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PARKINSON'S DISEASE PARKINSON'S DISEASE

Dr.Mohammad Shaikhani.Assistant professor

Sulaimanyah college of Medicine.Dept of Medicine.

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PARKINSON'S DISEASEPARKINSON'S DISEASE A number of degenerative diseases affecting the basal ganglia. Parkinsonism: differing combinations of slowness of movement

(bradykinesia), increased tone (rigidity), tremor & loss of postural reflexes(akinetic-rigid syndromes).

Parkinsonism have many causes. The most common cause of parkinsonism is idiopathic Parkinson's

disease.

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IDIOPATHIC PARKINSON'S DIS: IDIOPATHIC PARKINSON'S DIS: Annual incidence 0.2/1000 & prevalence of 1.5/1000. Prevalence rates are similar throughout the world,except lower rates in

China /West Africa. The incidence/ prevalence increase with age, to 1% > 60. 10% < 45 years at presentation,. Sex incidence is about equal. It is less common in cigarette smokers.

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Aetiology: Aetiology: The cause is unknown. No strong genetic factors, but genetic influence may be greater than

previously thought. The discovery that methyl-phenyl-tetrahydropyridine (MPTP) caused

severe parkinsonism in young drug users suggests that the idiopathic disease might be due to an environmental toxin.

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Pathology: Pathology: There is depletion of the pigmented dopaminergic neurons in the

substantia nigra, hyaline inclusions in nigral cells (Lewy bodies), atrophic changes in the substantia nigra& depletion of neurons in the locus coeruleus.

Reduced dopaminergic output from the substantia nigra to the globus pallidus leads to reduced inhibitory effects on the subthalamic nucleus, neurons of which become more active than usual in inhibiting activation of the cortex.

This in turn results in bradykinesia.

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Clin ical features: Clin ical features: The classical syndrome: tremor, rigidity&bradykinesia These may be absent initially, when non-specific symptoms of tiredness, aching

limbs, mental slowness, depression & small handwriting (micrographia) may be noticed.

Almost always unilateral, a resting tremor in an upper limb being a common presenting feature.

The tremor may also affect the legs, mouth & tongue. It may remain the predominant symptom for some years. Bradykinesia may develop gradually. Most have difficulty with rapid fine movements, as slowness of gait &difficulty

with tasks as fastening buttons, shaving or writing. Rigidity, or increased muscular tone, causes stiffness&a flexed posture. Postural righting reflexes are impaired early, but falls tend not to occur until later. As it advances, speech becomes softer & indistinct. There are a number of abnormalities on neurological examination.

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Clin ical features: Clin ical features: Although parkinsonian features are initially unilateral, gradual bilateral

involvement is the rule. Muscle strength / reflexes remain normal, plantar responses are flexor. There is a paucity of facial expression (hypomimia)& the blink reflex

may be exaggerated & fail to habituate (glabellar tap sign). Eye movements are normal to standard clinical testing, provided

allowance is made for the normal limitation of upward gaze with age. Sensation is normal & intellectual abilities are not affected initially. As the disease progresses, 1/3 develop cognitive impairment

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Clin ical features: Clin ical features:

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Clin ical features: Clin ical features:

General

Expressionless face(pocker face). Greasy skin Soft, rapid, indistinct speech Flexed posture Impaired postural reflexes

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Clin ical features: Clin ical features: Gait

Slow to start walking Shortened stride Rapid, small steps, tendency to run (festination) Reduced arm swing Impaired balance on turning

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Clin ical features: Clin ical features: Tremor

Resting 4-6 Hz Usually first in fingers/thumb Coarse, complex movements, flexion/extension of fingers Abduction/adduction of thumb Supination/pronation of forearm May affect arms, legs, feet, jaw, tongue Intermittent, present at rest & when distracted Diminished on action

Postural 8-10 Hz

Less obvious, faster, finer amplitude Present on action or posture, persists with movement

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Clin ical features:Clin ical features:

Rigidity

Cogwheel type, mostly upper limbs Plastic (leadpipe) type, mostly legs

Rigidity

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Clin ical features:Clin ical features:

Rigidity

Bradykinesia

Slowness in initiating or repeating movements Impaired fine movements, especially of fingers

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Investigations:Investigations:• The diagnosis is made clinically, as there is no diagnostic test for

Parkinson's disease.

• Sometimes necessary to exclude other causes of parkinsonism if there are any unusual features.

• Patients presenting before the age of 50 are usually tested for Wilson's disease

• Imaging (CT or MRI) of the head may be needed if there are any features suggestive of pyramidal, cerebellar or autonomic involvement,

or the diagnosis is otherwise in doubt.

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Investigations:Investigations:• Causes of parkinsonism:• Toxins (manganese, CO poisoning), CNS infs, structural

lesions, metabolic disorders, other neurologic disorders. • Most are rare& suggested by atypical features, history

or exam.• Routinely needed to consider 2 alternative diagnoses: • Drug-induced parkinsonism• “Parkinsonism-plus” syndromes: parkinsonian features

with other neurological signs atypical of parkinson disease.

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Drug-induced parkinsonism:Drug-induced parkinsonism:• Important because it is reversible, although may require weeks or

months after discontinuation.

• Accounted for 20%.

• Dopamine antagonists;neuroleptic agents, atypical neuroleptic agents, antiemetic drugs,CCB (flunarizine ,cinnarizine).

• Amiodarone, valproic acid,lithium,by uncertain mechanisms.

• Dopamine antagonists also exacerbate Parkinson’s disease& should be avoided, if possible, in the treatment of patients with the disease.

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Parkinson-plus syndromes:Parkinson-plus syndromes:

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Parkinson-plus syndromes:Parkinson-plus syndromes:• 25%.• Features suggesting other conditions include:• Falls or dementia early in the course of the disease• Symmetric parkinsonism• Wide-based gait• Abnormal eye movements• Babinski signs• Marked orthostatic hypotension• Urinary retention• Development of marked disability within 5 ys after the onset.• Responsdsc poorly to antiparkinsonians, have a worse prognosis than

idiopathic PD.• Neurologic consult needed if the clinical features suggest other diagnosis.

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ManagementManagement :drugs:drugs

COMTEtancap

Dopamin

DDDDI

L-Dopa

DDDDI

Dopamin

MAO-BSeliglein

COMTEtancap

DOP recstriatum

Niagrostriatal neuron

BBBProtein diet -ve

Amantadin

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ManagementManagement :drugs:drugs• Levodopa + peripheral-acting dopa-decarboxylase inhibitor. • Anticholinergic drugs• Dopamine receptor agonists• MAOB inhibitor selegiline.• COMT inhibitors.• Amantadine.

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1. 1. levodopalevodopa• Levodopa combined with a peripheral-acting dopa-decarboxylase

inhibitor provides the mainstay of treatment but should only be started to help overcome significant disability.

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Levo-dopa:Levo-dopa:• Although the number of dopamine-releasing terminals in the striatum is

diminished in Parkinson's disease, remaining neurons can be driven to produce more dopamine by administering its precursor, levodopa.

• If levodopa is administered orally, > 90% is decarboxylated to dopamine peripherally in GIT& blood vessels&only a small proportion reaches the brain.

• This peripheral conversion of levodopa is responsible for the high incidence of side-effects if used alone.

• The problem is largely overcome by giving a decarboxylase inhibitor that does not cross the blood-brain barrier along with the levodopa.

• 2 peripheral decarboxylase inhibitors, carbidopa & benserazide, are available as combination preparations with levodopa, as Sinemet & Madopar.

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Levo-dopa:Levo-dopa:• The initiation of levodopa should be delayed until there is significant

disability, since there is concern regarding long-term side-effects. • Some suggest to initiate treatment with a dopamine agonist or a slow-

release levodopa to minimise or delay the onset of long-term side-effects, sp 70.

• Levodopa is particularly effective at improving bradykinesia /rigidity. • Tremor is also helped but rather unpredictably. • The initial dose is 50 mg 8- or 12-hourly, increased if necessary. • The total levodopa dose may be increased to over 1000 mg/day, but

should be kept as low as possible.

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Levo-dopa:S/EsLevo-dopa:S/Es• Postural hypotension, nausea, vomiting, reduced by the use of a

peripheral dopamine antagonist as domperidone. • Involuntary movements, sp orofacial dyskinesias, limb &axial

dystonias,occasionally depression, hallucinations& delusions.• Involuntary movements (dyskinesia) may occur as a peak-dose

phenomenon, or as a biphasic phenomenon (during build-up & wearing-off phases). Management is difficult, but again involves modifying the way levodopa is administered to obtain constant levels in the brain& use of alternatives, particularly dopamine agonists.

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Levo-dopa:S/EsLevo-dopa:S/Es• Late deterioration despite levodopa occurs after 3-5 years in 1/3-1/2.

manifests as fluctuation in response; of 2 types:• End-of-dose deterioration due to progression of the disease& loss of

capacity to store dopamine, often can be improved by dividing the levodopa into smaller but more frequent doses, or by converting to a slow-release preparation

• ‘On-off' phenomenon: More complex fluctuations present as sudden, unpredictable changes in response, in which periods of severe parkinsonism alternate with dyskinesia&agitation,is difficult to treat, but sometimes SC apomorphine (a dopamine agonist) are helpful to 'rescue' the patient rapidly.

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2. Anticholinergic:2. Anticholinergic:• These have a useful effect on tremor & rigidity, but do not help

bradykinesia. • They can be prescribed early in the disease before bradykinesia is a

problem, but should be avoided in elderly patients in whom they cause confusion /hallucinations.

• Other side-effects include dry mouth, blurred vision, difficulty with micturition / constipation.

• Many anticholinergics are available-, trihexyphenidyl (benzhexol; 1-4 mg 8-hourly) , orphenadrine (50-100 mg 8-hourly).

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3. Amantadine3. Amantadine• This has a mild, usually short-lived effect on bradykinesia, but may be

used early in the disease before more potent treatment is needed.• Amantadine can be particularly useful in controlling the dyskinesias

produced by dopaminergic treatment later in the disease. • The dose is 100 mg 8- or 12-hourly. • Side-effects include livedo reticularis, peripheral oedema,

confusion,seizures.

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4. Selegiline:4. Selegiline:• Selegiline has a mild therapeutic effect in its own right. • Evidence that it slows the progression of the disease is highly

controversial. • There has been some doubt as to its safety, but this is also

controversial and the subject of ongoing research.• The usual dose is 5-10 mg in the morning.

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5. COMT (catechol-O-methyl-transferase) inhibitors5. COMT (catechol-O-methyl-transferase) inhibitors::• Entacapone (200 mg with each dose of levodoa) prolongs the effects of

each dose & reduces motor fluctuations when used with levodopa. • This allows the levodopa dose to be reduced & given less frequently.

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6. Dopamine receptor agonists 6. Dopamine receptor agonists ::• Apomorphine given alone causes marked vomiting & has to be

administered parenterally. • The vomiting can be overcome by the concomitant use of domperidone,

& parenteral administration achieved through continuous subcutaneous infusion from a portable pump, or direct injection as needed.

• This requires considerable nursing support but, used correctly, can be very useful.

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Dopamine receptor agonists Dopamine receptor agonists ::• More easily administered drugs include bromocriptine, lisuride, pergolide,

cabergoline, ropinirole & pramipexole, which can all be taken orally.• These drugs are less powerful than levodopa in controlling features of

parkinsonism, but they are much less likely to cause dose fluctuations or dyskinesia, though they will certainly exacerbate the latter once these have developed. Side-effects include nausea, vomiting, confusion and hallucinations.

• The dose of bromocriptine is 1 mg initially, increased to 2.5 mg 8-hourly, up to 30 mg/day.

• Pergolide dose starts at 50 μg, increased to 250 μg 8-hourly, possibly to 3000 μg/day.

• Dopamine agonists derived from ergot (e.g. pergolide / cabergoline) have recently been associated with the development of fibrotic reactions/ thickening of heart valves,so most are screened with echo, chest X-ray / renal function tests before commencing therapy&every 6 months

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Surgery Surgery ::• Stereotactic thalamotomy can be used to treat tremor, though this is

needed relatively infrequently because of the medical treatments available.

• Other stereotactic lesions are currently undergoing evaluation, in particular pallidotomy to help in the management of drug-induced dyskinesia.

• The implantation of fetal mid-brain cells into the basal ganglia to enhance dopaminergic activity remains experimental.

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Physiotherapy& rehabPhysiotherapy& rehab::• Patients at all stages of Parkinson's disease benefit from physiotherapy,

which helps reduce rigidity& corrects abnormal posture. • Speech therapy may help in cases where dysarthria & dysphonia

interfere with communication.

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Prognosis:Prognosis:• Variable& depends partly on the age of onset. • If symptoms start in middle life, the disease is usually slowly progressive

& likely to shorten lifespan because of the complications of immobility 7 tendency to fall.

• Onset after 70 is unlikely to shorten life or become severe.

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PARKINSON'S Dis IN OLD AGE PARKINSON'S Dis IN OLD AGE ::• Incidence: increasingly common with age. • Drug therapy: the long-term side-effects of levodopa, such as dyskinesia,

are less of a problem in patients whose disease starts after age 70, so it is reasonable to prescribe levodopa as the first-line agent, as opposed to a dopamine agonist in a younger patient.

• Side-effects of medication: much more common, particularly confusion and hallucinations, particularly with anticholinergic drugs.

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