1. The sign wasn’t placed there
By the Big Printer in the sky
Current Trends in the
Management of
Parkinson’s Diesease
Prof. A.V. SRINIVASAN
Institute of Neurology
Chennai
17th September 2004, Chennai

3. Current Trends in the
Management of Parkinson’s Disease
Introduction
UK P.D. Society Brain Bank and Clinical
Diagnostic Criteria
Neuro Protection
Symptomatic Therapy
Management of Adverse Reactions to Therapy
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

4. Current Research
Management of Complicated PD
Neuro Psychiatry Management
Surgical Management
Analytic Neurology – Parkinson’s Disease -
Conclusion
Discipline Weighs Ounces Regret Weighs Tons

5. Introduction
 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
‘ A rity can Rare ly Survive in the face o f do ubt’
utho
- R. Lindne r

6. “ M I as g ro w be tte r whe n transplante d into ano the r
any de
mind than in the o ne whe re the y sprang up”
- O. W. Ho lme s

7. 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

8. Newer drugs
Mid 1997 - Pramipexole
a) DRA Late 1997 - Ropinirole
b) Comt Inhib. Early 1998 - Tolcapone
c) Apomorphin Inj. 2001 -
(1951)
d) LDME, LDEE
Levodopa patches and nasal spray – Research
settings
“B N
y ature A M n/ Wo me n are alike but
ll e
by Educatio n wide ly diffe re nt”

9. Neuro protection
Neuro Degeneration
• Prevent / Delayed:
- Auto Immunity,
- Excess Excite Drive
- Dist. of Trophic Factors
- Increase toxic free Radicals.
“ M dical Scho o l can be a to o l o f to rture o r
e
an Instrume nt o f Inspiratio n”

10. 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

11. 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
I is a g re at misfo rtune no t to po sse s sufficie nt wit to spe ak
t
we ll no r sufficie nt judg e me nt to ke e p sile nt.
La B ye rs Characto r
ro

12. Symptomatic therapy
• EARLY SYMPTOMS
• Anti Cholinergics - Young Tremu. Pts.
• Amantidine - Mild Bradykinesia
Mild Rigid
Mild Gait Disturb.
Material Gains Soul Losses

13. LONG STANDING POLEMIC – EARLY OR LATE
Early:
Mortality is less Dyskin. increase in younger
loss 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
“ B pain – prize human be ing s pay
ack
fo r the ir UPRIGHT POSTURE”

14. DOPAMINE RECEPTOR AGONISTS
• STIM. STRIAT. Recept. And
By pass Degn nigra cell
 Do not increase dopam. Metabolism
 Monotherapy – Early – Advant. in late CBB
“ Yo u have g o t to be be fo re yo u can do
and do be fo re yo u can have ”

15. • 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
Motor
300 – 600 Agonist is Added
L Dopa Disability More
Side Effects: Hypotension, Dyskinesia, Halln
– Pramipexo: 45 mgm; Ropinirole 24 mgm /Days
Cabergoline – Once daily 1997; 1998. Rinne.
Seligi can be added to L Dopa; Olanow 1998
Atrue co mmitme nt is a he art fe lt pro mise to yo urse lf
fro m which yo u will no t back do wn - D. M cnally

16. 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
“ Wo man ne e ds so cie ty de mands”

17. 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

18. ADVANCED PARK. DISEASE
• Tremor, Bradykinesia, Motor Fluctuations
• Dyskinesias, Freezing, Dysphagia
• Dysautonomia, Beha., Psychia Symptoms
• Diff. Approach Free Interact May
limit Therapy
“ He althy M and He althy e xpre ssio n o f Emo tio n
ind
Go hand in Hand”

19. Motor fluctuations
• 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”

20. TREMOR
- Refract to L Dopa diff. to treat
- Pramipexole / Ropinirole – High Doses can be
tried
- Surgery
“ So cial I latio n is in itse lf a patho g e nic
so
Facto r fo r dise ase pro ductio n”
- Dr. Else n B rg
o

21. 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,
“ M O pinio ns are fo unde d o n kno wle dg e but
y
mo difie d by e xpe rie nce ”

22. 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

23. • Fluctuations (Motor) – Short, Medium, Long
• On
Peak Dose -
Square Wave Mobile Choreo –Dystonic
• Interface Diphasic
Diphasic
• Off Off Period Fixed Dystonic
Early Morning
Untreated/Drug Holiday
Starving Emo tio n - Humo r Le ss; Rig id; Ste re o type
Re pre ssing Emo tio n - Lite ral; Ho lie r than tho u
Enco urag ing Emo tio n - Pe rfo rms in Life
Disco urag e Emo tio n - Po iso n Life
Juse ph Co lins. 1 8 6 8

24. • 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
“ He who canno t fo rg ive o the rs de stro ys the bridg e o ve r which
he himse lf must pass” -A y
nno

25. • URINARY SYMPTOMS
Incontinence never occurs but urgency / Ppt. can
Obst. Sympt. Poor pharmacology
Off period anuria
High inciden of post surg. Incontinence
• CONSTIPATION
– Mild - Exercise/Fluid/Fiber/Fresh leaves/Stool
softener
– Bowel stimulant Bisacodyl; Senna casenca
• IMPOTENCE
– Devices and Drugs : Sildenafil
The Truth is fe ar and immo rality are two o f the g re ate st
inhibito rs o f Pe rfo rmance to o pro g re ss

26. 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
“ M n o f Ge nius A
e dmire d: M n o f We alth e nvie d:
e
wo me n o f po we r fe are d: B o nly wo me n o f characte r are truste d”
ut
-A- Friedman

27. 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
“ Maintaining the rig ht attitude is e asie r than re g aining the
rig ht me ntal attitude ”

28. SURGERY BILAT
• Asymmetrical Tremor- Thalamus STIM ABLAT
• Asym. Dyskinesia - GB(I) -Mood
-Cognit
-Behavior Changes
• 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
“ Pe ace Rule s the day whe re re aso n Rule s the mind”
- Co lling

29. ALTERNATE THERAPY
• Vita/Herb/Massage/Acu Puncture
• 40%
• Younger age/Married
• Higher Income.
“ Characte r g e ts yo u o ut o f be d
Co mmitme nt mo ve s yo u to actio n
Faith, ho pe and Discipline fo llo w thro ug h to co mple tio n”

30. • 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
“ Give us the GRACE to acce pt with se re nity the thing s that canno t be
chang e d;
The COURAGE to chang e the thing s that sho uld be chang e d and;
The WISDOM to kno w the diffe re nce ”

31. 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

32. 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

33. 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

34. 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

35. DBS Conclusion
Symptoms 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

36. 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

37. 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

38. 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

39. Gene Therapy for PD
Other Potential Targets
• Mutation of α synnuclein intervene directly at the
level of Pathogenesis, Forestall clinical manifestation
Future Issues
1. 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

40. 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 power
Take time to read; it is the foundation of wisdom
Take time to work; it is the price of success

41. 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

42. 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

45. Dedicated to my family
for making everything worthwhile

46. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU
My sincere thanks to
Mr. G. Kakuthan for his meticulous
computer work