1. PARKINSON’S DISEASE Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

2. James Parkinson Born11 April 1755 Shoreditch, London, England Died21 December 1824 (aged 69) Langthorne, North Yorkshire, England Cause of deathStroke NationalityBritish EthnicityWhite British OccupationSurgeon Known forFirst description of Parkinson's disease Spouse(s)Mary Dale

3. James Parkinson  Four generations of family were surgeon- apothecaries in London  He was initially medical apprentice with his father  Became medical student at London Hospital (1776)  Awarded diploma of the company of surgeons (1784)  Founding member Medico-Chirurgical Society (1812)  Founding member of Huntarian Society (1819)  Gold Medalist of Royal College of Surgeons (1822)

5.  Idiopathic PD ~ 85% of all PS cases  Neuroleptic-induced parkinsonism (DIP) 7% - 9%  MSA (SDS, SND, OPCD) ~ 2.5%  PSP ~ 1.5%  Vascular Parkinson syndrome ~ 3%  PS due to MPTP, CO, Mn, recurrent head trauma is extremely rare  No new cases of post- encephalitic parkinsonism since l960s Classification of Parkinson Syndromes in a Community

6. Descriptive Epidemiology of Parkinson Syndrome Incidence 5-24/ 10 5 worldwide (USA: 20.5/10 5 ) Incidence of PS/PD rising slowly with aging population Prevalence 57-371/10 5 worldwide (USA/Canada 300/10 5 ) 35%-42% of cases undiagnosed at any time Onset mean PS 61.6 years; PD 62.4 years rare before age 30; 4-10% cases before age 40

7. Pathology of Parkinson’s Disease A.Normal substantia nigra B.Severe depigmentation due to loss of nigral neurons in PD. C.Loss of pigmented neurons in the PD brain D.Lewy body A B CD

8. Main Biochemical Abnormality Marked striatal DA depletion “Striatal dopamine deficiency syndrome” At death, DA loss > 90% <50% DA loss is asymptomatic ~70% DA loss for symptom manifestations Severity of DA loss best correlates with bradykinesia in PD

9. Parkinson’s Disease Risk Factors Definite: Old age Highly likely: MZ co-twin with early- onset PD Probable: Positive family history Possible: Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head trauma, etc. Possible protective effect: Smoking

10. Cause of PD Unknown in most cases Genes AD inheritance very rare; mutation unknown Mutation of Alpha synuclein gene (chromosome 4q) identified in one large Italian (Contursi) and 5 Greek autosomal dominant families Mutation of parkin gene in autosomal- recessive juvenile parkinsonism Environment – Majority of cases believed caused by environmental factor (s) but none identified so far Genes plus environment?

11. Environmental Toxin Model: MPTP Reproduces all the major motor features of PD MAO-B MPTP MPP+ (In astrocytes) Dopaminergic neuron mitochondria Inhibits NADH--CoQ1 (Complex I) of mitochondrial respiratory chain ATP production falls Cell death

12. Early Signs and Symptoms Cardinal Characteristics Resting tremor Bradykinesia Rigidity Postural instability Other Micrographia Masked face Slowing of ADLs Stooped, shuffling gait Decreased arm swing when walkin g

13. Difficulty arising from a chair Difficulty turning in bed Hypophonic speech Sialorrhea Loss of the sense of smell Foot dystonia Additional Signs and Symptoms

14. At least two of three: Resting tremor Bradykinesia Rigidity Absence of a secondary cause— drugs, metabolic, etc. Definitive diagnosis can only be made by autopsy Criteria for Diagnosis

15. Early onset of, or rapidly progressing, dementia Rapidly progressive course Supranuclear gaze palsy Upper motor neuron signs Cerebellar signs—dysmetria, ataxia Urinary incontinence Early symptomatic postural hypotension Clues Suggesting Atypical Parkinsonism

16. Progressive supranuclear palsy Supranuclear downgaze palsy, square wave jerks Upright posture/frequent falls Pseudobulbar emotionality Furrowed brow/stare Corticobasal degeneration Dystonia/unilateral, coarse tremor Limb apraxia/limb alien limb Neurodegenerative disorders with Parkinsonism (I)

17. Neurodegenerative disorders with Parkinsonism (II) Multiple system atrophy Shy-Drager syndrome Autonomic insufficiency— orthostasis, impotence Striatonigral degeneration Tremor less prominent Olivopontocerebellar atrophy Cerebellar signs

18. Neurodegenerative Disorders with Parkinsonism (III) Diffuse Lewy body disease Early onset of dementia Delusions and hallucinations Agitation Alzheimer’s disease Dementia is the primary clinical syndrome Rest tremor is rare

19. Differential Diagnosis of PD: Drug-induced Toxin-induced Metabolic Structural lesions (vascular parkinsonism, etc.) Normal pressure Hydrocephalus Infections Secondary Parkinsonism

20. Toxin-induced Parkinsonism MPTP Carbon monoxide Manganese Cyanide

21. Vascular Parkinsonism Abrupt onset, usually unilateral Step-wise or no progression Other signs—hemiparesis, aphasia, hyperreflexia Infarcts on neuroimaging helpful in confirming diagnosis

22. Hydrocephalus-induced Parkinsonism (NPH) Normal pressure hydrocephalus— idiopathic Clinical triad: parkinsonism/gait disorder urinary/fecal incontinence dementia Normal pressure hydrocephalus

23. Treatment Options Preventive treatment No definitive treatment available Symptomatic treatment Pharmacological Surgical Non-motor management Restorative—experimental only Transplantation Neurotrophic factors

24. Drug Classes in PD I.Dopaminergic agents Levodopa Dopamine agonists II.COMT inhibitors III.MAO-B inhibitors IV.Anticholinergics V.Amantadine

25. DA GABA ACh Striatum Substantia Nigra levodopa Amantadine* Selegiline Dopamine agonists bromocriptine pergolide pramipexole ropinirole baclofen trihexiphenidyl BBB carbidopa benserazide tolcapone entacapone Sites of Action of PD Drugs

26. Anticholinergics Dopaminergic depletion  cholinergic overactivity Initially used in the 1950s Effective mainly for tremor and rigidity Common agents (Start low, go slow): Trihexyphenidyl: 2-15 mg/day Benztropine: 1-8 mg/day Side effects: Dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention

27. Levodopa Most effective drug for parkinsonian symptoms First developed in the late 1960s; rapidly became the drug of choice for PD Large neutral amino acid; requires active transport across the gut-blood and blood-brain barriers Rapid peripheral decarboxylation to dopamine without a decarboxylase inhibitor (DCIs: carbidopa, benserazide) Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations

28. Selegiline Irreversible MAO-B inhibitor Clinically active by inhibiting dopamine metabolism in brain May be neuroprotective Dosage: 5 mg at breakfast and lunch Side effects: insomnia, hallucinations, nausea (rarely), OH Potential interactions with tricyclics and SSRI antidepressants

29. Levodopa/Carbidopa Formulations Type Onset Duration Immediate Release 10/100, 25/100, 25/250 20-40 min2-4 hr Controlled Release 25/100, 50/200 30-60 min 3-6 hr “Liquid levodopa” (dissolved tablets) 10-20 min0.5-1 hr

30. DAs: Common Adverse Effects Nausea, vomiting Dizziness, postural hypotension Headache Dizziness Drowsiness & somnolence Dyskinesias Confusion, paranoia hallucinations, Erythromelalgia; pulmonary & retroperitoneal fibrosis; pleural effusion & pleural thickening; Reynaud's phenomena. May be more common with ergotoline DAs

31. Levodopa-Induced Dyskinesias Manifestation of excessive dopaminergic stimulation Typically late effect, and with higher doses Narrowing of therapeutic window Rare in LD-naive patients on DA monotherapy Most common is “peak dose” dyskinesia – disappears with dose reduction Choreiform, ballistic and dystonic movements Most patients prefer some dyskinesias over the alternative of akinesia and rigidity

32. COMT Inhibitors Newest class of antiparkinsonian drugs: tolcapone, entacapone MOA similar to dopa decarboxylase inhibitors Potentiate LD: prevent peripheral degradation by inhibiting catechol O-methyl transferase Reduces LD dose necessary for a given clinical effect Helpful for both early and fluctuating Parkinson’s disease May be particularly useful for patients with “brittle” PD, who fluctuate between off and on states frequently throughout the day

33. Dopamine Receptor Subtypes D1, D2 subcortical D3, D4, D5 cortical Differentiated biochemically & pharmacologically into two families: – D1 family: D1, D5 – D2 family: D2, D3, D4

34. DAs: Receptor Effects D1 D2 D3 D4 D5 Ergot Bromocriptine++ ++ Cabergoline0+++??? Lisuride+++??? Pergolide++++ ++ Non-Ergot Pramipexole0++++++++0 Ropinirole0 Neurology 1998; 50(suppl 3)

35. Initial Therapy: What is the Chief Complaint? Predominant Symptom Clinical Options No functional impairment Delay therapy Mild symptoms Amantadine, selegiline Discrete symptoms Tremor—anticholinergic Depression— antidepressant Anxiety—anxiolytic Functionally disabling Levodopa, dopamine symptoms agonist, COMT inhibitor

36. Off-period Dystonia Appears when LD level is low, especially early AM w/ or w/o parkinsonism Dose adjustments, add-ons: more frequent LD dosing to avoid low plasma levels add DA, COMT inhibitor, MAO-B inhibitor

37. Apomorphine D1/D2 agonist Parenteral delivery (s.c., i.v., sublingual, intranasal, rectal) Rapid “off” period rescue – 2-5 mg s.c.; pen injection systems Treatment of unpredictable, frequent motor fluctuations – continuous s.c. infusion via mini-pump SE: nausea, vomiting, hypotension – trimethobenzamide 250 mg t.i.d. – domperidone 20 mg t.i.d.; not available in U.S.

38. Managing Early Complications: Altered Mental States Confusion, sedation, dizziness, hallucinations, delusions Reduce or eliminate CNS-active drugs of lesser priority – anticholinergics – sedatives – amantadine – muscle relaxants – hypnotics – urinary spasmodics Reduce dosage of DA, COMT inhibitor, or LD

39. Managing Early Complications: Wearing Off/Mild Dyskinesia For pts on DA monotherapy: – elevate dosage of agonist – add LD, w/ or w/o COMT inhibitor For pts on LD: – add DA, COMT inhibitor, or MAO inhibitor – reduce LD dosage – use combination of immediate and CR

40. Late Complications Motor – response fluctuations, dyskinesias, dystonia, freezing, falls Behavioral/neuropsychological – depression, sleep disorders, psychosis Autonomic – orthostatic hypotension; hyperhidrosis, constipation, impotence, urinary incontinence or retention

41. Peak Dose Dyskinesia or Dystonia Chorea more common than dystonia May be worse on more affected side May not be as disabling as akinesia/rigidity Dose adjustments, add-ons: – reduce LD dose, increase dose frequency – convert to LD-CR – reduce LD, add DA, COMT inhibitor, or MAO-B inhibitor

42. Wearing Off Regular and predictable decline in response 2-4 hours after LD dose Most common motor fluctuation Dose adjustments, add-ons: – change to LD-CR, or increase LD frequency – reduce LD, add DA or COMT inhibitor

43. On-off Response Sudden and unpredictable off periods unrelated to dosing schedule One of the hardest features to manage Dose adjustments, add-ons: – reduce LD, add DA

44. Other Motor Complications Diphasic dyskinesia – dyskinesia at beginning and end of dose – Dose adjustments, add-ons: add DA Drug failure – late afternoon, probably related to poor gastric emptying or absorption – liquid preparations; increase gastric motility; decrease dietary protein – apomorphine rescue

45. Freezing and Falls Freezing – motoric block; at initiation of gait, turning, narrow spaces – use auditory, visual, proprioceptive cues Falls – physical therapy evaluation – cane, scooter, wheelchair may be necessary

46. Cognitive Assessment Memory difficulties: 11-29% of PD patients – Benign forgetfulness – Delirium – Alzheimer’s disease – Other dementias Evaluation – Brain imaging – Lumbar puncture – EEG – Blood work for thyroid profile, vitamin B12, serology, chemistry panel

47. Orthostatic Hypotension Light-headedness, dizziness, fatigue, shoulder or neck pain, blood pressure drops when standing Taper anti-hypertensive agents Taper non-PD drugs Increase salt intake Compression stockings Fludrocortisone (0.1-0.4 mg/d) Midodrine (2.5 - 20 mg/d)

48. Surgical Treatments for Parkinson’s Disease Ablative – thalamotomy – pallidotomy Electrical stimulation – VIM thalamus, globus pallidus internus, sub-thalamic nucleus Transplant – autologous adrenal, human fetal, xenotransplants, genetically engineered transplants

49. Improvements with Pallidotomy Specific Features: – Dyskinesia70-90 % – Wearing off dystonia70-90 % – Tremor25-60 % – Rigidity25-50 % – Bradykinesia25-50 % – Gait25-50 %

50. Deep Brain Stimulation (DBS) High frequency, pulsatile, bipolar electrical stimulation Stereotactically placed into target nucleus Can be activated and deactivated with an external magnet Exact physiology unknown, but higher frequencies mimic cellular ablation, not stimulation

51. Cell Transplants Autologous adrenal transplants – No efficacy Allogenic human fetal transplants – Initial encouraging clinical results Xenogenic fetal transplant (porcine and bovine) – Preliminary results pending Genetically engineered cells – Research ongoing

52. Efficacy – Encouraging preliminary results in young (<60) PD pts – Patients greater than 50 years did not improve – PET studies consistent with cell functioning – Autopsies (2) show cell survival Problems – 4-10 embryos < 10 weeks gestation needed – Immunosuppression requirements unknown – Numerous technical problems – Potential for dyskinesias, even without any PD medications