Prof. A.V. SRINIVASANInstitute of Neurology

Chennai

Prof. A.V. SRINIVASANInstitute of Neurology

Chennai

Current Trends in the Management of

Parkinson’s Diesease

The sign wasn’t placed there

By the Big Printer in the sky

17th September 2004, Chennai

Introduction UK P.D. Society Brain Bank and Clinical

Diagnostic Criteria Neuro Protection Symptomatic Therapy Management of Adverse Reactions to Therapy

Current Trends in the Management of Parkinson’s Disease

Success is a prize to be won. Action is the road to it.

Chance is what may lurk in the shadows at the road side.

- O. Henry

Discipline Weighs Ounces Regret Weighs Tons

Current Research Management of Complicated PD Neuro Psychiatry Management Surgical Management Analytic Neurology – Parkinson’s Disease -

Conclusion

Disease Const. Signs of Clinical +Def. cause Syndrome Const. Signs of Clinical +No Def. Cause 180 yrs ago – James Parkinson Described

Facial Hypomia Missed

– 1912 - Lewy-Eosin Inclusion Body– 1919 - Tretiakoff SN Damage– 1953 - Green Field– 1973 - Bern Hlener L.B. Described – 1989 - GIBBS

Introduction

‘Authority can Rarely Survive in the face of doubt’

- R. Lindner

“Many Ideas grow better when transplanted into another mind than in the one where they sprang

up”- O.W. Holmes

Drugs 1800 - Anti Cholinergics (Bell. Alkaloids) 1950 - Synthetic 1960 - L Dopa 1970 - L Dopa / C Dopa 1976 - Dopa Recep.agonists, BCP pergolide 1987 - LD / CD – SR 1989 - M.A.O.B Inhibitor selegiline

Expert is one who think to his

chosen mode of ignorance

“By Nature All Men/ Women are alike butby Education widely different”

Mid 1997 - Pramipexole a) DRA Late 1997 - Ropiniroleb) Comt Inhib. Early 1998 - Tolcaponec) Apomorphin Inj. 2001 - (1951)d) LDME, LDEE Levodopa patches and nasal spray –

Research settings

Newer drugs

“Medical School can be a tool of torture or an Instrument of Inspiration”

Neuro Degeneration • Prevent / Delayed:

- Auto Immunity,

- Excess Excite Drive

- Dist. of Trophic Factors

- Increase toxic free Radicals.

Neuro protection

Drugs: • Younger onset Slow Prog. (Quinn)- Selegiline: PSG 1993

Prot. Factors:• Race – African Americans - Rare• Smoking (Checkoway Isoto – 1998)• Estrogen (Mardor – 1998)• Exp. to Pesticides (Gorr 98, Fall 1999)• Drug induced parkins. (Chabolla 1998)• Oxidative Stress and high lipid per oxidation

related to pathog. of park. disease ( Anderson 1999)

Thought is the labour of the intellect; Reverie is its pleasure

It is a great misfortune not to posses sufficient wit to speak well nor sufficient judgement to keep silent.

La Broyers Charactor

CLINICAL TRIALS• MAO Inhib - Rasagiline

• Glutamate Antagonist - Riluzole

• NMDA Blocker - Remacemide

• Neurotropic factors - GDNF

• Lazabemide -

• Nicot. Ach. Recept Antag - S/B – 1508

• L Dopa itself - Fahn 1999

GENE THERAPY - ! Role

Symptomatic therapy

• EARLY SYMPTOMS• Anti Cholinergics - Young Tremu. Pts.• Amantidine - Mild Bradykinesia

Mild Rigid

Mild Gait Disturb.

Material Gains Soul Losses

“Back pain – prize human beings pay for their UPRIGHT POSTURE”

LONG STANDING POLEMIC – EARLY OR LATE Early:

Mortality is less Dyskin. increase in youngerloss of Eficacy and onset PD (Cederbium and side effect Increase kosnc 1991)

(Diamond 1987, Scigil 1990• Empirical clin. observation to cellu. biochemist- Murer 1998 – No Study – Detrim. to human Nigral cells

Sign of Independence Decreased – Start

“You have got to be before you can do and do before you can have”

DOPAMINE RECEPTOR AGONISTS

• STIM. STRIAT. Recept. And

By pass Degn nigra cell Do not increase dopam. Metabolism Monotherapy – Early – Advant. in late CBB

A true commitment is a heart felt promise to yourself

from which you will not back down - D. Mcnally

• 4 DRUGS– 10 mgm BCP– 1mgm Perg. – 1 mgm Prami. - 3 mgm. Ropir

– (Goeth 1999)

– All are D2 Agonists, each has unique profile to D1, Noradr, Serto, Activit

– High Dose BCR – 50 mgm / Day – Comp. To L Dopa (Moutastrier 1989 – 3 years)

– Other drugs not studied

– Reduction of Motor Fluctuations

Motor300 – 600 Agonist is Added

L Dopa Disability More

Side Effects: Hypotension, Dyskinesia, Halln

– Pramipexo: 45 mgm; Ropinirole 24 mgm /DaysCabergoline – Once daily 1997; 1998. Rinne.Seligi can be added to L Dopa; Olanow 1998

“Woman needs society demands”

Catecholamine – O – Methyl Transferase inhibited ‘ COMT Inhib.’

• Entacopone Tolcapone

ACTS• Prim. Extracerebrally Extra and intra cerebrals

Inhi. Meta. of Dopam. in brain (NUTT 98)

- Hepatic Toxicity

Non dopaminergic therapies

• Estrogen -Women (Dementia less motor disab.

less)• VIT D-Elderly people Mards 98 Saunders 95

Hip #s (SATO 1999)

Many Ideas grow better when transplanted into another mind than in the one where they sprang UP

O.W. Holmos

“Healthy Mind and Healthy expression of Emotion

Go hand in Hand”

ADVANCED PARK. DISEASE• Tremor, Bradykinesia, Motor Fluctuations• Dyskinesias, Freezing, Dysphagia• Dysautonomia, Beha., Psychia Symptoms• Diff. Approach Free Interact May

limit Therapy

• Pred. Period of mobility without unacccep dyskinesias or dystonia• Dose and freq. Of L Dopa depends

• Wearing off• Unpred. Off• Failure of L Dopa doses• On Period• Off Dyskinesia • Off Dystonia.

• Indiv. Doses to the effect short on – Higher dose of L-Dopa (Immen + CR)

• To Prolong On and decrease off period Use Dopamine Agonists• DOPA agonist + L-Dopa “ Worsen Dyskinesia and Peak dose adverse

eff. of L Dopa

“Fools Admire but of men of sense approve”

Motor fluctuations

“Social Isolation is in itself a pathogenicFactor for disease production”

- Dr. Elsen Borg

TREMOR

- Refract to L Dopa diff. to treat- Pramipexole / Ropinirole – High Doses can be

tried- Surgery

“My Opinions are founded on knowledge but modified by experience”

L-Dopa Dyskinesia• Presentation : On Period on Diphasic (DD)

– Off Period, ON + OFF, ON + Diphasic, – DD – OFF, ON + OFF + DD

• Type of Dyskinesias:– ON – Chorea, Blepharospasm – OFF – Dystonic Posturing– ON + OFF – Mobile Dystonia, Cranial, Cervical Dystonia – Diphasic OFF – RLMS– MMD, Myoclonus, Tics,

L-Dopa Dyskinesia• Time Interval: 1 Week - 12 years• Experimental: Chronic L Dopa Therapy

–Produce oxidative stress–Accelerate Neuro degeneration

• Apoptosis (PC 12 Cells)• DNA Damage

A open foe may prove a curse ; but

a pretended friend is worse

Starving Emotion - Humor Less; Rigid; StereotypeRepressing Emotion - Literal; Holier than thouEncouraging Emotion- Performs in LifeDiscourage Emotion - Poison LifeJuseph Colins. 1868

• Fluctuations (Motor) – Short, Medium, Long• On

Peak Dose - Square Wave Mobile Choreo –Dystonic

• Interface DiphasicDiphasic

• Off Off Period Fixed Dystonic

Early Morning

Untreated/Drug Holiday

“ He who cannot forgive others destroys the bridge over which

he himself must pass” - Annoy

• DYSARTHRIA / HYPOPHONIA– Speak Slowly– Aug. Comm. Devices– Using Writt. Notes– Rule out Imp hearing

• DYSPHAGIA– Diff. to treat– Coughing after swallow – Early ASPN– Weight - Gastrostomy

• IMBALANCE AND FREEZING Diff. to treat Wheelchair – Walker

The Truth is fear and immorality are two of the greatest inhibitors of Performance too progress

• URINARY SYMPTOMSIncontinence never occurs but urgency / Ppt. canObst. Sympt. Poor pharmacologyOff period anuriaHigh inciden of post surg. Incontinence

• CONSTIPATION– Mild - Exercise/Fluid/Fiber/Fresh leaves/Stool

softener– Bowel stimulant Bisacodyl; Senna casenca

• IMPOTENCE – Devices and Drugs : Sildenafil

“Men of Genius Admired: Men of Wealth envied: women of power feared: But only women of character are

trusted”-A- Friedman

ORTHOSTATIC HYPOTENSION• Avoid Hypnotics and anti depress.; increase hypotension

• Avoid Deprenyl – Worsen L Dopa Hypotension

• Take Sometime to resolve

• High Sodium diet; pressure stockings;

• Fludrocortisone; MIDODRINE (Low 1997)

Alpha Agonist Well Tolerated

• NSAIDS; CLONIDINE;EDHEDRINE;DOMPERIDONE PROPANALOL

“ Maintaining the right attitude is easier than regaining the right mental attitude”

COGNITIVE AND BEHAVIOUR PROBLEMS• Fecal impaction – Worsens Behaviour Hypersexual; Visu. Hallu; Paranoid Ideation;

Reversal of sleep wake cycle decrease NREM - Dopa agonist

Confusion can be produced by digoxin; propanalol oxybutynin or Diphenhydramine

Haloper/Thioridazine - Paranoid ideation; or agitation

clozapine is ideal (PSG – 1999) – Agranulocytosis Risperidone / Olanzapine - Do not tolerate Quetiapine – Promising

“Peace Rules the day where reason Rules the mind”

- Colling

SURGERY• Asymmetrical Tremor- Thalamus• Asym. Dyskinesia - GB(I)• Both - STN

(Bler 1999)

IMPLANT OF EMBRY. DOPA TISSUE• Fahn 1995 - Benefits under 60• (40 Pts) - No improv. in

Dyskinesias/Motor Fluctuations

-Improve in off symptoms

• Genetically engineered cells. Pre clinical Develop

BILAT

STIM ABLAT-Mood-Cognit-Behavior Changes

“Character gets you out of bed Commitment moves you to action

Faith, hope and Discipline follow through to completion”

ALTERNATE THERAPY• Vita/Herb/Massage/Acu Puncture

• 40%

• Younger age/Married

• Higher Income.

“Give us the GRACE to accept with serenity the things that cannot be changed;

The COURAGE to change the things that should be changed and;

The WISDOM to know the difference”

• RESEARCH• Trans Magnetic Stimulation• 10 Hz - Akinesia / Rigidity• 0.5 Hz - Post and Gait Distur.• GM1 Ganglioside• Transdermal Nicotine patch• Flumazenil• Lazabemide• Viagra• Trophic effect of L Dopa

Deep Brain Stimulation(DBS) Exact mechanism of action not known High frequency stimulation is inhibitive Inhibition from stimulation of GABAergic

neurons, Preferential excitation Absence of permanent lesion

A woman’s desire for revenge outlasts all her other emotions

Methods• Location of target - Micro Recording• Micro electrode placement• Setting electrical parameters

Disadvantages• Expensive• Progressive tolerance phenomenon • Electrical problems

Truth comes out of error sooner than that of confusion

Methods Advantage

• Complication of lesion production is absent• No risk of Neurological Deficit• Reversible morbidity

THALAMIC DBS• Essentially for Tremors.

At twenty the will rules

At thirty the intellect

At forty the Judgment

Methods STN STIMULATION

• For severe motor complication of Chronic L-dopa therapy

• Severe immobility off motor periods • Painful dystonia, Dyskinesia• Improves Akinesia Tremor, Gait, and Dystonia

Opinion is ultimately determined by the feelings

and not by the intellect

DBS ConclusionSymptoms STN GPI VIM

Tremor +++ ++ +++

Akinesia +++ + 0

Rigitidy +++ ++ +

Gait +++ ++ 0

Dyskinesia Short +++ +

Off Period Dystonia +++ ++ 0

Experience can be defined as yesterday’s answer to today’s problems

Gene Therapy for PD Strategies for PD

• DA replacement by delivering NT Synthesizing agent

• Repair and Protection Strategy by Neuro tropic factor delivery

• Other potential agents - intervention of Pathogenesis.

Memory, Pity & Beauty are short lived in life,

Tinged with emotions persist in life

Gene Therapy for PD• DA Replacement by delivering NT Synthesizing

gene• Donor cell or genitically enginered cells as alternate

to fetal cells• To provide L-dopa into brain by introducing

Tyrosine Hydroxylase (TH) gene• Initial studies - Cell line Rat fibroblast, NIH 3 T3

cells, Endorcrine cell line, Primary cell, Neuro Precursor cells

Being ignorant is not so much a shame as being unwilling to learn

Gene Therapy for PD• GTP Cyclo Hydrolas 1(GCH) - Co-factor for TH

enzymes production• Decorboxylation by Aromatic L-amino acid

decorboxylase (AAOC)

Repair and Protection• Neurotropic factor - Big molecule, do not cross BBB• Gene therapy provides efficient delivery (BDNP)

producing fibro blasts cells protects against neuro toxin

Dual action of brain is reflected in the duality of god;

Each is in-separable but has individual existence

Gene Therapy for PD Other Potential Targets

• Mutation of synnuclein intervene directly at the level of Pathogenesis, Forestall clinical manifestation

Future Issues1. Safety

2. Gene expression Modulation

3. Regulation of gene expression

GT Product efficient delivery of various genes and products into localized site

Memory, the daughter of attention ,

is the teeming mother of knowledge

- Martin Tupper

Gene Therapy for PD Tropic Factors

• To support survival of ND neurons or neuronal tissue• Glial cell line dervied neurotrophic factor(GDNF)• Neurtumin - Survival of Nigral Neurons• Persephin survival of TH Neurons• Changes delivery across BBB Nigro striatal neurons

controls delivery of TF

Take time to think; it is the source of powerTake time to read; it is the foundation of wisdom

Take time to work; it is the price of success

Analytic Neurology – Examining the Evidence of Clinical Practice – M. Benatar Koller W C – Parkinson’s Disease prevalence risk is

increased in Essential Tremor – 6.1% Selegiline – Limited symptomatic antiparkinsonian

effect Deprenyl and Tocopherol – No neuroprotective effect L-Dopa therapy and emergence of motor fluctuations –

Largely retrospective, limited quality and contradictory.

Success in life is a matter not so much of talent and opportunity as of concentration and perseverance

- C.W. Wendte

Analytic Neurology – Examining the Evidence of Clinical Practice – M. Benatar

Early use of Dopamine agonist in the treatment of PD is not proven

Amantidine reduces the severity of motor fluctuations and peak dose dyskinesias.

COMT inhibitors – The role is definite in stable and advanced PD and varying of motor fluctuations

Tolcapone is more effective than Entacapone, but has more hepatic toxicity

Mind is the great level of all things; Human thought is the process by which,

Human ends are ultimately answered

Dedicated to my family for making everything worthwhile

My sincere thanks to Mr. G. Kakuthan for his meticulous

computer work

My sincere thanks to Mr. G. Kakuthan for his meticulous

computer work

READ not to contradict or confute

Nor to Believe and Take for Granted

but TO WEIGH AND CONSIDER

THANK YOU