in reducing motor symptoms (initially ergots) and reducing cumulative dose of L-dopa Initially developed as adjunctive to L-dopa so had established role in reducing motor symptoms (initially ergots) and reducing cumulative dose of L-dopa Now recognized to have specific side effects as class Now recognized to have specific side effects as class

21 Dopamine Agonists Ergots: not recommended due to fibrotic complications Ergots: not recommended due to fibrotic complications Ropinirole (Requip / Requip XL) Ropinirole (Requip / Requip XL) –Start 0.25mg tid and titrate to 3mg tid as minimal therapeutic dose Pramipexole (Mirapex / Mirapex ER) Pramipexole (Mirapex / Mirapex ER) –Start 0.125mg tid and titrate to 0.5mg tid as initial therapeutic goal Rotigotine (Neupro) Rotigotine (Neupro) –Transdermal patch: start 2mg patch initially and titrate if no response, to 4mg or 6mg patch Apomorphine (Apokyn) Apomorphine (Apokyn) –For advanced PD only as rescue medicine –Subcutaneous injection

22 Dopamine Agonists: Caution Ankle / leg edema Ankle / leg edema Orthostatic Hypotension* Orthostatic Hypotension* –Patients treated with dopamine agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation and in advanced PD –Patients should be informed of this risk Hallucinations* Hallucinations* –Observed more frequently in patients taking dopamine agonists in both early and advanced double-blind trials –The elderly (>70) are at higher risk of hallucinations and cognitive decline Sleep Attacks Sleep Attacks –Patients taking dopamine agonists have reported falling asleep while engaging in activities of daily living, including the operation of a motor vehicle, which sometimes resulted in accidents –Many of these patients reported somnolence while taking dopamine agonists, but did not perceive any warning signs prior to falling asleep

23 Impulse Control Disorders Dopamine agonist medications have been associated with the development of Compulsive behaviors such as gambling Dopamine agonist medications have been associated with the development of Compulsive behaviors such as gambling It is recommended to screen for these before starting therapy and at each visit once on therapy It is recommended to screen for these before starting therapy and at each visit once on therapy Typically reverses with discontinuation of medicine Typically reverses with discontinuation of medicine Weintraub et al, 2010 (Arch. Neuro) did a x- sectional study of 3090 pts and found: Weintraub et al, 2010 (Arch. Neuro) did a x- sectional study of 3090 pts and found: –13.6% had ICDs –DA tx associated with a fold increased odds of having ICD. –(Gambling, sexual ICDs, shopping and binge-eating)

24 MAOB-Inhibitors Selegeline (Eldepryl, Deprenyl) Selegeline (Eldepryl, Deprenyl) –Inhibits catabolism of dopamine –Amphetamine metabolites –Dose 5mg – 10mg per day (usually before noon) Zydis Selegeline (Zelapar) Zydis Selegeline (Zelapar) –Same as selegeline but absorbed through oral mucosa so bypasses gut metabolism (less amphetamine) –Approved for adjunctive tx of levodopa –Faster to CNS, faster action –Dose 1.25mg – 2.5mg once daily Rasageline (Azilect) Rasageline (Azilect) –Approved for mono- and adjunctive tx –About 10X more potent than selegeline (oral) –Dose 0.5mg – 1mg once daily

25 MAOB-Inhibitors Monoamines = neurotransmitters dopamine, norepinephrine, 5HT Monoamines = neurotransmitters dopamine, norepinephrine, 5HT MAOs intracellular enzymes throughout body MAOs intracellular enzymes throughout body MAO – B selective inhibitors used in PD (MAO-B ~ 70% of brain MAO) MAO – B selective inhibitors used in PD (MAO-B ~ 70% of brain MAO) Disease-modifying effect in agents with propargyl structures (selegeline, rasageline) Disease-modifying effect in agents with propargyl structures (selegeline, rasageline) SE: insomnia, HA, gastrointestinal upset, hallucinations, orthostasis SE: insomnia, HA, gastrointestinal upset, hallucinations, orthostasis Contraindicated with meperidine Contraindicated with meperidine Caution with SSRI / SNRI (serotonin syndrome)- though risk is extremely small Caution with SSRI / SNRI (serotonin syndrome)- though risk is extremely small

26 Dual Inhibition of the Two Major Levodopa Degradation Pathways With dual inhibition, significantly more levodopa reaches the brain, with a 35–40% increase in bioavailability and a 30–50% reduction in plasma variability Nutt et al Gordin et al 2002 Stalevo PI, 2003 Schematic of Dual Inhibition of DDC* and COMT Enzyme Pathways

27 COMT-Inhibitors WHAT THEY ARE NOT! WHAT THEY ARE NOT! –Not symptomatically effective alone (use ONLY with levodopa) –Not indicated for early PD, indicated for Advanced PD with EODWO Enhance levels of exogenous levodopa Enhance levels of exogenous levodopa Tolcapone (Tasmar) Tolcapone (Tasmar) –Has black box warning –Associated with fatal liver failure –Monitoring needed Entacapone (Comtan, Stalevo) Entacapone (Comtan, Stalevo) –Taken with each dose of levodopa –Increases availability of levodopa in the plasma –Only peripheral action

28 Amantadine Antiviral agent Antiviral agent Several mechanisms of action Several mechanisms of action –Anticholinergic –Dopamine release enhancement –Anti-glutamatergic (NMDA) Generally well tolerated in younger population Generally well tolerated in younger population Effective in tremor-predominant PD Effective in tremor-predominant PD Side effects: confusion, hallucinations, dry mouth, blurred vision. Idiosyncratic reactions: livedo reticularis and ankle edema Side effects: confusion, hallucinations, dry mouth, blurred vision. Idiosyncratic reactions: livedo reticularis and ankle edema Dosing usually 100mg bid-tid, max dose 500 – 600mg/ day Dosing usually 100mg bid-tid, max dose 500 – 600mg/ day Antidyskinetic Property due to anti-glutamate (NMDA antagonist) activity, make it useful in advanced PD in fluctuators with dyskinesias Antidyskinetic Property due to anti-glutamate (NMDA antagonist) activity, make it useful in advanced PD in fluctuators with dyskinesias

29 Anticholinergics Earliest class of agents for PD Earliest class of agents for PD –Belladonna used for centuries –1940s trihexyphenidyl created Little use in advanced disease Little use in advanced disease Trihexyphenidyl, Benztropine Trihexyphenidyl, Benztropine Effective PD tremor therapy Effective PD tremor therapy Side effects can be prominent: Confusion, hallucinations, dry mouth, constipation, blurred vision, orthostasis, urinary retention Side effects can be prominent: Confusion, hallucinations, dry mouth, constipation, blurred vision, orthostasis, urinary retention Increased risk with use in elderly or if cognitive problems at baseline Increased risk with use in elderly or if cognitive problems at baseline

30 Apomorphine – Rescue Therapy Apokyn (2mg-6mg per dose) Apokyn (2mg-6mg per dose) D1/D2 agonist D1/D2 agonist Older dopamine agonist Older dopamine agonist Very short T1/2 Very short T1/2 Rescue for unpredictable or predictable significant off times. Rescue for unpredictable or predictable significant off times. Very effective, rapid onset Very effective, rapid onset Associated with significant GI side effects Associated with significant GI side effects –Nausea and vomiting –Must pre-treat with antiemetic (trimethobenzamide, domperidone) –Orthostatic hypotension –Initial titration should be in physicians office Subcutaneous administration difficult for some patients Subcutaneous administration difficult for some patients Yawning, Increased libido, priapism Yawning, Increased libido, priapism

31 Surgical Therapies Ablative – permanent lesioning Ablative – permanent lesioning –Thalamotomy –Pallidotomy Deep Brain Stimulation Deep Brain Stimulation –Reversible implantation of electrodes into specific nuclei targets –Thalamus (VIm), Globus pallidus internus, Subthalamic nucleus –Not for everyone! Choosing the right candidate is a process that should include at least: –Initial evaluation to determine diagnosis of Idiopathic PD –Levodopa challenge –Cognitive testing, Neuropsychological testing –General health evaluation as surgical candidate –Initial counseling and establishment of goals of surgery, with acknowledged patient understanding

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34 Global Presentation of PD MOTOR RIGIDITY RIGIDITY BRADYKINESIA BRADYKINESIA TREMOR TREMOR POSTURAL INSTABILITY* POSTURAL INSTABILITY* POSTURAL CHANGES POSTURAL CHANGES SPEECH CHANGES* SPEECH CHANGES* DECREASED DEXTERITY DECREASED DEXTERITY HYPOMIMIA HYPOMIMIA FESTINATING/FREEZING GAIT* FESTINATING/FREEZING GAIT* DYSTONIA DYSTONIA MICROGRAPHIA MICROGRAPHIA DYSPHAGIA* DYSPHAGIA* *LIKELY NON-DOPAMINERGIC FEATURES NON-MOTOR* CONSTIPATION CONSTIPATION ANOSMIA ANOSMIA GERD GERD DEPRESSION/ ANXIETY DEPRESSION/ ANXIETY APATHY APATHY COGNITIVE CHANGES COGNITIVE CHANGES SLEEP DISTURBANCES SLEEP DISTURBANCES SEBORRHEIC DERMATITIS SEBORRHEIC DERMATITIS BLADDER URGENCY / FREQUENCY BLADDER URGENCY / FREQUENCY SWEATING SPELLS SWEATING SPELLS HYPOTENSION HYPOTENSION SEXUAL DYSFUNCTION SEXUAL DYSFUNCTION

35 Nonmotor Symptoms in PD Nonmotor Symptoms in PD –Despite emphasis on managing motor symptoms in clinical practice, evidence suggests Non-Motor Symptoms may have a greater influence on: HRQOL HRQOL Institutionalization Institutionalization Health economics Health economics In advancing PD HRQOL = health-related quality of life Schrag A, et al. J Neurol Neurosurg Psychiatry. 2000;69: Chaudhuri KR, et al. Lancet Neurol. 2006;5:

36 NON-MOTOR SYMPTOMS Seen in Early & Late PD MOOD DISTURBANCE Depression May be present up to 5-10 years prior to PD diagnosis May be present up to 5-10 years prior to PD diagnosis 10% of general population 10% of general population 50-60% in PD 50-60% in PD –5%-25% major –10%-30% minor –Suicidal ideation common, suicide is not SSRIs, SNRIs, Tricyclics, Buproprion SSRIs, SNRIs, Tricyclics, Buproprion Newer medications found more beneficial Newer medications found more beneficial Anxiety 40% of patients with PD –May be off anxiety (concept of NON-MOTOR FLUCTUATIONS) –Move levodopa dosing closer together or add another medication (eg, entacapone or rasagiline) –Treat with anti-anxiety medication (Escitalopram, Sertraline, Duloxetine and Venlafaxine

37 Nonmotor Symptoms in PD Other Neuropsychiatric –Anhedonia (inability to experience pleasure) –Apathy- different than depression different than depression Assoc. with cognitive impairment Assoc. with cognitive impairment –Pseudo Bulbar Affect – emotional lability emotional lability 5%-10% in PD but under-recognized 5%-10% in PD but under-recognized Nudexta Nudexta –Frontal executive dysfunction Planning, Working memory (spatial, goal pursuit), Distractibility Planning, Working memory (spatial, goal pursuit), Distractibility –Bradyphrenia (slowed thought processes) –Dementia –Psychosis

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39 Cognitive Decline ( Cognitive changes, psychosis, behavior changes most common reason for institutionalization in PD) Affects several cognitive domains Affects several cognitive domains Lewy Bodies & Alzheimers pathology present Lewy Bodies & Alzheimers pathology present Long-term disease dementia occurs in up to 80% of PD Long-term disease dementia occurs in up to 80% of PD Even early PD can cause cognitive deficits Even early PD can cause cognitive deficits Non-demented PD pts can have MCI (25%) and this increases risk of eventual dementia Non-demented PD pts can have MCI (25%) and this increases risk of eventual dementia Dementia within 3-5 years = PDD Dementia within 3-5 years = PDD –Rivastigmine patch (Exelon patch) 4.6–9.2 mg daily –Galantamine (Razadyne ER) 8–16 mg daily –Addition of Memantine (Namenda) 5–10 mg 1–2x daily –Non-medication approaches to improve memory (games)

40 Hallucinations and Paranoia Reduce or discontinue Reduce or discontinue dopamine agonists Check dose timing of Amantadine. Check dose timing of Amantadine. May need to discontinue May need to reduce May need to reduce or stop MAO-B inhibitors Reduce levodopa or Reduce levodopa or switch formulation Add acetylcholinesterase inhibitor Add acetylcholinesterase inhibitor (eg, Donepezil, Rivastigmine) (eg, Donepezil, Rivastigmine) Quetiapine (Seroquel) Quetiapine (Seroquel) Clozapine Clozapine

41 Non-Motor Symptoms Seen Early and Late PD SLEEP –Fragmentation –Initial and terminal insomnia –Reduced sleep efficiency –Reduced slow wave sleep –REMBD –Reduced rapid REM sleep –Nocturnal akinesia/tremor –Restless leg syndrome (RLS) –OSA REMBD –Now considered an early early feature of PD Tx: clonazepam quetiepineInsomnia Valerian root ChamomileMelatoninDiphenhydramine Trazadone, Ambien Daytime Fatigue Activity / Exercise Caffeine Rarely – Stimulants Sleep Study should be considered

42 Orthostasis –Autonomic dysregulation –PD meds, anti- hypertensives, tricyclic antidepressants, and poor salt and fluid intake can worsen this. –Conservative measures: s: 1. Increase salt intake 2. Drink sports/electrolyte beverage (eg, Gatorade or similar) 3. Raise head of bed 6 inches 4. Compression hose/Jobst stockings 5. Take time getting up from chair or bed, do leg / ankle pumps 6. Eat small frequent meals –Drink 16 oz of water first thing in the am. –Drink caffeine in the am and after lunch –Add fludrocortisone (Florinef) or midodrine (ProAmatine) –SSRIs (paroxetine) –Pyridostigmine (little evidence)

43 GI Dysmotility / Constipation Delayed gastric emptying Delayed gastric emptying Results in food remaining in stomach for a longer period of time than normal Results in food remaining in stomach for a longer period of time than normal Symptoms: nausea, vomiting, bloating, feeling full Symptoms: nausea, vomiting, bloating, feeling full Treatment: Medications motility agents (domperidone, amitiza) diet modifications (small, frequent meals, lemon water) Treatment: Medications motility agents (domperidone, amitiza) diet modifications (small, frequent meals, lemon water) GERD can lead to infection and pneumonia GERD can lead to infection and pneumonia Avoid large meals and high fat meals Avoid large meals and high fat meals Fewer than 3 bowel movements per week Fewer than 3 bowel movements per week Caused by PD, PD medications, lack of fluids and fiber, decreaseda activity Caused by PD, PD medications, lack of fluids and fiber, decreaseda activity Risk of fecal impaction Risk of fecal impaction Treatments include: increased fluid intake-6-8 cups of water or juice a day Treatments include: increased fluid intake-6-8 cups of water or juice a day Juices starting with a P-Prune, pear, plum or peach Juices starting with a P-Prune, pear, plum or peach Fiber supplement such as Metamucil or Citrucel Fiber supplement such as Metamucil or Citrucel Flax seed, almonds Flax seed, almonds Increase fiber intake-25 grams of fiber daily Increase fiber intake-25 grams of fiber daily Stool softeners such as pericolace or colace Stool softeners such as pericolace or colace Miralax Miralax

44 Dysphagia 50% of patients with PD have swallowing problems 50% of patients with PD have swallowing problems Causes: Causes: 1. PD causes motor impairment of oral and swallowing muscles. 1. PD causes motor impairment of oral and swallowing muscles. 2. Poor dentition 2. Poor dentition 3. Dry mouth 3. Dry mouth Diagnosis: barium swallow or endoscopy Diagnosis: barium swallow or endoscopy Complications: Aspiration pneumonia, weight loss, malnutrition, choking, coughing or drooling Complications: Aspiration pneumonia, weight loss, malnutrition, choking, coughing or drooling Treatment: Speech therapy for strengthening exercises Treatment: Speech therapy for strengthening exercises Diet modifications Diet modifications Feeding tube Feeding tube

45 Drooling (sialorrhea) Greatest contributor is not overproduction of saliva but from slowing of the automatic swallowing reflex. Greatest contributor is not overproduction of saliva but from slowing of the automatic swallowing reflex. Treatments: Treatments: Mindfule Swallowing Mindfule Swallowing Facial exercises / Posture exercises Facial exercises / Posture exercises Chewing gum Chewing gum 1% atropine eye drops under the tongue 1% atropine eye drops under the tongue Oral anticholinergics such as robinul Oral anticholinergics such as robinul Botulinim toxin Botulinim toxin

46 Nonmotor Symptoms in PD Skin Changes: Seborrhea dermatitis-oily, flaky or inflamed skin Seborrhea dermatitis-oily, flaky or inflamed skin Rx shampoos or lotions containing selenium, ketoconazole or corticosteriods Rx shampoos or lotions containing selenium, ketoconazole or corticosteriods Excessive sweating (can be a wearing- off phenomenon) Excessive sweating (can be a wearing- off phenomenon) Adjust Sinemet, lukewarm showers, wear lightweight clothing in warm weather, increase fluids, and in severe cases Rx meds (propranolol,gabapentin,) Adjust Sinemet, lukewarm showers, wear lightweight clothing in warm weather, increase fluids, and in severe cases Rx meds (propranolol,gabapentin,) Too little perspiration-usually side effect of medication Too little perspiration-usually side effect of medication Decrease dose of anticholinergic Decrease dose of anticholinergic Skin Cancer of all types esp. Melanoma- 2-7x higher risk in PD Skin Cancer of all types esp. Melanoma- 2-7x higher risk in PD Annual screening Annual screening Sensory Changes: Sensory Changes: –Hyposmia / Anosmia Decrease or loss of sense of smell) – one of the earliest features of PD, may occur decades prior to motor symptoms Decreased sense of taste (not all, sweet preserved) –Pain is reported in up to 1/3 of PD patients, with variability in type –Peripheral Neuropathy Small studies, percentage uncertain –Visual changes Impaired visual contrast

47 GU Dysfunction ED in males, vaginal dryness, and loss of libido ED in males, vaginal dryness, and loss of libido PD can cause this due to lack of dopamine PD can cause this due to lack of dopamine PD meds are not associated except for anticholinergics PD meds are not associated except for anticholinergics Hypersexuality secondary to medications Hypersexuality secondary to medications Treatment: urological or gynecological exam to rule out non-PD problem Treatment: urological or gynecological exam to rule out non-PD problem PDIs are safe PDIs are safe Cant treat unless you know, Cant know unless you ask! Cant treat unless you know, Cant know unless you ask! Urinary frequency, urgency, incontinence, incomplete emptying, hesitancy, enuresis Urinary frequency, urgency, incontinence, incomplete emptying, hesitancy, enuresis Treatments: Treatments: Medications: oxybutynin, Tolterodine, Solifenacin, Darifenacin Medications: oxybutynin, Tolterodine, Solifenacin, Darifenacin Non-medication: pelvic floor exercises, decrease liquids before bed, avoid caffeinated drinks, wear pads at night, wear easily removable clothing, regular toileting. Non-medication: pelvic floor exercises, decrease liquids before bed, avoid caffeinated drinks, wear pads at night, wear easily removable clothing, regular toileting.

48 Falls in PD Meta-analysis of several studies of falls in PD (Pickerington et al. Mov Dis 2007) Meta-analysis of several studies of falls in PD (Pickerington et al. Mov Dis 2007) –showed very high fall rate (46%) with injury rate from 25% - 78% –Best predictor was prior fall within previous year Incidence of falls significant even in early PD (Kerr et al.2010) Incidence of falls significant even in early PD (Kerr et al.2010) Turning in PD is hazardous and associated with imbalance and FOG Turning in PD is hazardous and associated with imbalance and FOG –Responds to auditory cueing ( Willems et al. Mov Dis 2007) Tinetti Mobility Scale validated for inter / intra-rater reliability and found predictive of falls in PD by Kegelmeyer and Kloos et al. (Physical Therapy, 2007) Tinetti Mobility Scale validated for inter / intra-rater reliability and found predictive of falls in PD by Kegelmeyer and Kloos et al. (Physical Therapy, 2007) AAN Practice Parameter on Falls (EBR) (Thurman et al. Neurology 2008) AAN Practice Parameter on Falls (EBR) (Thurman et al. Neurology 2008) –Clinical metrics predictive of falls = Timed Up & Go test and the Tinetti Mobility Scale Falling / Postural instability / Balance problems are NOT responsive to PD medications Falling / Postural instability / Balance problems are NOT responsive to PD medications

49 MULTIDISCIPLINARY APPROACH Requires a PD Treatment TEAM! Requires a PD Treatment TEAM! –The Patient –Movement Disorders Neurologist –Nurse Practitioner –Medical Assistant –PCP –Physical Therapist –Speech Therapist / Occupational Therapist –Psychologist / Counselor –Carepartners EACH TEAM MEMBER HAS A DIFFERENT BUT VITAL ROLE!!

50 Non-Medication Therapies Physical therapy (LSVT- BIG, PWR) Physical therapy (LSVT- BIG, PWR) –Balance / Gait – focused –Posture, flexibility –Core, COG –Amplitude Speech therapy Speech therapy –LSVT, Facial exercises, Breathing exercises, Singing, Swallowing techniques Occupational therapy Occupational therapy –ADLs, Home safety, Dexterity Others: Others: –Manual Medicine –Tai Chi –Music therapy Encourages rhythmic movements, coordinating multiple movements Encourages rhythmic movements, coordinating multiple movements –Art therapy Encourages both large and small amplitude movements, stress relief, emotional expression Encourages both large and small amplitude movements, stress relief, emotional expression –Recreational therapy –Massage, acupuncture

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52 The James Parkinsons Tulip April is PD Awareness Month!


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