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

2. Born 11 April 1755 Shoreditch, London, England Died 21 December 1824 (aged 69) from stroke Langthorne, North Yorkshire, England NationalityBritish Spouse(s)Mary Dale OccupationSurgeon Known forFirst description of Parkinson's disease

3.  1817: James Parkinson “An Essay on the Shaking Palsy”  Diagnosis requires 2 of 3:  Bradykinesia;  Rigidity  Tremor (primarily at rest) Other signs:  Masked face,  Hypovolemic speech, – swallowing difficulty, micrographia, flexed posture, – shuffling gait, start hesitancy and freezing  Onset: Insidious, unilateral progressing to bilateral Clinical Features/Cardinal Signs

4. Classification of Parkinson Syndromes in a Community  Idiopathic PD ~ 85% of all PS cases  Neuroleptic-induced parkinsonism 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 postencephalitic parkinsonism since l960s

5. Morbidity in Parkinsonism Progressive (except drug-induced and vascular) – More rapid in MSA and PSP than in PD – Non-linear, wide individual variations Prognosis is best in non-demented PD cases Symptomatic and QOL improvement with L-dopa

6. Pathology of Parkinson’s Disease

7. 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

8. 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

9. Cause of PD Unknown in most cases; not accelerated aging 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?

10. 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

11. 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 walking

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

13. Criteria for Diagnosis At least two of three: rest tremor, bradykinesia, rigidity Absence of a secondary cause— drugs, metabolic, etc. Definitive diagnosis can only be made by autopsy

14. Clues Suggesting Atypical Parkinsonism 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

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

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

17. 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

18. Differential Diagnosis of Parkinson’s Disease Part 2 of 7

19. Hereditary disorders associated with parkinsonism Wilson’s disease Huntington’s disease Dentatorubro-pallidoluysian atrophy (DRPLA) Machado-Joseph disease (SCA-3) Differential Diagnosis of PD:

20. Drug-induced Toxin-induced Metabolic Structural lesions (vascular parkinsonism, etc.) Hydrocephalus Infections Secondary Parkinsonism

21. Crucial to rule out, since most cases are reversible Careful medication history—list drug names Common offending drug types – Antipsychotics haloperidol, chlorpromazine, thioridizine, perphenazine risperidone, olanzapine – Antiemetics— metoclopramide, prochlorperazine – Dopamine depletors— methyldopa, reserpine, tetrabenazine – Combination drugs— e.g., Triavil ® (amitriptyline, perphenazine) Treatment: Stop offending medication Drug-Induced Parkinsonism

22. Metabolic and Infectious Causes of Parkinsonism Metabolic – Often reversible – Hypo- or hyper-thyroidism – Hypo- or hyper-parathyroidism – Liver failure – Central pontine myelinolysis Infectious – Post-encephalitic – Creutzfeldt-Jakob disease – Infectious masses – HIV

23. Toxin-induced Parkinsonism MPTP Carbon monoxide Manganese Cyanide

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

25. Hydrocephalus-induced Parkinsonism (NPH) Can be communicating or obstructive Normal pressure hydrocephalus— idiopathic Clinical triad: – parkinsonism/gait disorder – urinary/fecal incontinence – dementia

26. Parkinson’s Disease vs. Essential Tremor Essential tremor should be tremor with no other signs of parkinsonism Both can have a kinetic and rest component Kinetic tremor can interfere with RAM Cogwheel rigidity can be found in ET

27. Pharmacologic Treatment of Parkinson’s Disease Part 3 of 7

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

29. Drug Classes in PD Dopaminergic agents – Levodopa – Dopamine agonists COMT inhibitors MAO-B inhibitors Anticholinergics Amantadine

30. 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 – Ethopropazine: 10-200 mg/day Side effects: – Dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention

31. 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

32. 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

33. 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

34. Levodopa/Carbidopa Formulations OnsetDuration Immediate Release 20-40 min2-4 hr 10/100, 25/100, 25/250 Controlled Release 30-60 min3-6 hr 25/100, 50/200 “Liquid levodopa” 10-20 min 0.5-1 hr (dissolved tablets)

35. 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

36. Entacapone Dosage: 200 mg w/each levodopa dose Parkinson’s Study Group 1997: Increased on time by 5%, more in pts w/least on time Rinne et al., 1998: Increased on time by ~10%; decreased levodopa Diarrhea, dopaminergic SEs

37. Dopamine Agonists: Distinguishing Features Directly stimulate dopamine receptors No metabolic conversion; bypasses nigrostriatal neurons No absorption delay from competition with dietary amino acids Longer half-life than levodopa Monotherapy or adjunct therapy May delay or reduce motor fluctuations & dyskinesias associated with levodopa May be neuroprotective

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

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

40. Initial Therapy: The Young Patient Long-term treatment horizon Increased risk of long-term complications Increased patient responsibilities Dopamine agonist monotherapy Levodopa-sparing strategies Putative neuroprotective strategies Role of levodopa is not adequately defined

41. Initial Therapy: What is the Chief Complain t? 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

42. Dopamine Agonists: Guidelines in Early PD Effective as monotherapy Less symptomatic benefit than levodopa May delay need for levodopa approx. 12 months – data up to >3 years has been presented Start low and increase slowly Titrate to efficacy – bromocriptine 7.5-30 mg/day – pergolide 1.5-4.5 mg/day – pramipexole 1.5-4.5 mg/day – ropinirole 3-24 mg/day Acute SEs: nausea, dizziness, somnolence, confusion

43. 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

44. 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

45. Management of Late-Stage Parkinson’s Disease Part 5 of 7

46. 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

47. LD Response Fluctuations Peripheral causes: – delayed gastric emptying – dietary protein – short plasma half-life Central causes: – pulsatile delivery to striatal receptors – impaired storage capacity – alteration of DA recept ors

48. Response Fluctuations: Treatment Increase LD dose Increase DCI dose Add dopamine agonist Add COMT inhibitor – reduce LD – liver function monitoring Apomorphine rescue

49. 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

50. 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

51. 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

52. 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

53. 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

54. The Surgical Treatment of Parkinson’s Disease Part 6 of 7

55. 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

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

57. 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

58. 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

59. 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 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