parkinson disease slide update

8/2/2019 Parkinson Disease Slide Update

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Update on Management of

Parkinsons Disease

Dr. Alim Akhtar Bhuiyan

Consultant & Co-ordinatorNeurology Department


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Parkinsons Disease -

A real concern

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Prevalence of Parkinsons disease:

In US , approximately 1 million people are suffering from Parkinsons disease.

There is no exact epidemiological data regarding PD is available in our Country.But approximate Prevalence is 0.37%.

Parkinsons disease is age related and life expectancy of people is growing day byday. So the prevalence will be much higher in near future.


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CORE BIOCHEMICAL PATHOLOGY

DECREASED DOPAMINE NEURO -TRANSMISSION IN THE

BASAL GANGLIA.

MOST PARKINSON SYNDROMES HAVE DEGENERATION OF

THE NIGROSTRIATAL DOPAMINE SYSTEM WITH MARKEDLOSS OF STRIATAL DOPAMINE.

IN SOME STRIATAL DEGENERATION WITH LOSS OF

DOPAMINE RECEPTORS OCCURS.


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PATHOGENESIS OF PARKINSON

DISEASEACTUAL CAUSE UNKNOWNFACTORS IMPLICATED

INCLUDE:

GENETIC, ENVIRONMENTAL TOXINS, AND ENDOGENOUSTOXINS, FROM CELLULAR OXIDATIVE REACTIONS. TWO

MAJOR PATHOGENETIC HYPOTHESES:

MISFOLDING OF PROTEINS, ETC.

MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS


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What goes wrong in

Parkinsons disease?

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Death of specificbrain cells in the

substantia nigra

Effects onother systems

Inability toco-ordinatemuscular activity

LOSS OF

DOPAMINE

Parkinsons disease symptoms result from loss of dopaminergic

neurons in the brain which cause depletion of Dopamine in the brain.


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Parkinsonism and

Classification of Symptoms

Parkinsonism is a collective term that is used to describe a number of

conditions that cause distinctive motor signs.

Parkinsonism is typically classified into the following 3 categories:

1) Primary parkinsonism (Idiopathic)

2) Secondary parkinsonism-Drugrelated, stroke ,encephalitis

3) Parkinsonism-plus(MSA)


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CARDINAL FEATURES

REST TREMOR

RIGIDITY

BRADYKINESIAHYPOKINESIA

LOSS OF POSTURAL REFLEXES

TO DIAGNOSE: TWO OF ABOVE, WITH AT LEAST ONE BEING

REST TREMOR OR BRADYKINESIA


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INITIAL SYMPTOMS OF PARKINSON

DISEASE

60% -70% OF SUBSTANTIA NIGRA DOPAMINERGIC NEURONSALREADY LOST AT ONSET

DOPAMINE CONTENT OF STRIATUM IS ONLY 20% OF NORMAL

MOTOR SYMPTOMS ARE PROMINENT , i.e. TREMOR, STIFFNESS &SLOWNESS, LOSS OF DEXTERITY, GAIT DISTURBANCE, AND

MUSCLE ACHES, PAINS AND CRAMPS.


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NON-MOTOR SYMPTOMS OF PARKINSON

DISEASE

BEHAVIORAL DEPRESSION, ANXIETY, DECREASEDMOTIVATION, PERSONALITY CHANGES, LESS INCLINATION TO

SPEAK, BRADYPHRENIA

SENSORY NON-SPECIFIC PAINS, AKATHISIA, RESTLESS LEGSAND OTHER SLEEP PROBLEMS

AUTONOMIC

CONSTIPATION, BLADDER DYSFUNCTION,IMPOTENCE, LOW BLOOD PRESSURE


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DIFFERENTIAL DIAGNOSIS OF

PARKINSON DISEASE ESSENTIAL TREMOR OCCASIONALLY CONFUSED WITH

PARKINSON DISEASE. HOWEVER, 20% OF ET PATIENTSDEVELOP PD

SECONDARY PARKINSONISM, i.e. DRUGS, NPH, INFECTIONS,etc.

PARKINSONPLUS SYNDROMES, i.e. CBD, LBD, AD, MSA,PSP

HEREDODEGENERATIVE HD, WILSON, HALLERVORDEN-SPATZ


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Overview of

Parkinsons Disease Therapies In general, patients with Parkinsons disease are managed in 3 ways:

Pharmacologic treatments

Surgical intervention

Non-pharmacologic Treatments

Other Complementary therapies include the following:

Patient education

Counseling

Speech therapy

Physical therapy

Occupational therapy


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WHY DELAY THERAPY?

MINIMAL EFFECT ON ADL

DRUG SIDE EFFECTS

LEVODOPA SPARING STRATEGY TO FORESTALL LONG

TERM COMPLICATIONS OF THE DRUG

PATIENT PREFERENCE


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MORE NEUROPROTECTIVE AGENTS

AMANTADINENMDA RECEPTOR ANTAGONIST

DOPAMINE AGONISTS ANTI-OXIDANT, PROTECT DOPAMINE NEURONS,

etc.

CALM-PD STUDYPRAMIPEXOLE VS. L-DOPASPECT

REAL-PET STUDYROPINIROLE VS. L-DOPAFD-PET

EARLY PD - CO-Q-10, MAOBIS. DOPAMINE AGONISTS AS SYMPTOMATIC

TREATMENT


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TREATMENT OF EARLY PARKINSON

DISEASE CONSIDER: CO-Q-10, VITAMIN E (TS)MAY HELP LEG CRAMPS?

SELEGILINE OR RASAGILINE (2ND GENERATION MAOBI)

AMPHETAMINE EFFECT?

AMANTADINE RAPID ONSET OF ACTION, AVOID IN COGNITIVE

PROBLEMS

ANTI-CHOLINERGICSESPECIALLY GOOD FOR TREMORNOT SO

FOR ELDERLY

DOPAMINE AGONISTS PRAMIPEXOLE AND ROPINIROLE. LONG

ACTING

T t t Al ith


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Treatment Algorithm


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WHAT ABOUT

LEVODOPA / CARBIDOPA?

STILL THE BEST, ESPECIALLY SHORT TERM

LONG TERM USEMOTOR FLUCTUATIONS, DYSKINESIAS

INVERSELY PROPORTIONAL TO AGE

BUTNEARLY ALL PATIENTS EVENTUALLY REQUIRE IT

COMTANEXTENDS HALF-LIFE OF LEVODOPA, EARLY USE??


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WHEN TO START

LEVODOPA/CARBIDOPA FOR EARLY SYMPTOMATIC TREATMENT AND FOR RAPID RESPONSE, i.e.

TO AID PATIENT TO CONTINUE WORKING SPECIALLY FOR RIGIDITY &

BRADYKINESIA

WHEN OTHER MEDICATIONS FAIL OR BECOME LESS EFFECTIVE

AS ADD-ON TREATMENT TO DOPAMINE AGONISTS, ETC.

FOR DE- NOVO ELDERLY PATIENT. DOPAMINE AGONISTS SIDE EFFECTS?


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SOME STRATEGIES TO ENHANCE

L-DOPA EFFECT

BREAK CRS IN HALF

LIMIT DIETARY PROTEIN DURING THE DAY

USE CR FORM AT BEDTIME

START OFF THE DAY WITH BOTH REGULAR AND CR MEDS

ADD COMTAN TO PROLONG EFFECT AND INCREASE ON-TIME


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OTHER THERAPEUTIC OPTIONS -

SURGERY

ABLATIVETHALAMOTOMY, PALLIDOTOMYIRREVERSIBLE

DEEP BRAIN STIMULATION THALAMIC, PALLIDAL,SUBTHALAMICMORE TREATMENT FLEXIBILITY

RESTORATIVE EMBRYONIC DOPAMINERGIC TISSUETRANSPLANTATIONSOME GRAFTED NEURONS DIFFERENTIATED

AND RE-INNERVATEDNOT VERY USEFUL.


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MOTOR COMPLICATIONS OF

PARKINSON DISEASE

MAJOR THERAPEUTIC PROBLEM OVER TIME

MOST STUDIES SHOW 50% COMPLICATIONS AT 5 YEARS

ASSOCIATED WITH-

DISEASE PROGRESSION

PULSATILE NON-PHYSIOLOGIC STIMULATION OFDOPAMINE RECEPTORS FROM LEVODOPA


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MOTOR COMPLICATIONS INCLUDE

INVOLUNTARY CHOREIC OR ATHETOID MOVEMENTS

MOTOR FLUCTUATIONS INCLUDING WEARING-OFF

ACUTE DYSTONIAS

ON-OFF PATTERN WITH RAPID FLUCTUATIONS

PEAK-DOSE

DIPHASIC DYSKINESIAS

FOG


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TREATMENT STRATEGIES FOR MOTOR

FLUCTUATIONS

PERSISTENT DYSKINESIAS LOWER L-DOPA DOSE, ADDAMANTADINE, TRY SINEMET CR

PREVENTIVE STRATEGY IS TO START DOPAMINE AGONIST &MAOBI PRIOR TO L-DOPA

WEARING-OFF - CR PREPS, ADD COMTI

EARLY AM FOOT DYSTONIACR AT HS, AND/OR BOTOX


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MORE TREATMENTS FOR MOTOR

FLUCTUATIONS

ON-OFF PATTERN WITH RAPID FLUCTUATIONSTHESE PATIENTSHAVE NARROW THERAPEUTIC WINDOW FOR L-DOPA. CONSIDER:1) CR PREPS, 2)COMTI, 3) MAOBI,

4) DOPAMINE AGONISTS, 5) APOMORPHINE,

6) LIQ. L-DOPA

PEAK DOSE AND DIPHASIC DYSKINESIASTREAT AS PERSISTENTDYSKINESIA

FREEZING (OFF & ON)PREVENT OFF LOWER DOSE FOR ON


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WHAT ABOUT DEEP BRAIN STIMULATION?

OFTEN HELPFUL IN TREATMENT OF MOTOR FLUCTUATIONS

MOST COMMON TYPE IS DEEP BRAIN STIMULUS OF STN. ACTS

LIKE ELECTRONIC LEVODOPA. REDUCES TREMOR, RIGIDITYAND BRADYKINESIA, ALLOWS REDUCTION OF L-DOPA DOSE, BUT

ANTI PD-EFFECT NO BETTER THAN L-DOPA.


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MORE ON DEEP BRAIN STIMULATION

DEEP BRAIN STIMULATION IS ACTUALLY BETTER FOR TREMORALONE THAN L-DOPA

CONTRAINDICATIONS INCLUDE LACK OF RESPONSE TO L-DOPA

AND COGNITIVE PROBLEMS

ADVERSE EFFECTS OF DBS HEMORRHAGE, INFECTION, WIREBREAKAGE, SPEECH IMPAIRMENT, DYSTONIA


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MORE ON

NON-MOTOR SYMPTOMS ANXIETY & DEPRESSION HIGH PREVALENCE BUT

UNDERDIAGNOSED AND UNDERTREATED

USE ANXIETY & DEPRESSION SCALES

SCREEN PERIODICALLY, i.e. DOWN OR HOPELESS OR LITTLE

INTEREST

MEDS AND LAB SCREENING MAY DETECT TREATABLE

CONDITION


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TREATMENTS FOR ANXIETY-

DEPRESSION

BZPSUSE JUDICIOUSLY IF AT ALL. SHORT TERM?

BUSPIRONESLOW ONSET OF ACTION. HIGH DOSES MAYWORSEN SYMPTOMS

SSRIEFFECTIVE, AMANTADINE LOWERS RISK OF ED. 5H-T SYNDROME RARE

TCAS MAY HELP DROOLING & BLADDER SYMPTOMS.BUPROPRION, MIRTAZAPINE, NEFAZODONE, VENLAFAXINEALSO USED


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ADDITIONAL TREATMENTS FOR

ANXIETY-DEPRESSION

COGNITIVE BEHAVIORAL OFTEN BETTER OUTCOME IFCOMBINED WITH MEDICATIONS

SERIAL ECTBUT MAY AFFECT MEMORY AND COGNITION

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION

STRUCTURED PHYSICAL THERAPY PROGRAM


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HALLUCINATIONS AND PSYCHOSIS

MOST HALLUCINATIONS ARE VISUAL DUE TO DISTURBEDSENSORY PERCEPTION

RELATED TO CHRONIC DOPAMINERGIC TREATMENT

EARLY ONTHINK LBD

TWO CATEGORIESMINOR AND ELABORATE

OCCUR IN LOW LIGHT AND SLEEPWAKE TRANSITION


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HALLUCINATIONS AND PSYCHOSIS

OCCURRENCE WITH CLOUDED SENSORIUM OR DELIRIUM.USUALLY RELATED TO PHARMACOTOXIC, INFECTIOUS,METABOLIC OR ENDOCRINE CAUSES

TREAT UNDERLYING CONDITION

DELUSIONAL STATES OCCUR WITH CLEAR SENSORIUMWITH LOSS OF INSIGHT

MORE LIKELY IN DEMENTED PARKINSON PATIENTS


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TREATMENT OF

HALLUCINATIONS/PSYCHOSIS

SEARCH FOR CORRECTABLE (PIME) ETIOLOGIES

COGNITIVE BEHAVIORAL THERAPY

GRADUAL REDUCTION OF PARKINSON MEDS

QUETIAPINE OR CLOZAPINE WITH OR WITHOUT ECT

CHOLINESTERASE INHIBITORS


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SO, WHATS NEW IN PD

TREATMENT?

DOPAMINE AGONISTS:

APOMORPHINERESCUE TREATMENT FOR OFF

ROTIGOTINE PATCHMONOTHERAPY EARLY; ADJUNCT TREATMENT FOR

OFF

SUMANIROLEALSO NEUROPROTECTIVE

ROPINIROLE CR

MAOBIS

ZYDIS SELEGILINE (ONCE DAILY)

RASAGILINENO AMPHETAMINE EFFECT


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Plasmalevodo

paconcentrations

Time

Therapeuticwindow

Early disease

On Off

Moderate disease

On Off

Dyskinesiathreshold

Efficacythreshold

Dyskinesiathreshold

Efficacythreshold

Dyskinesiathreshold

Efficacythreshold

Advanced disease

On Off


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Repeated daily dosing of levodopa/DDCI/entacapone extends thebioavailable levodopa while reducing peaktrough variations

0

500

1000

1500

2000

2500

3000

3500

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Levodopap

lasmalevels(ng/m

l)

After 4 weeks levodopa/DDCI/entacapone treatmentLevodopa


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Delayed start analysis of 3 long-term studies

Over 5 years, early initiation of Levodopa with a DDCI and Entacaponeresulted in a significant benefit compared with a delayed start in treatment

-6.0

0.0

6.0

12.0

18.0

Baseline(N=484)

1(N=410)

2(N=101)

3(N=90)

4(N=44)

5(N=37)

Years

UPDRS

IIIscores

Levodopa with DDCI and entacapone

Traditional levodopa plus placebo


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THANKYOU

parkinson disease slide update

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