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Current trends in the management of parkinsons diseases

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  • 1. The sign wasn’t placed there By the Big Printer in the skyCurrent Trends in the Management ofParkinson’s Diesease Prof. A.V. SRINIVASAN Institute of Neurology Chennai 17th September 2004, Chennai
  • 2. Current Trends in theManagement 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
  • 3. Current ResearchManagement of Complicated PDNeuro Psychiatry ManagementSurgical ManagementAnalytic Neurology – Parkinson’s Disease -Conclusion Discipline Weighs Ounces Regret Weighs Tons
  • 4. 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
  • 5. “ 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
  • 6. Drugs1800 - Anti Cholinergics (Bell. Alkaloids)1950 - Synthetic1960 - L Dopa1970 - L Dopa / C Dopa1976 - Dopa Recep.agonists, BCP pergolide1987 - LD / CD – SR1989 - M.A.O.B Inhibitor selegiline Expert is one who think to his chosen mode of ignorance
  • 7. Newer drugsMid 1997 - Pramipexolea) DRA Late 1997 - Ropiniroleb) Comt Inhib. Early 1998 - Tolcaponec) 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”
  • 8. Neuro protectionNeuro 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”
  • 9. 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
  • 10. 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 - ! RoleI is a g re at misfo rtune no t to po sse s sufficie nt wit to spe ak twe ll no r sufficie nt judg e me nt to ke e p sile nt. La B ye rs Characto r ro
  • 11. Symptomatic therapy• EARLY SYMPTOMS • Anti Cholinergics - Young Tremu. Pts. • Amantidine - Mild Bradykinesia Mild Rigid Mild Gait Disturb. Material Gains Soul Losses
  • 12. 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”
  • 13. 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 ”
  • 14. • 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
  • 15. Catecholamine – O – Methyl Transferaseinhibited ‘ 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”
  • 16. 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 intoanother mind than in the one where they sprang UP O.W. Holmos
  • 17. 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”
  • 18. 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”
  • 19. 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
  • 20. 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 ”
  • 21. 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
  • 22. • 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 HolidayStarving Emo tio n - Humo r Le ss; Rig id; Ste re o typeRe pre ssing Emo tio n - Lite ral; Ho lie r than tho uEnco urag ing Emo tio n - Pe rfo rms in LifeDisco urag e Emo tio n - Po iso n LifeJuse ph Co lins. 1 8 6 8
  • 23. • 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
  • 24. • 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 : SildenafilThe 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
  • 25. 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: ewo 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
  • 26. 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 ”
  • 27. 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
  • 28. 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 nFaith, ho pe and Discipline fo llo w thro ug h to co mple tio n”
  • 29. • 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 ”
  • 30. 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 lesionA woman’s desire for revenge outlasts all her other
  • 31. Methods • Location of target - Micro Recording • Micro electrode placement • Setting electrical parameters Disadvantages • Expensive • Progressive tolerance phenomenon • Electrical problemsTruth comes out of error sooner than that of confusion
  • 32. MethodsAdvantage• Complication of lesion production is absent• No risk of Neurological Deficit• Reversible morbidityTHALAMIC DBS• Essentially for Tremors. At twenty the will rules At thirty the intellect At forty the Judgment
  • 33. MethodsSTN STIMULATION• For severe motor complication of Chronic L-dopa therapy• Severe immobility off motor periods• Painful dystonia, Dyskinesia• Improves Akinesia Tremor, Gait, and DystoniaOpinion is ultimately determined by the feelings and not by the intellect
  • 34. DBS Conclusion Symptoms STN GPI VIM Tremor +++ ++ +++ Akinesia +++ + 0 Rigitidy +++ ++ + Gait +++ ++ 0 Dyskinesia Short +++ + Off Period Dystonia +++ ++ 0Experience can be defined as yesterday’s answer to today’s problems
  • 35. Gene Therapy for PDStrategies 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
  • 36. 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 cellsBeing ignorant is not so much a shame as being unwilling to learn
  • 37. 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
  • 38. Gene Therapy for PDOther Potential Targets• Mutation of α synnuclein intervene directly at the level of Pathogenesis, Forestall clinical manifestationFuture Issues1. Safety2. Gene expression Modulation3. Regulation of gene expressionGT Product efficient delivery of various genes and products into localized site Memory, the daughter of attention , is the teeming mother of knowledge
  • 39. Gene Therapy for PDTropic 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
  • 40. Analytic Neurology – Examining theEvidence 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
  • 41. Analytic Neurology – Examining theEvidence 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
  • 42. Dedicated to my familyfor making everything worthwhile
  • 43. READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOU My sincere thanks to Mr. G. Kakuthan for his meticulous computer work