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