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PARKINSON’S DISEASE Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin James Parkinson Born Died Cause of death Nationality Ethnicity Occupation Known for Spouse(s) 11 April 1755 Shoreditch, London, England 21 December 1824 (aged 69) Langthorne, North Yorkshire, England Stroke British White British Surgeon First description of Parkinson's disease Mary Dale 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 MedicoChirurgical Society (1812) Founding member of Huntarian Society (1819) Gold Medalist of Royal College of Surgeons (1822) Classification of Parkinson Syndromes in a Community 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 Descriptive Epidemiology of Parkinson Syndrome • Incidence – 5-24/ 105 worldwide (USA: 20.5/105) – Incidence of PS/PD rising slowly with aging population • Prevalence – 57-371/105 worldwide (USA/Canada 300/105) – 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 Pathology of Parkinson’s Disease A B C a) b) c) d) Normal substantia nigra Severe depigmentation due to loss of nigral neurons in PD. Loss of pigmented neurons in the PD brain Lewy body D 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 Normal Basal Ganglia Functional Anatomy Normal Cortex Cingulate Sensory Motor Prefrontal Insular + GPe D2 - D1 + Premotor Prefrontal + + Thalamus VA/VL + = excitatory SNc STN - + Striatum Suppl. Motor Premotor + + + + SNr GPi - - = inhibitory - Brainstem SC Functional Anatomy of Parkinson’s Disease Parkinson’s Disease Cortex Cingulate Sensory Motor Prefrontal Insular + GPe + Striatum D2 - D1 + Premotor Prefrontal + + Thalamus VA/VL -+ = excitatory SNc STN -- Suppl. Motor Premotor + ++ ++ ++ - = inhibitory SNr GPi - -- Brainstem SC 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 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 autosomalrecessive juvenile parkinsonism • Environment – Majority of cases believed caused by environmental factor (s) but none identified so far • Genes plus environment? 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 Schematic representation of the mechanisms involved in toxicity of 1methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP). BBB, blood— brain barrier;MPDP+, 1methyl-4-phenyl-2,3dihydropyridinium; MPTP 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; MPP+, its four-electron oxidation product 1-methyl-4phenylpyridinium; MAO, monoamine oxidase. 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 Additional Signs and Symptoms • Difficulty arising from a chair • Difficulty turning in bed • Hypophonic speech • Sialorrhea • Loss of the sense of smell • Foot dystonia Criteria for Diagnosis • 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 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 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 Neurodegenerative disorders with Parkinsonism (II) • Multiple system atrophy –Shy-Drager syndrome • Autonomic insufficiency— orthostasis, impotence –Striatonigral degeneration • Tremor less prominent –Olivopontocerebellar atrophy • Cerebellar signs 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 Differential Diagnosis of PD: Secondary Parkinsonism • • • • Drug-induced Toxin-induced Metabolic Structural lesions (vascular parkinsonism, etc.) • Normal pressure Hydrocephalus • Infections Toxin-induced Parkinsonism • MPTP • Carbon monoxide • Manganese • Cyanide Vascular Parkinsonism • Abrupt onset, usually unilateral • Step-wise or no progression • Other signs—hemiparesis, aphasia, hyperreflexia • Infarcts on neuroimaging helpful in confirming diagnosis Hydrocephalus-induced Parkinsonism (NPH) • Can be communicating or obstructive • Normal pressure hydrocephalus— idiopathic • Clinical triad: –parkinsonism/gait disorder –urinary/fecal incontinence –dementia Treatment Options • Preventive treatment – No definitive treatment available • Symptomatic treatment – Pharmacological – Surgical • Non-motor management • Restorative—experimental only – Transplantation – Neurotrophic factors Drug Classes in PD • Dopaminergic agents –Levodopa –Dopamine agonists • COMT inhibitors • MAO-B inhibitors • Anticholinergics • Amantadine Sites of Action of PD Drugs Substantia Nigra selegiline Amantadine* levodopa GABA DA BBB carbidopa benserazide tolcapone entacapone Dopamine agonists bromocriptine pergolide pramipexole ropinirole ACh Striatum baclofen trihexiphenidyl 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 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 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 tricyclic and SSRI antidepressants Levodopa/Carbidopa Formulations Onset Duration Immediate Release 10/100, 25/100, 25/250 20-40 min 2-4 hr Controlled Release 25/100, 50/200 30-60 min 3-6 hr “Liquid levodopa” (dissolved tablets) 10-20 min 0.5-1 hr 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 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 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 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 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 DAs: Receptor Effects D1 D2 D3 D4 D5 Ergot Bromocriptine ++ ++ + + Cabergoline 0 +++ ? ? ? Lisuride + ++ ? ? ? Pergolide + +++ +++ + + ++ ++++ ++ 0 Non-Ergot Pramipexole 0 Ropinirole 0 Neurology 1998; 50(suppl 3) 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 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 TDS. – domperidone 20 mg TDS; not available in U.S. 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 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 symptoms Levodopa, dopamine agonist, COMT inhibitor 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 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 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 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 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 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 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 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 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) 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 Improvements with Pallidotomy • Specific Features: –Dyskinesia –Wearing off dystonia –Tremor –Rigidity –Bradykinesia –Gait 70-90 % 70-90 % 25-60 % 25-50 % 25-50 % 25-50 % 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 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 • 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