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Parkinson Disease

Dr Mansour Al-Moallem KKUH

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%.

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.

Genetic factors seem to play greater role in PD in earlier onset. .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. Increased incidence of family history of PD is observed in affected individual (16% vs. 4% of control).

Manganese. Carbon disulfide. Organic solvent. Pesticide Well water.Environmental toxin Cyanide. Methanol. Medications cause Parkinsonisim Metoclopramide Domperidone Reserpine containing anti-hypertensive medication Neuroleptic . etc.

000 / year Prevalence : 100-200 cases /100. though no changes in the pathological process or in the progressive nature of the disease. Post levodopa treatment mortality dropped to 50% .Frequency Internationally Incidence : 10-20 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. .

female ratio in PD 3:2. < 40 years 5 cases / 100. Age Incidence increased by age.000 > 70 years > 700 cases / 100.000 . Some population seem to have lower incidence in South Africans Nigerians black Asian population SEX Male-to.Race PD is word wide spread.000 < 70 years 300-700 cases / 100.

rapid speech) small handwriting slowness in performing activities of daily living sialorrhea .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.

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. assumes a stooped forward posture festinating gait also retropulsive decreased arm swinging in ambulatory activity resting tremor / pill-rolling tremor ( frq. cog wheeling type bradykinesia postural instability . orthostatic hypotension .Physical findings in PD Hands preferentially are affected but legs. chin and head are involved with advanced disease.g. muscle rigidity .

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 .

The investigations include: Plasma ceruloplasmin & copper Thyroid stimulating hormone (TSH) Toxin screening Brain imaging CT-scan or MRI Lumbar puncture Sphincter EMG .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.

Drugs Used In Parkinson Disease 1.Amantadine 5.Methyl Transferase inhibitors .Anticholinergic 6.Monoamine Oxidase B inhibitors 4.Catechol O .Dopaminergic agents 2.Dopamine Agonist 3.

Usually combined with benserazide or carbidopa.Dopaminergic Agents It is the most effective drug for treatment of PD. 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 .

. After several years of favorable response (L-dopa honeymoon) patient often developed disabling motor complication including fluctuation between the on & off state and dyskinesias.L-dopa cont. all symptoms usually improve with limited side effects : psychiatric symptoms orthostatic hypotension nausea High dose may be needed to treat tremor. For 1st 10 years of treatment. 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 .

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. .

Classified into : * Ergot derivates bromocreptine pergolide lisuride cabergoline * Non ergoline apomorphine pramipexole ropinirole .Dopamine Agonist Act directly on dopamine receptors mimicking the endogenous neurotransmitters.

they are not metabolized by oxidative pathway and do not produce free radicals They are commonly used as adjuvant therapy to L.Dopamine Agonist cont.dopa after motor complication but could be used as monotherapy Common side effects * nausea can be alleviated by domperidone * psychiatric such as hallucination . The advantage * reduce motor fluctuation because of longer duration of action * neuroprotective .

Dopamine Agonist cont.dopa. it has shown more effective than bromocreptine. 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. 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.

Apomorphine * Orally reduce on & of phenomenon but it use limited by side effects ( nausea. * It give quick response but limited use due to complexity. * It can be given by repeated injection subcutaneously or by continue infusion. . Cabergoline (D2) * It is effective as adjuvant therapy in advanced PD.Dopamine Agonist cont. * No very effective as monotherapy. postural hypotension & sedation).

* It is also inhibit re-uptake of dopamine from synaptic cleft * Adding selegeline to L-dopa. it may enhanced the side effects of L-dopa such as dyskinesias. * The combination with L-dopa . postural hypotension and psychiatric problem. allow to reduce the dose of L-dopa by 10-15% up to 30%. * Selectively & irreversibly inhibits intra and extracellullar MOAB which delay breakdown of dopamine to dihydroxy phenyl acetic acid and hydrogen peroxide (oxidative to dopamine neurons). . * The use as monotherapy may delay the need for L-dopa by one year.Monoamine Oxidase B inhibitor * Selegeline is an example of this class.

Increase dopamine synthesis ? . lividoreticularis and ankle edema . * 2/3 of patients showed improvement as monotherapy but benefit short lived.Has mild anticholinergic action * It has mild effect on resting tremor. * Caution in renal failure as it is excreted in urine. * Side effects include : hallucination. * In combination. nightmares.Amantadine * Antiviral agent * Mechanism not Known .Pre-synaptic reuptake blocker ? . it reduce L-dopa induced dyskinesias. insomnia.

Anticholinergics * Examples: Biperiden Procyclidine Orphenadrine Benzhexol Benztropine * All mildly effective and may improve tremor and stiffness more than akinesias. impaired concentration and confusion * They should be used cautiously in elderly . side effects include : glaucoma. * Due to peripheral parasympathomimetic action. urinary retention. constipation. dryness of mouth. blurred vision.

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 .

after 3 years in 2 groups of (L-dopa + placebo ) and (L-dopa+selegeline): no clinical difference . Selegeline Amantadine Evidence not very strong e..g.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.

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 .

* Antcholinergic should be avoided as it cause more confusion. * Selegeline has no advantage to delay L-dopa. (above 70 years) * L-dopa remain the best choice even early with wide therapeutic range and less psychiatric problems. . * Dopamine agonist and amantadine can be tried.Early treatment in old pts.

more frequent dose of L-dopa eg 5-6 times/daily .end -of .Subcutaneous apomorphine or continuous infusion .addition of COMT inhibitor eg entacapone to L-dopa and carbidopa .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 .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 . * To avoid wearing off .early morning akinesias .slow release formulation . Stalevo .

More common in young patient. Trial of adding dopamine agonist.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 : .Dyskinesias * Generally difficult to manage.Diphasic dyskinesia (at beginning or end of the dose) Often refractory to medical treatment. * In : . amantadine or overlapping L-dopa dose may help.Peak dose dyskinesia . .

apomorphine injection .period dystonia * Commonly occurred in the morning * It may be associated with dysphoria including panic attack.lithium .botulinium toxin into dystonic muscle . depression. delusion or hallucination * Can be avoided by .dispersible L-dopa preparation on waking up .Off .

good diagnosis. * Good cognitive functions. * Optimal medication but not effective or major side effects.Surgical treatment for PD * Advanced. * No contraindication for surgery. Modalities of surgery * Deep brain simulation * Destructive surgery * Transplantation .

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 .

Destructive surgery * Pallidotomy .Good response for : tremor .Bilateral surgery is not preferable .Performed under local anesthesia . rigidity and dyskinesias * Thalamotomy Usually reserve for patient with drug-induced tremor .Used for advanced conditions by thermo coagulation at postero-ventral part of pallidum for the contra-lateral side .

mainly from pig mesencephalon .not commonly used .Xenograft .increased morbidity & mortality from adrenalectomy 3 .ethical concern .Transplantation 1 .Fetal mesencephalon graft .Adrenal medulla transplant .insufficient tissue 2 .efficacy not determine yet .

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  .

Prevention Breathing exercises. postural re-education and trunk exercises. If pulmonary function progressively worsens.Cardiopulmonary impairment Flexed posture can lead to kyphosis and cause a reduction in pulmonary capacity and restrictive lung disease pattern. assisted coughing technique by respiratory therapy. .

caution to avoid worsening in the symptoms of  of Parkinson and agitation  .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.

vomiting and malabsorbtion . Management include : Frequent smaller meals Increase bulking agent Stool softeners Suppositories *Urinary incontinence. Management usually based on results of investigation . retention and bladder infection.*Impaired intestinal motility can lead to constipation.

*Erectile dysfunction Management include : Medication such as sildenafil Pump Prosthetic device .

Thank you .