1. Dr. M. A. 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. Parkinson was the first person to systematically describe six individuals with symptoms of the disease that bears his name. In his "An Essay on the Shaking Palsy", he reported on three of his own patients and three persons who he saw in the street. He referred to the disease that would later bear his name as paralysis agitans, or shaking palsy. He distinguished between resting tremors and the tremors with motion. Jean-Martin Charcot coined the term "Parkinson's disease" some 60 years later. Parkinson erroneously predicted that the tremors in these patients were due to lesions in the cervical spinal cord

4.  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

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 postencephalitic parkinsonism since l960s

6.  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.  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

9.  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

10.  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

11.  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?

12.  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

13.  No specific clinical markers known  4-13% of autopsies in elderly showing incidental Lewy bodies are regarded as preclinical cases  Increased risk of neuroleptic parkinsonism  Duration of preclinical phase unknown (several years to several decades?)  PET studies may identify preclinical cases

14.  Cardinal Characteristics  Resting tremor  Bradykinesia  Rigidity  Postural instability  Other  Micrographia  Masked face  Slowing of ADLs  Stooped, shuffling gait  Decreased arm swing when walking

15.  Difficulty arising from a chair  Difficulty turning in bed  Hypophonic speech  Sialorrhea  Loss of the sense of smell  Foot dystonia

16.  Constipation.  Bladder symptoms and sometimes incontinence.  Hallucinations (seeing, hearing or smelling things that are not real).  Sweating.  Sexual difficulties.  Alterations in your sense of smell.  Difficulties with sleeping.  Weight loss.  Pain.  Depression.  Anxiety.  Problems with controlling impulses Additional Signs and Symptoms

17.  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

18.  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

19.  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

20.  Multiple system atrophy  Shy-Drager syndrome ▪Autonomic insufficiency— orthostasis, impotence  Striatonigral degeneration ▪Tremor less prominent  Olivopontocerebellar atrophy ▪Cerebellar signs

21.  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

22. PDMSAPSPCBD Symmetry of deficits ++++ -- Axial rigidity++ +++++ Limb dystonia++++++ Postural instability++ ++++ Vertical gaze restriction ++++++++ Frontal behavior+++++++ Dysautonomia+++-- L-dopa response early +++++-- L-dopa response late +++-- Asym cortical atrophy on MRI -- ++ CLINICAL DIFFERENTIATING OF PARKINSONIAN DISORDERS

23. Part 2 of 7

24.  Wilson’s disease  Huntington’s disease  Dentatorubro-pallidoluysian atrophy (DRPLA)  Machado-Joseph disease (SCA-3) Differential Diagnosis of PD:

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

26. 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

27.  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

28.  MPTP  Carbon monoxide  Manganese  Cyanide

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

30.  Can be communicating or obstructive  Normal pressure hydrocephalus—idiopathic  Clinical triad:  parkinsonism/gait disorder  urinary/fecal incontinence  dementia

31.  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

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33.  Preventive treatment  No definitive treatment available  Symptomatic treatment  Pharmacological  Surgical  Non-motor management  Restorative—experimental only  Transplantation  Neurotrophic factors

34.  Dopaminergic agents  Levodopa  Dopamine agonists  COMT inhibitors  MAO-B inhibitors  Anticholinergics  Amantadine

35. 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

36.  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

37.  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

38.  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

39.  Early patients develop motor fluctuations, but may be a function of neuronal cell loss  Increased life expectancy with LD introduction  LD-naive advanced PD patients develop fluctuations almost immediately with LD induction  No LD neuronal dropout in laboratory animals  Recent data suggest possible neuroprotection  Some believe continuous infusion may be safer than pulsatile therapy

40.  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

41. 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)

42.  Newest class of antiparkinsonian drugs: tolcapone, entacapone  MAO 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

43.  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

44.  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

45.  D1, D2 subcortical  D3, D4, D5 cortical  Differentiated biochemically & pharmacologically into two families:  D1 family: D1, D5  D2 family: D2, D3, D4

46. D1D2D3D4D5 Ergot Bromocriptine-++++++ Cabergoline0+++??? Lisuride+++??? Pergolide++++++++++ Non-Ergot Pramipexole0++++++++? Ropinirole0+++++++0 Neurology 1998; 50(suppl 3)

47. T1/2 Dosage (monotherapy) Bromocriptine (Parlodel)6 hr 7.5-30 mg/day Cabergoline65+ hr2-5 mg/day Lisuride2-4 hr1-5 mg/day Pergolide (Permax)12-27 hr 1.5-12 mg/day Pramipexole (Mirapex) 8 hr1-4.5 mg/day Ropinirole (Requip) 4 hr3-24 mg/day

48.  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

49.  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.;

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51.  Provide symptomatic relief  Reduce functional disability  Reduce or delay long-term complications of drug therapy  motor fluctuations  dyskinesia  Slow disease progression: “neuroprotection”

52.  Disease severity  degree of functional impairment  impact on quality of life  Age of patient  comorbidities  risk of acute drug intolerance  risk of long-term complications

53.  Definitive neuroprotective therapy not yet available  Timing of symptomatic therapy is individual  degree of functional impairment  lifestyle of patient

54.  Shorter treatment horizon  Lower risk of long-term complications  Higher likelihood of comorbidities  Levodopa: well tolerated, effective  Use adjunctive medications cautiously  Avoid sedating medications

55.  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

56. 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

57.  Start low and increase slowly  Titrate dosage to efficacy (~200-600 mg/day)  Immediate release  more rapid onset  shorter duration of benefit  generic available  Controlled release  longer duration of benefit  some patients prefer less frequent dosing  Acute side effects: nausea, dizziness, somnolence

58.  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

59.  Bromocriptine, pergolide, pramipexole, ropinirole  Agonist choice is more art than science  Reduce levodopa dosage when adding the agonist  Failure of one does not predict failure of another  Agonists may be switched either gradually or rapidly to a comparable dosage

60.  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

61.  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

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63.  Motor  response fluctuations, dyskinesias, dystonia, freezing, falls  Behavioral/neuropsychological  depression, sleep disorders, psychosis  Autonomic  orthostatic hypotension; hyperhidrosis, constipation, impotence, urinary incontinence or retention

64.  Peripheral causes:  delayed gastric emptying  dietary protein  short plasma half-life  Central causes:  pulsatile delivery to striatal receptors  impaired storage capacity  alteration of DA receptors

65.  Increase LD dose  Increase DCI dose  Add dopamine agonist  Add COMT inhibitor  reduce LD  liver function monitoring  Apomorphine rescue

66.  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

67.  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

68.  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

69.  Sudden and unpredictable off periods unrelated to dosing schedule  One of the hardest features to manage  Dose adjustments, add-ons:  reduce LD, add DA

70.  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

71.  Freezing  motoric block; at initiation of gait, turning, narrow spaces  use auditory, visual, proprioceptive cues  Falls  physical therapy evaluation  cane, wheelchair may be necessary

72.  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

73.  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)

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75.  Ablative  thalamotomy  pallidotomy  Electrical stimulation  VIM thalamus, globus pallidus internus, sub-thalamic nucleus  Transplant  autologous adrenal, human fetal, xenotransplants, genetically engineered transplants

76.  Specific Features:  Dyskinesia70-90 %  Wearing off dystonia70-90 %  Tremor25-60 %  Rigidity25-50 %  Bradykinesia25-50 %  Gait25-50 %

77.  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

78.  All cardinal features of PD noted to improve in open label trials  “Off” UPDRS improved 60%  “On” UPDRS improved 10%  Dyskinesia tends to improve but this is probably due to decreased levodopa dose

79.  Bilateral placement appears to be superior to unilateral placement  Theorized neuroprotective mechanism, but no clinical evidence supporting this  AE: confusion and hallucinations, increased dyskinesia before medication adjustments, eyelid opening apraxia, weight gain, surgical complications

80.  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

81.  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