Parkinson disease

1. PARKINSON’S DISEASE
Dr. SHOBHIT SHAH

2. GENERAL ASPECTS
Components of basal ganglia:
• Striatum (caudate nucleus and putamen )
• Globus pallidus
• Substantia nigra
• Nucleus accumbens
• Subthalamic nucleus
• Affernts : 1) from cerebral cortex to striatum
• 2)from centromedian nucleus of thalamus to striatum
• Efferents : 1) mainly from internal segment of globus pallidus to CM nucleus of
thalamus
• 2)from substantia nigra to thalamus
• Intrastriatal pathways are cholinergic
• Striatonigral pathways are GABAergic
• Nigrostriatal pathways are dopaminergic
• In Parkinson disease, all pathways are effected but nigrostriatal pathway is effected
the most

3. FUNCTION OF BASAL GANGLIA
• Planning and programming of movement
( skilled movements)
• Role in cognitive process
( esp. that of caudate )

4. • Parkinson disease is a chronic
progressive disease of nervous
system characterised by cardinal
features of tremors , rigidity ,
bradykinesia and postural instability.
• UK brain bank criteria ( resting tremors,
asymmetry and good response to levodopa).
Diagnosis of PD is confirmed in 99% cases by this
criteria.

5. TREMORS
• Resting tremor: causes "pill rolling" between thumb and
index fingers and illegible writing
• Parkinsonian tremor is characteristically slow, of medium to
coarse amplitude (3-7 Hz); present at rest; increased by
emotion, fatigue, stress, and anxiety; absent in sleep; and
decreased by volitional activity.
• It typically affects the distal appendicular muscles, leading to:
• Flexion-extension movements of the metacarpophalangeal
and interphalangeal joints of the fingers and thumb
• Adduction-abduction movements of the thumbs (pill rolling)
• Pronation-supination movements of the wrists.
• It often begins unilaterally in the hand and may be present
initially only in the thumb or a single finger.

6. TREMORS
• The tremor then typically spreads to the
ipsilateral lower extremity (hemiparkinsonism)
before involving the opposite half of the body.

7. BRADYKINESIA
• Bradykinesia (decreased movements).
• Bradykinesia is the most disabling manifestation of
parkinsonism
• It’s characterized by delay in the initiation and execution of
willed movements and a general reduction of associated
automatic movements.
• Bradykinesia explains (at least partially) the facial hypomimia,
reduced blinking, impaired ocular convergence, monotonous
and low-volume speech (bradylalia, eventually leading to
anarthria), drooling of saliva, micrographia, and slow shuffling
gait with reduced associated movements that occur in
parkinsonism.

8. RIGIDITY
• Muscle rigidity: causes slowness of voluntary
muscle movement (bradykinesia) and cogwheel
rigidity
• Rigidity is characterized by a plastic resistance to
passive movements that affects both agonist and
antagonist muscles (e.g., flexors and extensors,
pronators, and supinators) to a similar extent and
that is constant throughout the entire range of
movement.
• Rigidity affects more axial and proximal limb
muscles

9. OHTER ASSOCIATED FEATURES
(MOTOR FEATURES)
Micrographia
Masked facies (hypomimia)
Reduced eye blink
Soft voice (hypophonia)
Dysphagia
Freezing

10. ASSOCIATED NON MOTOR FEATURES
Anosmia
Sensory disturbances (eg. Pain)
Mood disorders ( eg. Depression)
Sleep disturbances
Autonomic disturbances( orthostatic hypotension,
GI disturbances, GU disturbances, sexual
dysfunction )
Cognitive impairment / dementia

12. PATHOLOGY
Degeneration of dopaminergic neurons in the
substantia nigra pars compacta (SNc), reduced
striatal dopamine and intracytoplasmic
proteinous inclusions ka lewy bodies
Neuronic degeneration can also affect cholinergic
neurons of nucleus basalis of meynert (NBM),
serotonin neurons in raphe nuclei of brainstem
and neurons of olfactory system, cerebral
hemispheres, spinal cord, and peripheral
autonomic nervous system

13. PATHOLOGY
• Symptom reflecting nondopaminergic
degeneration such as constipation,
anosmia, rapid eye movement(REM)
behavior sleep disorder and cardiac
depervation precede the onset of the
classic motor features of the illness

14. PATHOGENESIS
Nigral dopamine neurons and other cell dies
because of following facters :
Genetic vulnerability ( abnormal processing or
folding of alfa-synuclein  leds to lewy body
formation )
Oxidative stress ( due to mitochondrial
dysfunction)
Proteasomal dysfunction ( protease inhibition 
substrate accumulation)

15. PATHOGENESIS
• Abnormal kinase activity  inappropiate
phosphorylation
• Enviromental facters
• Oxidative stress plays major role in sporadic form
of PD. Free radicals produced by metabolism of
dopamine and melanin Defect in mitochondrial
complex 1 of oxidative phosphorylation chain.
• MPTP, a meperidine derivative ; rotenone inhibits
complex 1.

16. • Genetic factors:
• Autosomal dominant (AD) and autosomal recessive
(AR) patterns of inheritance have been identified.
chromosome 4q21-23:
• Alanine-53-threonine mutation in the α-synuclein
gene.
• Autosomal dominant (AD).
• Earlier disease onset (mean, age 45 years).
• Faster progression.
• Some with fluent aphasia.

17. • chromososme 6q25.2-27:
• The parkin gene.
• Autosomal recessive (AR).
• Relatively young-onset parkinsonism.
• Early dystonia.
• Symmetric involvement.
• Good levodopa response.
• Absence of Lewy bodies at autopsy.
• chromosome 2p13:
• Autosomal dominant (AD) but with 40% penetrance.
• All from northern Germany and southern Denmark.
• Nigral degeneration and Lewy bodies at autopsy.
• Dementia may be more common

18. • chromosome 4p14-16.3:
• Autosomal dominant (AD).
• From a family known as the Iowa kindred.
• Also younger age of onset (mean, 34 years).
• Rapid clinical course.
• Early-onset dementia.
• Equivocal response to levodopa.
• Some family members with only postural tremor
resembling essential tremor.
• Autopsy shows Lewy bodies in the nigra and
hippocampus.

19. mutation in ubiquitin carboxy-terminal hydrolase L1
on chromosome 4:
• Autosomal dominant (AD).
• Young-onset progressive parkinsonism.
chromosome 1p35-36:
• Autosomal recessive (AR).
• Early-onset parkinsonism.
• Slow progression.
• Marked response to levodopa.
• Gene not yet identified.

20. chromosome 1p3:
• Early Autosomal recessive (AR) parkinsonism.
• Slow progression.
• With levodopa responsiveness.

21. D/D
• Differential Diagnosis:
• There are other disorders that may cause
parkinsonism besides Parkinson disease (sometimes
called “Parkinson plus”).
• These disorders may be difficult to separate clinically
from Parkinson disease.
• A lack of response to medication for Parkinson, early
dementia, and other neurologic signs may all suggest
such conditions.
• Up to 30% of patients with parkinsonism ultimately
have a cause other than Parkinson disease.

22. D/D
• Medications may cause secondary parkinsonism
by blocking the D2 receptor in the basal ganglia.
• Common agents responsible for this effect
include typical neuroleptics such as haloperidol
and the anti-emetic metoclopramide.
• Up to 5% of patients on long-term valproic acid
will develop parkinsonism with a cognitive
decline that may be reversible.

23. D/D
• Progressive supranuclear palsy (PSP) is a
degenerative disorder in which patients have a
toppling gait, impaired voluntary up-and-
down eye movements, and pseudobulbar
palsy.
• PSP should be considered in a parkinsonian
patient who presents with falling as an early
symptom.

24. D/D
• Multiple system atrophy (MSA) refers to a group of
degenerative disorders in which there are
abnormalities in multiple neurologic systems, including
the basal ganglia, corticospinal tract, autonomic
nervous system, and cerebellum.
• The Shy-Drager syndrome is a subtype of MSA with
impotence, postural hypotension, and parkinsonism.
• Early urinary incontinence, orthostatic hypotension,
and dysarthia are suggestive of multiple system
atrophy.
• (MSAc – cerebellar) has intentional tremors, dysarthia
• (MSAp – parkinson ) has resting tremors.

25. D/D
• Diffuse Lewy body disease may cause
parkinsonism, accompanied by an early
cognitive decline, prominent visual
hallucinations, a fluctuating course, and
sensitivity to major antipsychotics.
• Pathologically, Lewy bodies are seen in
cortical areas in addition to the pigmented
nuclei.

26. D/D
• Normal pressure hydrocephalus (NPH) involves the triad of
gait disorder, cognitive decline, and incontinence.
• Patients may appear parkinsonian but the gait is usually
apraxic rather than parkinsonian (patients seem unable to
“figure out” how to walk but can still bicycle with their legs
effectively when lying in bed on their back).
• NPH may be a delayed manifestation following a head injury,
subarachnoid hemorrhage, meningitis, or may occur
spontaneously.
• On computed tomography (CT) or magnetic resonance
imaging, large ventricles are seen without significant atrophy.
• Gait is “magnetic,” with difficulty picking up the feet despite
good strength (gait apraxia).

27. D/D
• Parkinsonism may be secondary to toxins such
as chronic manganese or carbon monoxide
intoxication.

28. TREATMENT OUTLINE
• PD pharmacological interventions
neuroprotection - ? Resagiline  functional
disability if present then levodopa/ dopamine
agonists combination therapy with LEVODOPA/
DOPAMINE AGONISTS/ COMT INHIBITERS/ MAO
INHIBITERS SURGERY/CDS
• Non pharmacological measures : physiotherapy,
counselling, life style modifications.

29. TREATMENT
• Levodopa is the most effective anti-parkinsonian medication,
and is the cornerstone of therapy for most patients.
• Despite this, many physicians delay the use of levodopa until
later in the course with the hope that the long-term side
effects of this medication can be reduced or delayed.
• The effect may be dramatic when administered early in
disease. Used alone, large doses are needed for effect, and
the peripheral effect causes nausea and orthostatic
hypotension.
• When combined with a dopa-decarboxylase inhibitor
(carbidopa), the peripheral effects are minimized, and the
dose may be reduced as more of the dopa reaches the brain
to be converted to dopamine

30. TREATMENT
• Combination medication is available as a short-acting
or long-acting preparation.
• The short-acting medication is available as 10/100,
25/100, and 25/250, with the first number referring to
the milligrams of carbidopa and the second number
referring to the milligrams of levodopa.
• A long-acting (CR) form is available as 25/100 or
50/200 mg, but does not confer a significant added
benefit.
• Carbidopa/ Levodopa 25/100, 3 to 4 times a day is the
usual starting dose. The most common side effect of
levodopa therapy is nausea.

31. TREATMENT
• Early motor fluctuations, dyskinesia, and on-off
phenomena are common problems encountered
with levodopa/carbidopa as parkinsonism
progresses.
• Dystonia, agitation, hallucinations, and sleep
disorders also may occur, particularly in patients
with dementia.
• Providing levodopa/carbidopa 30 minutes before
meals and limiting protein intake during the day
may improve absorption and efficacy of
levodopa/carbidopa.

32. TREATMENT
• Dopamine replacement might excessively
inhibit the pallidal output system , there by
leading to increased thalamo-cortical
activity dyskinesia
• Levodopa induced alternation in Gpi neuronal
firing pattern.This leds to transmission of
misinformation from pallidum to
thalamus/cortex leding to dyskinesia.
Pallidotomy thus ameliorate dyskinesia

33. TREATMENT
• Advantages of Levodopa:
• Most efficacious antiparkinsonian drug
• Immediate therapeutic benefits (within 1 week)
• Easily titrated
• Reduces mortality
• Lower cost
• Disadvantages of Levodopa:
• No effect on disease course,
• No effect on nondopaminergic symptoms, such as dysautonomia,
cognitive disturbances, and postural instability, motor fluctuations
and dyskinesia develop over time (especially in younger patients,
those with more severe disease and those requiring higher doses).

34. TREATMENT
• Dopamine agonists are advocated by some authorities as
early monotherapy in an attempt to spare the use of levodopa
early in the disease.
• Pergolide, bromocryptine, ropinerole, pramipexole, and
rasagiline are available dopamine agonists.
• Because pergolide, pramipexole, and ropinerole are longer-
acting agents, they may help smooth out motor fluctuations
seen with levodopa therapy, and have fewer choreiform-like
dyskinesias than levodopa.
• However, they may cause nausea, hypotension,
hallucinations, and confusion, as well as excessive
somnolence.
• Gradual titration to the desired dose is the most effective
strategy.

35. TREATMENT
• They may be used as monotherapy or in combination with
other anti- parkinsonian medications.
• Ergot derived dopamine agonists (pergolide, bromocryptine,
cabergoline) have recently been shown to cause valvular
heart disease in up to 5% of treated patients.
• In addition, dopamine agonists may cause impulsive
behaviors, such as gambling and hypersexuality, particularly at
higher doses.
• Patients taking dopamine agonists should be warned not to
drive if excessive somnolence is a significant complaint. It is
not known if lowering the dose of dopamine agonist will help
this.

36. TREATMENT
• Catecholamine-O-methyltransferase
(COMT) inhibitors (entacapone and
tolcopone)
• Extend the pharmacologic half-life of
levodopa
• May decrease the amount of “off” time.

37. TREATMENT
• Selegiline is a selective monoamine-B oxidase inhibitor
that increases the availability of dopamine at the
synaptic terminal.
• Rasagiline, a selective monoamine-B oxidase inhibitor,
was recently approved for use in Parkinson disease.
• This can be used both as an initial agent early in
Parkinson disease, or as an add-on agent for “on-off”
problems later in the disease.
• In the usual dosing of 0.5 to 1.0 mg per day, there do
not appear to be problems with reactions to tyramine-
containing foods.

38. TREATMENT
• Anticholinergic medications were used in the
past, but are no longer commonly prescribed due
to their side effect profile.
• option for young patients (<60 y/o) whose
predominant symptoms are resting tremor and
hypersalivation
• available agents—trihexyphenidyl and
benztropine;
• adverse effects often limit use—memory
impairment, confusion, hallucinations

39. TREATMENT
• Amantidine, an NMDA antagonist, was
initially demonstrated to have a modest anti-
parkinsonian effect.
• This agent is now used to reduce dyskinesias
when that side effect of treatment occurs.

40. TREATMENT
• Treatment (Late Stage):
• After approximately 5 years of treatment with levodopa,
probably because of loss of buffering action by remaining
dopaminergic neurons, patients develop a variety of
difficult-to-treat side effects of levodopa.
• Such problems include the following:
• Wearing-off of levodopa may be improved by giving the
levodopa more frequently, using longer-acting dopa
preparations, adding dopamine agonists to levodopa,
adding COMT inhibitors such as tolcapone or entacapone,
or adding rasagiline (grade A).
• Fatal hepatotoxicity has occasionally occurred with
tolcapone.

41. TREATMENT
Peak-dose dyskinesias
• Use smaller and more frequent levodopa
doses, or lower the levodopa dose and add
dopamine agonists.
• Amantidine may also be helpful in this setting

42. TREATMENT
• “On-off” fluctuations refer to dramatic,
unpredictable shifts from under-treated to
over-treated states.
• These are difficult to treat.
• Adding dopamine agonists, using COMT
inhibitors, using rasagiline, and occasionally
using injectable apomorphine may be helpful.

43. TREATMENT
• Confusion, sleep disorder, and
psychosis may be helped by decreasing the
medication, particularly limiting
anticholinergics, amantidine, and other
medications with sedating or anticholinergic
effects.

44. TREATMENT
Impulse control disorders have recently
been identified in patients with Parkinson
disease (gambling, hypersexuality, excessive
shopping, etc.).
• These may be associated with the use of
dopamine agonists or be related to the
disease entity.

45. SURGICAL MANAGEMENT
Lesion surgery
• Thalamotomy— most effective for parkinsonian and
essential tremor
• Pallidotomy—improves bradykinesia, tremor, rigidity,
dyskinesia in PD
INDICATIONS : 1) INTRACTABLE TREMORS
• 2) DRUG INDUCED DYSKINESIA
• Deep brain stimulaters : most preferred site for
implantation is subthalamic nucleus but in parkinson
with depresion,the most preffered site is GPi

46. THANK YOU