Parkinson’s disease
Contents
• Parkinson’s Disease
• Etio-pathogenesis of Parkinson’s
Disease
• Complications and symptoms of Parkinson’s
Disease
• Management
of Parkinson’s Disease
Objectives
By the
end of this PDF Notes, students will be able to:
a) Explain the pathophysiology of
Parkinson’s disease
b) Describe the complications and
symptoms of Parkinson’s disease
c) Explain
the role of nigrostriatal pathway in the development of Parkinson’s Disease
Parkinson’s disease
Definition:
A neurological
syndrome characterized by tremor, rigidity, hypokinesia and postural
instability. As the symptoms progress patient may have difficulty in walking,
talking or completing other simple tasks.
Disease is named after the English
doctor James Parkinson, who published the first detailed description in “An
Essay on the Shaking Palsy” in 1817
“Involuntary tremulous motion, with
lessened muscular power, in parts not in action and even when supported; with
propensity to bend the trunk forward and to pass from walking to a running
pace; the senses and the intellects being uninjured.”
Parkinsonism
Epidemiology:
- Approximately 15 per 100000 to 90 per 100000 are estimated to
suffer from parkinsonism
- Less common in Asian countries
- Risk of developing during one’s lifetime
2-3 %
- The 2nd most common
neurodegenerative disorder
Etiology & Pathogenesis of Parkinson’s disease
Parkinsonism is either
idiopathic or secondary
Idiopathic: Denotes a disease of unknown cause
Secondary: Only small amount of cases:
- Trauma induced
- Chemical induced- heavy metals, carbon
monoxide, cyanide, pesticides, dyes, methyl chloride
- Drug induced- phenothiazines, reserpine,
butyrophenol, large doses of carbamazepine
- Infection induced- syphilis, typhoid,
herpes, encephalitis may mimic parkinsonism
- Tumour induced- Intracranial tumour
- Post cephalic- A sequel of the viral
infection Encephalitis lethargica
Physiology of nigrostriatal pathways
Anatomically,
the basal ganglia form a re-entrant loop by
• Receiving the input from the cerebral cortex.
• Processing this information in the context of
dopaminergic input from substantia nigra &
• Sending information back to the cortex by way
of the thalamus.
The outflow of
striatum proceeds along two distinct routes, identified as direct and indirect
pathways, the balance of which regulates the movement.
DIRECT PATHWAY:
• It is also known as pyrimidal pathway.
• Formed by striatal neurons expressing primarily
dopamine D1 receptors.
• These neurons projects directly to the output
of the basal ganglia, the internal segment of the globus pallidus.
• These neurons tonically inhibit the thalamus, which in turn, sends excitatory projections to the cortex that initiate movement.
INDIRECT PATHWAY :
• It is also known as extrapyrimidal pathway.
• Formed by the striatal neurons expressing
predominantly dopamine D2 receptors.
• These neurons projects to the external segment
of the globus pallidus, which in turn inhibits the neurons in the subthalamic
nuclei.
• The neurons in the subthalamic nucleus are
excitatory glutaminergic neurons that project to the internal segment of the
globus pallidus
• The indirect pathway inhibits movement.
• The differential expression of D1 & D2
receptors within the two pathways leads to differing effects of dopaminergic
stimulation.
• Increased levels of dopamine in the striatum
tend to activate the D1 expressing neurons of the direct pathway while
inhibiting the D2 expressing neurons of the indirect pathway. Both of these
effects promote movement.
• The opposite effect is seen in PD, a state of
dopamine deficiency: the direct pathway shows reduced activity while indirect
pathway is overactive, leading to reduced movement.
• In PD, neurons that extend from the substantia
nigra to the putamen and caudate nucleus degenerate, causing the disruptions.
Ø Thus loss of nigrostriatal dopamine neurons in
IPD results in reduction of cortical activation.
Ø Virtually all the motor deficits of IPD are
attributable to the marked loss in dopaminergic neurons projecting to the
putamen.
• DA has a balance with the excitatory
neurotransmitter Ach to initiate motor activities.
• Ach is secreted by cholinergic neurons present
in synapses.
• When there is a loss of DA in Parkinsonism,
balance is shifted to Ach. Over activity of Ach is responsible for the symptoms
of Parkinsonism.
Etiology & Pathogenesis of
• Parkinsonism is either idiopathic (primary) or
secondary parkinsonism.
• Unlike the idiopathic parkinsonism, many of the
secondary forms of parkinsonism can be cured.
Idiopathic Parkinsonism
• The term “idiopathic “denotes a disease of
unknown cause.
• Many theories have been proposed & each in
succession has been abandoned because of lack of supporting evidence.
Ø Neurotoxins highly selective for substantia
nigra pars compacta (SNc) dopaminergic neurons –
Ø 6-hydroxy
dopamine
Ø MPTP(N-methyl 4-phenyl tetrahydropyridine)
Ø Cellular damage from oxyradicals.
Ø Dopamine - free radicals from autooxidation and
from MAO metabolism
Secondary Parkinsonism
• It is either:
• Trauma induced- severe head injuries. They rarely produce Parkinson’s symptoms. usually
occurs soon after injury & recovery is the general rule
• Chemical induced- acute ingestion of large amount of chemicals’ such as heavy metals,
carbon monoxide, cyanide, pesticides, some photogenic dyes, methyl chloride can
produce symptoms of Parkinsonism. But recovery is possible in most cases.
• Drug induced- phenothiazines commonly produce extra pyramidal effects that ultimately
may manifest as Parkinsonism like syndrome. The true Parkinsonism like syndrome
usually appears 2-3 months after initiation of drug therapy. Other drugs
besides phenothiazines are haloperidol, butyrophenones, reserpine, large doses
of methyl dopa, metochlopramide,carbamazipines.
• Infection induced- infection condition like syphilis, typhoid, herpes, coxsakie virus,
Japanese encephalitis. Etc may mimic Parkinsonism complication.
Pathogenesis
• A progressive neurodegenerative disorder
• The pathological hallmark of PD is a loss of the pigmented,
dopaminergic neurons of the substantia nigra, with the appearance of
intracellular inclusions known as Lewy bodies.
• Caused by degeneration of substantia nigra in
the midbrain, and consequent loss of DA-containing neurons in the nigrostrial
pathway
• Two balanced systems are important in the
extrapyramidal control of motor activity at the level of the corpus striatum
and substantia nigra- first neurotransmitter – Ach & the second – D
- Neurons which produce the neurotransmitter
dopamine in the area of brain substantia nigra die or become impaired
resulting in result in loss of DA
- Lewy bodies are the pathological hallmark of the idiopathic
disorder
- Dopamine is responsible for transmitting
signals b/w substantia nigra to next relay station of brain, the corpus
striatum to produce smooth and co-ordinated muscle activity
- The symptoms of PD are
connected with loss of nigrostrial neurons and DA depletion
- The cause of selective degeneration of
nigrostrial neurones in PD
-
is not precisely known, appears to be multifactorial
- Oxidation of DA by MAO-B and aldehyde
dehydrogenase generate hydroxyl free radicals (˙OH) in the presence of
ferrous iron (basal ganglia are rich in iron)
- Normally these radicals are quenched by
glutathione and other endogenous antioxidants
- Age-related (e.g. in atherosclerosis)
and/or otherwise acquired defect in protective antioxidant mechanisms
allows the free radicals to damage lipid membranes and DNA resulting in
neuronal degenerations
- Genetic predisposition may contribute to
high vulnerability of substantia nigra neurons
- Environmental toxins or some infections
may accentuate these defects
- A synthetic toxin N-methyl-4-phenyl
tetrahydropyridine (MPTP), which occurs as a contaminant of some illicit
drugs, produces nigrostrial degenerations similar to PD
- Neuroleptics and other DA blockers may
cause temporary PD
Production of free radical by the metabolism of dopamine (DA)
DA is converted by MAO
and aldehyde dehydrogenase (AD) in 3,4-dihydroxyphenylacetic acid (DOPAC),
producing hydrogen peroxide
(H2O2). In the presence of ferrous ion hydrogen per-oxide undergoes spontaneous
conversion, forming a hydroxyl free
radical (The Fenton reaction).
Factors contributing to degeneration of nigrostrial DA-ergic neurones causing PD
The key steps in the synthesis and degradation of dopamine and the sites of action of various psychoactive substances at the dopaminergic synapse
Pathogenesis
- Nerve cells of striatum loose control in co-ordinate muscle
activity
- DA has a balance with the excitatory neurotransmitter Ach in
the corpus striatum , to initiate motor activities
- When there is a loss of DA in Parkinsonism , balance is shifted to Ach , therefore over activity of Ach is responsible for the symptoms of Parkinsonism.
Distribution and characteristics of DA receptors in the central nervous system
The disease is often accompanied by these additional
problems, which are variably treatable
- Thinking difficulties
- Depression and Emotional changes
- Sleep problems and sleep disorder
- Bladder problems
- Constipation
- Sexual dysfunction
Symptoms of
Parkinsonism
The signs of advanced
Parkinsonism are so striking and unique that it hardly ever possses a
diagnostic challenge.
The symptoms are connected with loss of
nigrostrial neurons and DA depletion.
Cardinal Features
• Bradykinesia
• Postural instability
• Resting tremor (may have postural and action
components)
• Rigidity
Motor Symptoms
• Decreased dexterity (lack of mental skill or quickness)
• Dysarthria (speech disorder)
• Dysphagia (difficulty in swallowing)
• Festinating gait
• Flexed posture
• “Freezing” at initiation of movement
• Hypomimia- mask like face
• Hypophonia- soft speech
• Micrographia- small cramped hand writing
• Slow turning
• Autonomic Symptoms
• Bladder and anal sphincter disturbances
• Constipation
• Diaphoresis
• Orthostatic blood pressure changes
• Paroxysmal flushing
• Sexual disturbances
•
• Bradyphrenia- slowness of thought
• Confusional state
• Dementia
• Psychosis (paranoia, hallucinosis)
• Sleep disturbance
• Fatigability
• Oily skin
• Pedal edema
• Seborrhea (excessive discharge from the sebaceous glands, forming greasy scales on the body)
Treatment
• Primarily at providing maximal relief of
symptoms and maintaining the independence and movement
• Successful treatment involves a total program
of drug therapy, physical therapy, psychological support, and occasionally
surgery
Surgical therapy- Most effective surgical technique is deep brain stimulation (DBS) of
the STN, which decreases outflow from this region and reduces input to the
thalamus.
Drugs are
classified as follows:
ü Drugs which increase the dopamine levels
ü Anticholinergics
ü Anti histamines
ü Dopamine agonist
Non Pharmacological
Therapy
• Well balanced high fiber diet
• Psychotherapy
• Physical therapy
• Speech therapy
Summary
• Many theories have been proposed & each in
succession has been abandoned because of lack of supporting evidence.
Ø Neurotoxins highly selective for substantia
nigra pars compacta (SNc) dopaminergic neurons –
§ 6-hydroxy dopamine
§ MPTP(N-methyl 4-phenyl tetrahydropyridine)
Ø Cellular damage from oxyradicals.
Ø Dopamine - free radicals from autooxidation and
from MAO metabolism
• Cardinal Features of PD: Bradykinesia, Postural instability, Resting tremor (may have postural and action components), Rigidity
1 Comments
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