Parkinson’s Disease superKAT :)

Parkinsonism Neurological syndrome Combination of: 77% -PD Rest tremors Rigidity Bradykinesia 77% -PD 12% -Parkinson plus syndromes 5% -Drug induced Parkinsonism *not recognized early

Primary/idiopathic parkinsonism Parkinson’s disease Juvenile parkinsonism Secondary Infectious, drugs, toxins, vascular, trauma Heredodegenerative parkinsonism Huntington’s Wilson Multiple-system degeneration/ parkinsonism-plus CBD (Cortical-Basal Ganglionic Degenration) LBD (Lytico-Bodig) Multisystem atrophy PSP (Progressive Supranuclear Palsy)

Definition – Parkinson’s Described by James Parkinson in 1817 as the “shaking palsy” Chronic progressive disorder occurring in the Central Nervous System Results from degeneration of dopamine-producing cells in the susbtantia nigra susbtantia nigra pars compacta – degenerate more pars reticularis

2nd most common neurodegenerative disease after Alzheimer’s disease Age-related, progressive disorder Dopamine, critical modulator of striatal output, is markedly decreased PD = control fine skillful movements

Prevalence PD is estimated to affect 100-180 in 100,000 Annual incidence of 4-20 per 100,000 Rising prevalence with age Male: Female ratio is 3:2 M>F

Pathogenesis Neurogenerative Loss of dopaminergic input to basal ganglia (extrapyramidal system) Result in imbalance with dopamine and acetylcholine Acetylcholine > Dopamine

Etiology Unknown Oxidative stress Proposed etiology Aging Environmental toxins Genetic susceptibility

Oxidative stress theory Increased iron level Lack of compensatory rise in isoferritins (iron-containing protein) Increased aluminum levels Reduced glutathione levels Selective defect in complex I of mitochondrial respiratory chain Evidence of oxidative damage to Lipids, DNA, proteins, tyrosine-containing molecules

Oxidative stress Mitochondrial dysfunction Excitotoxicity

Genetics Young onset < 40yrs Juvenile onset < 20yrs Parkin mutations: parkin gene Mutations in the alpha synuclein and ubiquitin carboxy hydrolase: seen in autosomal dominant PD

Pathology Loss of dopaminergic (DA) cells located in susbtantia nigra: most symptoms do not appear striata DA levels decline by at least 70-80%

Pathophysiology Degeneration of substantia nigra Reduced production of dopamine

Clinical Manifestations Bradykinesia – bumabagal Tremor Rigidity *Stooped posture

Symptoms T- Tremors at rest R- Rigidity A- Akinesia/Bradykinesia P- Postural instability

Tremors 4-6Hz Resting Disappears with voluntary movement Disappears with sleep Accentuated by stress/anxiety Pill rolling *Essential tremor & Physiology tremors 8-12 Hz and are kinetic and/or postural

Limb rigidity Resistance to passive movements of limbs Involuntary hypertonia Cogwheel

Bradykenisa Decreased speed and amplitude of complex voluntary movements Slowness and initiating and sustaining movement Fragmented Micrographia – lack of movement of the arm/difficulty Tapping fingers Twiddling

Postural instability Stooped, nanginginig ang kamay Shuffling gait Righting reflex equilibrium

Diagnosis Diagnosis depends on clinical findings Tests(include imaging) are most often used to rule out etiology of secondary Parkinson’s disease New technologies (PET scan) are used to visualize dopamin

Diagnosis Presence of at least 2 of the 3 cardinal features of parkinsonism: Tremor Rigidity Bradykinesia Presence of at least 2 of the ff: Marked response to levodopa Asymmetry of signs Asymmetry at onset Evidence of disease progression

Stages Stage O – No clinical signs evident Stage I – Unilateral involvement Stage II – Bilateral Stage III – Postural (minimal) problems Stage IV – Postural with need of assistance Stage V - Bedridden

Differential Diagnosis DISEASE HISTORY PHYSICAL Idiopathic Parkinson’s gradual onset of tremor gait disturbance slowed movement resting tremor cogwheel rigidity Drug induced parkinsonism exposure to haloperidol or metoclopramide similar to idiopathic PD Essential Tremor present for many years family history tremor w/ arms raised head involved Multisystem atrophy parkinsonism w/ autonomic system dysfunction Orthostatic Hypotension Hypotension skin changes Huntington’s disease involuntary movement cognitive or behavioral problem Chorea loose tone early dementia

Treatment Non-pharmacological approach Pharmacologic approach Exercise, nutrition Pharmacologic approach Neuroprotective treatment MAO B and Dopamine 4 classes: Anticholinergic (for resting tremor) Precursor of dopamine (carbidopa/levodopa) Direct-acting dopamine agonist Indirect-acting dopamine agonist

Drug therapy A. trycyclic antidepressants B. Beta blockers C. Antihistamine

Factors Age Comorbidities Severity of symptoms Cognitive function * For treatment plan

Management Treatment strategies Symptomatic relief Levodopa Amantadine Anticholinergic COMT inihibitors Surgery Symptomatic with neuroprotection Dopamine agonist MAO B inhibitors

Pharmacologic Options Levodopa Anticholinergic Amantadine Selegeline Catechol-O-methyltransferase (COMT) Inhibitor Dopamine Agonist

Levodopa Cabidopa-levodopa combination Taken up by dopamine nerve terminals in the striatum Converted to dopamine by dopa decarboxylase Released and acts at the dopamine receptors

Levodopa Mainstay of therapy Produce immediate symptomatic response Long-term use leads to dykinesias and motor response fluctuations Development of nonlevodopa-responsive features (freezing, autonomic dysfunction)

ANTICHOLINERGIC Block muscarinic cholinergic receptors Restore motor function Trihexiphenidyl

Anticholinergic Can be efficacious for tremors and dsystonia (agonist and antagonist acting simultaneously) May be used as secondary pharmacologic option Peripheral side effects – dry mouth, blurred vision, urinary retention, constipation CNS side effects: confusion, memory loss

Amantadine Improves bradykinesia and tremor Can be used as monotherapy or as adjunct therapy to levadopa Antiparkinsonian MOA is not completely understood – indirect dopamine agonist Restlessness, confusion, depression, nausea and hypotension Used to treat influenza Short term benefits

Selegeline Monoamine oxidase-B (MAO-B) inhibitor Reduces dopamine metabolism

Selegeline Postulated to have neuroprotective effect Reduce oxidative stress Reduce free radical production No benefit in producing Nausea and hallucinations

Catechol-O-methyltransferase (COMT) Inhibitor Increase the bioavailability of levadopa Useful adjunct in early stage of PD and in patients w/ mild response fluctuations Rare hepatocellular injury Possible neurotoxicity in PD

Dopamine Agonist Binds to dopaminergic receptors Restoration of effective neurotransmission

Dopamine Agonist Directly acting on the dopamine receptors Postulated to provide neuroprotection No conversion to dopamine Do not produce toxic metabolites Dec. endogenous dopamine turnover, decrease risk of oxidative stress Monotherapy in early stage of PD – delay levodopa Hypotension, nausea, vommiting and hallucinations

Dopamine Agonist Piribidel (Trivastal) Pramipexole (Sifrol) – indicated for both early and advanced stages of PD; selectively binds to dopamine receptors and activate D2 receptor but with little or no affinity to the D1 receptor. Has greater affinity for D3 receptor than D2. Ropinerole (Requip) – same as Pramipexole Bromocriptine

Surgical Options Pallidotomy Thalamotomy Thalamic stimulation Transplantation of fetal cells

Globus pallidus internus (Gpi) pallidotomy – resection of parts of Gpi. Deep brain stimulation Fetal nigral transplantation – not very successful

Nonpharmacologic Management Early Stage Advanced Stage Education -selective info -aimed at promoting general health Refer to PD organization -problem oriented Support -emotional needs assessment -support network assessment -financial/occupational counseling -Psychological counseling -respite care Exercise -aerobics, stretching -improves mood and mobility -improves postural equilibrium reaction -physiotherapy referral -PD exercise group -energy conservation techniques Nutrition -balanced diet -fibers and fluids vs constipation -calcium vs bone mass loss -dietetic referral -help preparing food -meal deliveries

Secondary Effects of PD Cardiovascular effects – orthostatic hypotension GI tract – constipation, arrhythmia Genitourinary effects – impotence, increase in urinary frequency CN effects – hallucinations, depression, psychosis

Late Disabilities Levodopa-related disabilities Toxicity Dyskinesia reduced response motor fluctuations Non-levodopa-related disabilities Cognitive impairment Dysphagia speech and language disturbance instability

Bleh Urinary urgency Urinary tension Pain Dysphonia Panic attacks