Overview ofTreatment of Advancing

Parkinson’s Disease

Karen M. Thomas, DODiplomate, ABPNAssociate Professor of Clinical Neurology, EVMSDirector, Movement Disorders ProgramSentara Neurology SpecialistsVirginia Beach, VA

WHAT IS PARKINSON’S DISEASE?

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

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”

Epidemiology 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

FOUND THROUGHOUT THE WORLD 1 – 1.5 MILLION IN U.S. 60,000 new cases diagnosed each year

Etiolotgy ETIOLOGY IS UNKNOWN RISK FACTORS SUSPECTED:

– GENETICS + RURAL LIVING / FARMING PESTICIDE EXPOSURE HEAVY METAL EXPOSURE NONSMOKER EARLY MENOPAUSE OR OTHER HORMONAL CONTRIBUTIONS

– EVOLVING CONCEPTS: AT-RISK GENES WITH RECOGNITION OF ROLE OF GENE &

IT’S INTERACTION WITH ENVIRONMENTAL FACTORS– Protein alteration– Cell clearing dysfunction– Chemical transport dysfunction– Different genes in different populations

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)

Lewy Bodies are filamentouscytoplasmic inclusions that are consideredthe pathological hallmark of PD and contain aggregated proteins includinga - 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 STRESSINFLAMMATION

(PD BRAINS HAVE MARKED GLIAL ACTIVATION)

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 Parkinson’s disease

Substantia nigraBrooks 1993

Marsden 1994 Lang & Lozano 1998

Braak stages I–IV in idiopathic Parkinson’s 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 3Symptomatic motorfeatures

Braak Staging based on LB Pathology

Current Hypothesis of PD Timeline

CN X = motor component of cranial nerve X; RF = reticular formation; CN = central subnucleus of the amygdala;Meynert’s n = basal nucleus of Meynert; PPN = pedunculopontine tegmental nucleus; TEC = transentorhinal cortex; CA2 = second section of the Ammon’s hornHawkes CH, et al. Parkinsonism Relat Disord. 2010;16(2):79-84.

Braak stage

ClinicalOnset

20 year prodrome

20 year disease stage

Symptoms:Hyposmia

ConstipationBladder disorder

-20y

Sleep disorder,Obesity,

Depression

-10y

IUnilateral

Tremor, Rigidity,Akinesia

0

IIBilateraldisease

IIIPoor

balance

+10y

IVFalls,

Dependency,Cognitivedecline

VChair/bed-

boundDementia

+20y

Hoehn & Yahrstage

Pathology: Enteric plexus;Olfactory bulb;

CN X

Coeruleus,Caudal raphe &magnocellular

RF

Substantia nigra;Amygdala (CN)

Meynert’s n;PPN

Temporal lobe: TEC,CA-2 plexus;

Intralaminar thalamicNuclei

Prefrontalcortex: tertiary

sensoryassociation

areas

Secondary, thenprimary motor & sensory areas

1 2 3 4 5 6

Sympatheticnervoussystem

CLASSIFICATION / RECOGNITION OF PD

EVOLVING CONCEPTS:– SEVERAL DISEASES OR

DIFFERENT PRESENTATIONS OF SAME DISEASE?

– TREMOR-PREDOMINANT

– PIGD– PDD– AKINETIC– YOPD

PRECLINICAL:– “PARS (Parkinson’s At Risk Syndrome) – genetic “at risk” – Biomarker (ytd)+, but – symptoms

PREMOTOR:– SUBTLE AND VARIOUS FEATURES OCCUR FOR YEARS

MOTOR:– CLASSIC MOTOR FEATURES OCCUR

ADVANCING DISEASE:– COGNITIVE CHANGES– SWALLOWING CHANGES– ADVANCED POSTURAL INSTABILITY– NON-MOTOR ISSUES– MEDICATION COMPLICATIONS

PD or “PD Plus”“TYPICAL” VS “ATYPICAL”

TOTAL APPROACH TO TREATMENT

Medication Treatments In early PD, any medication chosen will likely provide some

benefit However: the treatment path chosen early may change

the course of symptoms later 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: YOUNGER PT AT RISK OF LEVODOPA COMPLICATIONS,

START WITH SOMETHING ELSE OLDER PT AT RISK OF SIDE EFFECTS FROM MOST MEDS,

START LEVODOPA

ADVANCING DISEASE TREATMENT

ADDITIONAL MEDS, MULTIDRUG TX SAME MEDS, MORE FREQUENT, SMALL

ADJUSTMENTS– LESS of “WHAT” & MORE of “HOW”

TIMING BECOMES IMPORTANT MORE RISK OF SIDE EFFECTS SENSITIVITY TO PLASMA LEVELS RECEPTOR CHANGES MORE PROMINENT NON-MOTOR / NON-

DOPAMINERGIC SYMPTOMS

Levodopa L-3,4-dihydroxyphenylalanine Metabolic precursor to dopamine Approved by FDA in 1970 Combined with dopa decarboxylase inhibitor in 1973 Carbidopa/Levodopa, Sinemet, Sinemet CR, Parcopa,

Stalevo

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))

Motor complications can cause significant disability and impact QoL (Marras et al 2003)

Dopamine Dysregulation Syndrome

L-dopa-Associated Motor Complications

MOTOR COMPLICATIONS INCLUDE: Single wearing off times End-of –dose wearing off Delayed-on / no-on Unpredictable off times Peak-dose dyskinesia/dystonia Off-dose dystonia/dyskinesia Diphasic dyskinesia

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

With permission from R. Hauser

In Advanced Parkinson’s Disease, Brain Dopamine Levels Reflect Plasma Levodopa Levels

41

Mouradian et al 1990Olanow et al 2000 Stocchi et al 2002

Dopamine Agonists

Much longer T1/2 than levodopa 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

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

Dopamine Agonists Ergots: not recommended due to fibrotic

complications Ropinirole (Requip / Requip XL)

– Start 0.25mg tid and titrate to 3mg tid as minimal therapeutic dose

Pramipexole (Mirapex / Mirapex ER)– Start 0.125mg tid and titrate to 0.5mg tid as initial

therapeutic goal Rotigotine (Neupro)

– Transdermal patch: start 2mg patch initially and titrate if no response, to 4mg or 6mg patch

Apomorphine (Apokyn)– For advanced PD only as rescue medicine– Subcutaneous injection

Dopamine Agonists: Caution Ankle / leg edema 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*

– 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– 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

Impulse Control Disorders 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

Typically reverses with discontinuation of medicine

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 2-3.5 fold

increased odds of having ICD.– (Gambling, sexual ICDs, shopping and

binge-eating)

MAOB-Inhibitors Selegeline (Eldepryl, Deprenyl)

– Inhibits catabolism of dopamine– Amphetamine metabolites– Dose 5mg – 10mg per day (usually before noon)

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)– Approved for mono- and adjunctive tx– About 10X more potent than selegeline (oral)– Dose 0.5mg – 1mg once daily

MAOB-Inhibitors Monoamines = neurotransmitters dopamine,

norepinephrine, 5HT MAOs intracellular enzymes throughout body MAO – B selective inhibitors used in PD (MAO-B ~

70% of brain MAO) Disease-modifying effect in agents with propargyl

structures (selegeline, rasageline) SE: insomnia, HA, gastrointestinal upset,

hallucinations, orthostasis Contraindicated with meperidine Caution with SSRI / SNRI (serotonin syndrome)-

though risk is extremely small

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 1994. Gordin et al 2002Stalevo PI, 2003

Schematic of Dual Inhibition of DDC* and COMT Enzyme Pathways

COMT-Inhibitors 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 Tolcapone (Tasmar)

– Has “black box warning”– Associated with fatal liver failure– Monitoring needed

Entacapone (Comtan, Stalevo)– Taken with each dose of levodopa– Increases availability of levodopa in the plasma– Only peripheral action

Amantadine Antiviral agent Several mechanisms of action

– Anticholinergic– Dopamine release enhancement– Anti-glutamatergic (NMDA)

Generally well tolerated in younger population Effective in tremor-predominant PD 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

Antidyskinetic Property due to anti-glutamate (NMDA antagonist) activity, make it useful in advanced PD in fluctuators with dyskinesias

Anticholinergics Earliest class of agents for PD

– Belladonna used for centuries– 1940s trihexyphenidyl created

Little use in advanced disease Trihexyphenidyl, Benztropine Effective PD tremor therapy 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

Apomorphine – Rescue Therapy Apokyn (2mg-6mg per dose) D1/D2 agonist Older dopamine agonist Very short T1/2 Rescue for unpredictable or predictable significant off

times. Very effective, rapid onset Associated with significant GI side effects

– Nausea and vomiting – Must pre-treat with antiemetic (trimethobenzamide,

domperidone)– Orthostatic hypotension – Initial titration should be in physician’s office

Subcutaneous administration difficult for some patients Yawning, Increased libido, priapism

Surgical Therapies Ablative – permanent lesioning

– Thalamotomy– Pallidotomy

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

Global Presentation of PDMOTOR

RIGIDITY BRADYKINESIA TREMOR POSTURAL INSTABILITY* POSTURAL CHANGES SPEECH CHANGES* DECREASED DEXTERITY HYPOMIMIA FESTINATING/FREEZING GAIT* DYSTONIA MICROGRAPHIA DYSPHAGIA*

*LIKELY NON-DOPAMINERGIC FEATURES

NON-MOTOR* CONSTIPATION ANOSMIA GERD DEPRESSION/ ANXIETY APATHY COGNITIVE CHANGES SLEEP DISTURBANCES SEBORRHEIC DERMATITIS BLADDER URGENCY / FREQUENCY SWEATING SPELLS HYPOTENSION SEXUAL DYSFUNCTION

Nonmotor Symptoms in PD

– Despite emphasis on managing motor symptoms in clinical practice, evidence suggests Non-Motor Symptoms may have a greater influence on:

HRQOLInstitutionalizationHealth economics

In advancing PDHRQOL = health-related quality of lifeSchrag A, et al. J Neurol Neurosurg Psychiatry. 2000;69:308-312.Chaudhuri KR, et al. Lancet Neurol. 2006;5:235-245.

NON-MOTOR SYMPTOMSSeen in Early & Late PD

MOOD DISTURBANCEDepression

May be present up to 5-10 years prior to PD diagnosis

10% of general population

50-60% in PD– 5%-25% major

– 10%-30% minor

– Suicidal ideation common, suicide is not

SSRIs, SNRIs, Tricyclics, Buproprion

Newer medications found more beneficial

Anxiety40% 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

Nonmotor Symptoms in PD Other Neuropsychiatric

– Anhedonia (inability to experience pleasure)

– Apathy- different than depression Assoc. with cognitive impairment

– Pseudo Bulbar Affect – emotional lability 5%-10% in PD but under-recognized Nudexta

– Frontal executive dysfunction Planning, Working memory (spatial, goal pursuit),

Distractibility– Bradyphrenia (slowed thought processes)– Dementia– Psychosis

Cognitive Decline (Cognitive changes, psychosis, behavior changes most common reason for institutionalization in PD)

Affects several cognitive domains Lewy Bodies & Alzheimer’s pathology present Long-term disease dementia occurs in up to 80% of PD Even early PD can cause cognitive deficits Non-demented PD pts can have MCI (25%) and this

increases risk of eventual dementia 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)

Hallucinations and Paranoia Reduce or discontinue

dopamine agonists Check dose timing of Amantadine.

May need to discontinue May need to reduce

or stop MAO-B inhibitors Reduce levodopa or

switch formulation Add acetylcholinesterase inhibitor

(eg, Donepezil, Rivastigmine) Quetiapine (Seroquel) Clozapine

Non-Motor SymptomsSeen 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 PDTx: clonazepamquetiepine

InsomniaValerian rootChamomile Melatonin DiphenhydramineTrazadone, Ambien

Daytime Fatigue Activity / ExerciseCaffeineRarely – Stimulants

Sleep Study should be considered

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)

GI Dysmotility / Constipation Delayed gastric emptying Results in food remaining in stomach for a longer period of

time than normal Symptoms: nausea, vomiting, bloating, feeling full Treatment: Medications motility agents (domperidone,

amitiza) diet modifications (small, frequent meals, lemon water)

GERD can lead to infection and pneumonia Avoid large meals and high fat meals

Fewer than 3 bowel movements per week Caused by PD, PD medications, lack of fluids and fiber, decreaseda

activity Risk of fecal impaction Treatments include: increased fluid intake-6-8 cups of water or

juice a day Juices starting with a “P”-Prune, pear, plum or peach Fiber supplement such as Metamucil or Citrucel Flax seed, almonds Increase fiber intake-25 grams of fiber daily Stool softeners such as pericolace or colace Miralax

Dysphagia

50% of patients with PD have swallowing problems Causes: 1. PD causes motor impairment of oral and swallowing

muscles. 2. Poor dentition 3. Dry mouth Diagnosis: barium swallow or endoscopy Complications: Aspiration pneumonia, weight loss,

malnutrition, choking, coughing or drooling Treatment: Speech therapy for strengthening exercises Diet modifications Feeding tube

Drooling (sialorrhea) Greatest contributor is not overproduction

of saliva but from slowing of the automatic swallowing reflex.

Treatments: Mindfule Swallowing Facial exercises / Posture exercises Chewing gum 1% atropine eye drops under the tongue Oral anticholinergics such as robinul Botulinim toxin

Nonmotor Symptoms in PDSkin Changes: Seborrhea dermatitis-oily, flaky or

inflamed skin● Rx shampoos or lotions containing selenium, ketoconazole or corticosteriods

∙ 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,)

∙ Too little perspiration-usually side effect of medication∙ Decrease dose of anticholinergic

∙ Skin Cancer of all types esp. Melanoma-2-7x higher risk in PD∙ Annual screening

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

GU Dysfunction

ED in males, vaginal dryness, and loss of libido

PD can cause this due to lack of dopamine

PD meds are not associated except for anticholinergics

Hypersexuality secondary to medications

Treatment: urological or gynecological exam to rule out non-PD problem

PDIs are safe Can’t treat unless you

know, Can’t know unless you ask!

Urinary frequency, urgency, incontinence, incomplete emptying, hesitancy, enuresis

Treatments: 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.

Falls in PD

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)

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)

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

MULTIDISCIPLINARY APPROACH

Requires a PD Treatment TEAM!– The Patient– Movement Disorders Neurologist– Nurse Practitioner– Medical Assistant– PCP– Physical Therapist– Speech Therapist / Occupational Therapist– Psychologist / Counselor– CarepartnersEACH TEAM MEMBER HAS A DIFFERENT BUT

VITAL ROLE!!

Non-Medication Therapies Physical therapy (LSVT- BIG, PWR)

– Balance / Gait – focused– Posture, flexibility– Core, COG – Amplitude

Speech therapy– LSVT, Facial exercises, Breathing exercises, Singing, Swallowing

techniques Occupational therapy

– ADLs, Home safety, Dexterity Others:

– Manual Medicine– Tai Chi– Music therapy

Encourages rhythmic movements, coordinating multiple movements– Art therapy

Encourages both large and small amplitude movements, stress relief, emotional expression

– Recreational therapy– Massage, acupuncture

The James Parkinson’s Tulip

April is PD Awareness Month!