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Slide 1 :
Parkinson Disease Dr Mansour Al-Moallem KKUH
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Described by James Parkinson in 1817 Degeneration of dopamine producing cells in the substantia nigra resulting in decreased level of dopamine in the striatum. Exact effect of dopamine in movement is not clear since 4 kind of post synaptic receptors for dopamine has its own anatomical distribution & pharmacological action. Symptoms begin to appear when dopamine level drop to 50%.
Slide 3 :
The theories include : Accelerated ageing: Aging is associated with decreased of pigmented neurons in the substantia nigra & with decreased level of striatal dopamine & dopa decarboxylase. Some authorities believe it may result from the effects of aging superimposed on an insult to the nigrostriatal system earlier in life.
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Oxidative Stress It received much support & attention in recent literatures as damage from multiple free radicals . Dopamine oxidation may result from hydrogen peroxide which can undergo reactions with ferrous ions resulting in formation of high toxic hydroxyl radicals which cause cell membrane damage. Genetic Susceptibility Twin studies often have proven inconclusive. Genetic factors seem to play greater role in PD in earlier onset. Increased incidence of family history of PD is observed in affected individual (16% vs. 4% of control).
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Environmental toxin Cyanide, Manganese, Carbon disulfide, Pesticide Well water, Methanol, Organic solvent, etc. Medications cause Parkinsonisim Metoclopramide Domperidone Reserpine containing anti-hypertensive medication Neuroleptic
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Frequency Internationally Incidence : 10-20 cases / 100,000 / year Prevalence : 100-200 cases /100,000 population Mortality / Morbidity Before levodopa Disability & death : 25% within 5 years of onset 65% in next 5 years 89% in 15 years Mortality rate for PD 3 times of matched general population. Post levodopa treatment mortality dropped to 50% , though no changes in the pathological process or in the progressive nature of the disease.
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Race PD is word wide spread. Some population seem to have lower incidence in South Africans Nigerians black Asian population SEX Male-to- female ratio in PD 3:2. Age Incidence increased by age. < 40 years 5 cases / 100,000 < 70 years 300-700 cases / 100,000 > 70 years > 700 cases / 100,000
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The History * Symptoms & signs in PD typically begin in one extremity or one side but eventually involve other limbs and trunk * The classical triad of PD TREMOR + RIGIDITY + AKINISIA. * Symptoms reported by patients can include the following: stiffness & slowed movements tremor or shaking at rest difficulty getting out of chair or rolling in bed frequent falls or tripping difficulty walking memory loss speech changes (whispering, rapid speech) small handwriting slowness in performing activities of daily living sialorrhea
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Physical findings in PD Hands preferentially are affected but legs, chin and head are involved with advanced disease. muscle rigidity , cog wheeling type bradykinesia postural instability , assumes a stooped forward posture festinating gait also retropulsive decreased arm swinging in ambulatory activity resting tremor / pill-rolling tremor ( frq. 3-5 Hz) masked facies micrographia dysarthria hypokinetic, monotonous low volume painful dystonia dementia depression up to 50% akathisia inability to sit still seborrheic dermatitis face & scalp autonomic dysfunction e.g. orthostatic hypotension
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Deferential diagnosis: Progressive supranuclear palsy Multisystem atrophy Shy-drager syndrome olivopontocerebellar atrophy Wilson disease Multiple strokes Subdural hematoma Normal pressure hydrocephalus Basal ganglion lesion (vascular or tumor) hypothyroidism & hyperparathyroidism Post encephalitis Creutzfeldt – Jacob disease
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Laboratory Studies : Diagnosis of PD is based almost entirely on history and physical examination . In atypical cases lab. investigation should be performed to exclude other cases of Parkinsonism. Up to 25% of patients with a diagnosis of PD in life are shown to have a different diagnosis when postmortem carried out. The investigations include: Plasma ceruloplasmin & copper Thyroid stimulating hormone (TSH) Toxin screening Brain imaging CT-scan or MRI Lumbar puncture Sphincter EMG
Slide 12 :
Drugs Used In Parkinson Disease 1- Dopaminergic agents 2- Dopamine Agonist 3- Monoamine Oxidase B inhibitors 4- Amantadine 5- Anticholinergic 6- Catechol O - Methyl Transferase inhibitors
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Dopaminergic Agents It is the most effective drug for treatment of PD. Usually combined with benserazide or carbidopa, both do not cross BBB but inhabit peripheral conversion by blocking aromatic acid decarboxylase with advantage of reducing the requiring dosage increase central delivery reducing the side effects It is decarboxylated in the presynaptic terminals to form dopamine
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L-dopa cont. For 1st 10 years of treatment, all symptoms usually improve with limited side effects : psychiatric symptoms orthostatic hypotension nausea High dose may be needed to treat tremor. After several years of favorable response (L-dopa honeymoon) patient often developed disabling motor complication including fluctuation between the on & off state and dyskinesias. This fluctuation related to increase loss of dopaminergic nerve terminal so L-dopa can not be longer store and the effect depend on the plasma level .
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L-dopa cont. There is theoretical concern that L-dopa is neurotoxic and it has the potential to form radicals and other toxic metabolites which injure surviving dopaminergic neurons & speeding progression of PD. It appears prudent to delay treatment with L-dopa and to star with other medication.
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Dopamine Agonist Act directly on dopamine receptors mimicking the endogenous neurotransmitters. Classified into : * Ergot derivates bromocreptine pergolide lisuride cabergoline * Non ergoline apomorphine pramipexole ropinirole
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Dopamine Agonist cont. The advantage * reduce motor fluctuation because of longer duration of action * neuroprotective , they are not metabolized by oxidative pathway and do not produce free radicals They are commonly used as adjuvant therapy to L- dopa after motor complication but could be used as monotherapy Common side effects * nausea can be alleviated by domperidone * psychiatric such as hallucination
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Dopamine Agonist cont. Bromocreptine (D2) * It is the most one studies as monotherapy * It showed good response in 1/3 of patients without L- dopa for the initial 2-5 years Pergolide (D1+D2) * In comparative review as adjunctive to L- dopa, it has shown more effective than bromocreptine. Pramipexole ((D2+D3) * Effective as add-on therapy in advanced PD with motor fluctuation. Ropinirole (D2+D3) * Probably equally effective as L-dopa in early mid PD * As an adjunct to L-dopa , it reduces motor fluctuation * On-going study suggests more effective as monotherapy than bromocretine.
Slide 19 :
Dopamine Agonist cont. Cabergoline (D2) * It is effective as adjuvant therapy in advanced PD. * No very effective as monotherapy. Apomorphine * Orally reduce on & of phenomenon but it use limited by side effects ( nausea, postural hypotension & sedation). * It can be given by repeated injection subcutaneously or by continue infusion. * It give quick response but limited use due to complexity.
Slide 20 :
Monoamine Oxidase B inhibitor * Selegeline is an example of this class. * Selectively & irreversibly inhibits intra and extracellullar MOAB which delay breakdown of dopamine to dihydroxy phenyl acetic acid and hydrogen peroxide (oxidative to dopamine neurons). * It is also inhibit re-uptake of dopamine from synaptic cleft * Adding selegeline to L-dopa, allow to reduce the dose of L-dopa by 10-15% up to 30%. * The use as monotherapy may delay the need for L-dopa by one year. * The combination with L-dopa , it may enhanced the side effects of L-dopa such as dyskinesias, postural hypotension and psychiatric problem.
Slide 21 :
Amantadine * Antiviral agent * Mechanism not Known - Increase dopamine synthesis ? - Pre-synaptic reuptake blocker ? - Has mild anticholinergic action * It has mild effect on resting tremor. * 2/3 of patients showed improvement as monotherapy but benefit short lived. * In combination, it reduce L-dopa induced dyskinesias. * Caution in renal failure as it is excreted in urine. * Side effects include : hallucination, insomnia, nightmares, lividoreticularis and ankle edema
Slide 22 :
Anticholinergics * Examples: Biperiden Procyclidine Orphenadrine Benzhexol Benztropine * All mildly effective and may improve tremor and stiffness more than akinesias. * Due to peripheral parasympathomimetic action, side effects include : glaucoma, dryness of mouth, blurred vision, constipation, urinary retention, impaired concentration and confusion * They should be used cautiously in elderly
Slide 23 :
Catechol O-Methyl Transferase inhibitors (COMT) * Significant peripheral metabolite of L-dopa is mediated by COMT * Addition of COMT inhibitor as adjunction therapy to L-dopa and either carbidopa or benserazide , reduce peripheral and prolonged half life of L-dopa * Side effects: potentiates dyskinesias nausea sleep disturbance orange discoloration of the urine * The drug available in form Tolcapone : (withdrawn from the market) hepatic toxicity & severe diarrhea Entacapone : more save
Slide 24 :
Treatment Strategies Optimal treatment of PD is still controversial mainly based on empirical experience * when to start - neuroprotection - symptomatic * which drug should be selected Neuroprotection for possible halting or reverse progression E.g.. Selegeline Amantadine Evidence not very strong e.g.. after 3 years in 2 groups of (L-dopa + placebo ) and (L-dopa+selegeline): no clinical difference
Slide 25 :
Early treatment in young pts.(under 50 years) * Best to delay the use of L-dopa as long as possible * Start with selegeline as monotherapy * Amantadine and anticholinergic can be tried (They give modest benefit & may be not enough ) * Dopamine agonist as monotherapy (better to be introduced with domperidone) * Eventually symptoms will not sufficiently control and L-dopa has to be added and when start use smaller dose or sustained release
Slide 26 :
Early treatment in old pts. (above 70 years) * L-dopa remain the best choice even early with wide therapeutic range and less psychiatric problems. * Antcholinergic should be avoided as it cause more confusion. * Dopamine agonist and amantadine can be tried. * Selegeline has no advantage to delay L-dopa.
Slide 27 :
Management of late stage * After five years about half of the patient develop motor fluctuation or dyskinesias that may be difficult to treat * Commonly 1st fluctuations to occur - early morning akinesias - end -of - dose deterioration (wearing off) * Motor fluctuating could dramatic from on to off in second due to depletion of dopaminergic neurons and delayed gastric emptying or high protein diet . * To avoid wearing off - more frequent dose of L-dopa eg 5-6 times/daily - slow release formulation - addition of COMT inhibitor eg entacapone to L-dopa and carbidopa ; Stalevo - Subcutaneous apomorphine or continuous infusion
Slide 28 :
Dyskinesias * Generally difficult to manage. * In : - Peak dose dyskinesia - Square wave (persist through the on period) dyskinesia Some time possible to treat by reducing the dose of L-dopa or partial replacement of L-dopa by dopamine agonist. * In : - Diphasic dyskinesia (at beginning or end of the dose) Often refractory to medical treatment. More common in young patient. Trial of adding dopamine agonist, amantadine or overlapping L-dopa dose may help.
Slide 29 :
Off - period dystonia * Commonly occurred in the morning * It may be associated with dysphoria including panic attack, depression, delusion or hallucination * Can be avoided by - dispersible L-dopa preparation on waking up - apomorphine injection - lithium - botulinium toxin into dystonic muscle
Slide 30 :
Surgical treatment for PD * Advanced, good diagnosis. * Optimal medication but not effective or major side effects. * Good cognitive functions. * No contraindication for surgery. Modalities of surgery * Deep brain simulation * Destructive surgery * Transplantation
Slide 31 :
Deep brain stimulation * Implantation electrodes inside the subthalamus connected to pacemaker implanted under the skin * To perform any activity , patient has to switch on the device with help of patient programmer * It regress the stiffness and tremor * It can be adjusted according to patient need * The pacemaker can last for 5 years and the electrodes for life * It reduce the need for medications by 50-75% resulting in improving drug induced side effects * Can be done in both sides
Slide 32 :
Destructive surgery * Pallidotomy - Used for advanced conditions by thermo coagulation at postero-ventral part of pallidum for the contra-lateral side - Performed under local anesthesia - Bilateral surgery is not preferable - Good response for : tremor , rigidity and dyskinesias * Thalamotomy Usually reserve for patient with drug-induced tremor
Slide 33 :
Transplantation 1 - Fetal mesencephalon graft - ethical concern - insufficient tissue 2 - Adrenal medulla transplant - not commonly used - increased morbidity & mortality from adrenalectomy 3 - Xenograft - mainly from pig mesencephalon - efficacy not determine yet
Slide 34 :
Other medical problems Autonomic dysfunction is common Among PD * Orthostatic hypotension especially at late stage Management include Arising slowly Elevating bed Using pressure garments Consuming a high-salt diet Medication : pseudoephedrine mineralocorticids
Slide 35 :
Cardiopulmonary impairment Flexed posture can lead to kyphosis and cause a reduction in pulmonary capacity and restrictive lung disease pattern. Prevention Breathing exercises, postural re-education and trunk exercises. If pulmonary function progressively worsens, assisted coughing technique by respiratory therapy.
Slide 36 :
Dysphagia If swallowing difficulties do not respond to conservative intervention then consider more aggressive management such as nasogastric tube or gastrostomy Depression It may be related to a deficit in serotonergic neurotransmission decreased cortical level of norepinephrine and dopamine. It can occur in approximately 50% of PD Selective serotonin reuptake inhibitor (SSRI) is the best selection, caution to avoid worsening in the symptoms of of Parkinson and agitation
Slide 37 :
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increased morbidity & mortality from adrenalectomy. 3Xenograft.mainly from pig mesencephalon.effica
increased morbidity & mortality from adrenalectomy. 3Xenograft.mainly from pig mesencephalon.efficacy not determine yet. Other medical problems ...
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