Parkinson's disease

1. PARKINSON’S DISEASE
UNDER GUIDANCE OF-
MENTOR PROFESSOR DR.MANIRAM KUMHAR SIR
DEPT OF GENERAL MEDICINE
JLN MEDICAL COLLEGE, AJMER (RAJ)

2. • Parkinson’s disease (PD) is the second most common age-related
neurodegenerative disease, exceeded only by Alzheimer’s disease
(AD).
• Its cardinal clinical features were first described by the English
physician James Parkinson in 1817.
• James Parkinson was a general physician who captured the essence
of this condition based on a visual inspection of a mere handful of
patients, several of whom he only observed walking on the street
and did not formally examine.
• The mean age of onset of PD is about 60 years, and the lifetime risk
is ~2% for men and 1.3 % for women.

3. • The frequency of PD increases with age, but cases can be seen in
individuals in their twenties and even younger, particularly when
associated with a gene mutation.
• Clinically , PD is characterized by
- Rest Tremor
- Rigidity(Stiffness)
- Bradykinesia(Slowing)
- Gait Dysfunction with postural instability.
These are known as cardinal features of disease.

4. • Additional clinical features includes-
- Freezing of gait
- Speech difficulty
- Swallowing impairment
- Autonomic disturbances
- Series of non-motor features that include sensory alterations, mood
disorders, sleep dysfuntions, cognitive impairment and dementia.

7. Pathogenesis-
• The hallmark features of PD are-
1.Dopaminergic pathology-
- Degeneration of dopaminergic neurons in the substantia nigra pars
compacta (SNc).
- Reduced striatal dopamine
- Intraneuronal proteinaceous inclusions known as Lewy bodies and
Lewy neurites that primarily contain protein α-synuclein

8. 2. Non-dopaminergic pathology-( Responsible for non-
dopaminergic clinical features)
Neuronal degeneration with inclusion body can also affect –
-Cholinergic neurons of Nucleus basalis of Maynert(NBM),
-Norepinephrine neurons of locus coeruleus (LC) ,
-Serotonin neurons in raphe nuclei of brain stem
- Neurons of olfactory system, cerebral hemispheres, spinal
cordd and peripheral autonomic nervous system.

10. Diagnosis and Differential Diagnosis:-
• Parkinsonism(Generic term) has multitude of differential diagnosis
which reflects differences in the site of damage and pathology in
various components of basal ganglia.
• Basal ganglia or Basal nuclei comprise of subcortical nuclei that
include the-
- Striatum (Putamen and caudate nucleus )
- Subthalamic nucleus ( STN)
- Globus pallidus pas externa ( GPe)
- Globus pallidus par interna ( GPi)
- Substantia Nigra pars compacta

14. • Etiology-
• Most PD cases occur sporadically ( 85 -90 %) and are of unknown
cause. Gene mutations are only known cause of PD.
• Twin studies suggested that environmental factors might play an
important role in patients with an age of onset ≥ 50years.Genetic
factors play more important role in younger onset patients.
• Confirmed Genetic causes of Parkinson’s disease includes-
• Classical PD- PARK SNCA, PARK LRRK2, PARK VPS35.
• Early onset PD- PARK Parkin, PARK PINK1, PARK DJ1.
• Parkinsonism- PARK-ATP13A2, PARK FBX07,PARK DNA JC6,
PARK-SYN J1 Etc

15. Role of Neuro-imaging in diagnosis of Parkinson’s Disease-
• In routine practice neuroimaging is rarely
necessary as diagnosis can usually be
established on clinical criteria alone.
• Imaging can be useful where there is
diagnostic uncertainty ( Essential tremors,
dystonic tremors, psychogenic tremors) or
in research studies.
• Imaging of brain dopamine system in
in patients with PD can be performed using
Positron Emission Tomography (PET) or
Single Photon Emission Computed
Tomography(SPECT)

16. • These studies typically shows reduced and asymmetric uptake of
striatal dopaminergic biomarkers, particularly in the posterior
putamen with relative sparing of caudate nucleus.
• These findings reflect the degeneration of nigrostriatal dopaminergic
neurons and loss of striatal terminals.

17. • International Parkinson’s Disease and Movement Disorders Society-
• MDS (Movement Disorders Society) has prescribed certain clinical
diagnostic criteria for diagnosis of Parkinson’s Disease.
• Motor Parkinsonism has been retained as core feature of disease
characterised by cardinal motor features ie- Bradykinesia, tremor,
rigidity and postural instability.
• 3 Additional categories of diagnostic features are-
• 1. Supportive criteria-Features that increase confidence in the
diagnosis of PD

19. • 2.Red flags criteria-
• Which must be counter-balanced by supportive criteria to permit a
diagnosis of PD.

22. • 3.Absolute Exclusion criteria- Criteria which rule out PD.

23. • Stages of Parkinson’s Disease-

24. • Treatment of Parkinson’s Disease-
• It is to be noted that none of the anti-parkinsonian drug alter the
course of disease, rather they merely improve the quality of life for
few years.

25. • Dopamine Precursors-
• Drug included in this class is Levodopa.
• Levodopa- Introduced in late 1960s , since then it is mainstay of
therapy for PD.
• It is inactive by itself but is immediate precursor of transmitter
Dopamine(DA).
• More than 95% of oral dose is decarboxylated in peripheral
tissues(mainly gut and liver) only 1-2% of administered Levodopa
crosses to brain, is taken up by surviving dopaminergic neurons,
converted to DA which is stored and released as neurotransmitter

26. • Actions of Levodopa on CNS-
• Levodopa hardly produces any effect in normal individuals or in
patients with other neurological disease.
• It offers marked symptomatic improvement in PD patients
• Hypokinesia and rigidity resolve first later tremor as well.
• Secondary symptoms of posture, gait, handwriting, speech, facial
expression, mood ,self care and interest in life are gradually
normalized.
• It has general alerting response on behavior and in some patients it
progress to excitement and frank psychosis may occur.
• Levodopa has been used to produce a non-specific awakening effect
in hepatic coma.

27. • Levodopa is rapidly absorbed from small intestine and undergoes first
pass metabolism in gi mucosa and liver.
• Only 1% of administered drug enters in the brain. Plasma t1/2 is is
1-2 hours.
• Adverse Effects includes
• At initiation of therapy-
• Nausea and vomiting .Tolerance develops gradually.
• Postural Hypotension- in about 1/3 patients.More pronounced in
patients receiving anti-hypertensives.Tolerance develops gradually.
• Cardiac arrhythmias and exacerbation of angina – due to β
adrenergic action of peripherally formed DA.More in patients
with preexisting heart disease.
• Alteration in taste sensation.

28. • Adverse effects after prolonged therapy –
• 1.Abnormal movements (Dyskinesias)-
• No tolerance develops to this side effect it includes
• Facial tics,grimacing, tongue thrusting, choreoathetoid movements of
limbs after few months of use of levodopa at optimum therapeutic
dose.
• 2.Behavioral effects-
• They range from mild anxiety, nightmares to severe depression,
mania,hallucinations, mental confusion and frank psychosis.
• Excessive DA action in the limbic system is probably responsible(
Antidopaminergic drugs are antipsychotics)
• Levodopa is contra-indicated in patients with psychiatric illness.
• Dopamine dysregulation syndrome-patients have craving for
Levodopa.

29. • 3.Fluctuation in motor performance-
• It occurs after 2-5 years of therapy.
• Wearing off effect- With continued treatment , the duration of
benefit following an individual dose becomes progressively shorter till
it approaches half life of the drug. This loss of benefit known as
wearing-off effect.
• Wearing off effect produces what is known as on-off effect. With time
‘all or none response’ develops ie patient is alternatively well and
disabled.
• In more advanced states, patients may cycle between “on” periods
complicated by disabling dsykinesias and “off” periods when they
suffer from sever parkinsonism.

30. • Dyskinesias are usually choreiform but can manifest as dystonic
movements, myoclonus and other movement disorders and
predominantly involve lower extremities.
• Cause of levodopa induced motor complications is not precisely
known.
• Cautious use of levodopa is needed in-
• Elderly patients
• Patients with IHD,CVA, psychiatric, hepatic and renal disease, peptic
ulcers (Risk of bleeding is increased) ,Glaucoma, and gout

31. • Interactions-
• 1.Pyridoxine-Abolishes therapeutic effect of Levodopa.
• 2.Phenothiazines( Anti-psychotics ie Chlorpromazine, Trifluperazine)
• Butyrophenone(Haloperidol,Trifluperidol etc)
• Metoclopramide (Prokinetic drug) reverse therapeutic effects of
levodopa by blocking DA receptors.
• Domperidone can be used to allay nausea, vomiting due to levodopa
as it reaches CTZ but does not cross blood brain barrier.
• 3.Anti-hypertensive drugs-May accentuate postural hypotension.

32. • Peripheral decarboxylase inhibitors-
• Carbidopa and Beserazide are the drugs of this class.
• These are extra-cerebral dopa decarboxylase inhibitors.
• Administered along with levodopa, they increase it’s t1/2 in periphery
and make more of it available to cross blood brain barrier and reach
site of action.
• Benefits of the combination(Levodopa+ Carbidopa/Benserazide)
are-
• 1.Plasma t1/2 of levodopa is prolonged and its dose is reduced
approximately ¼.
• 2.Systemic concentration of DA is reduced, Nausea and vomiting are
minimized- Therapeutic doses of Levodopa can be attained quickly.

33. • 3. Cardiac complications are reduced.
• 4.Pyridonxine reversal of levodopa effect does not occur.
• 5. On-off effect is minimized since cerebral levels of DA are more
sustained.
• 6.Degree of improvement may be higher; some patients, not
adequately responding to levodopa alone ,also improve.
• Problems not resolved (by combination)or accentuated are-
• 1.Involuntary movements
• 2.Behavioral abnormalities.
• 3.Excessive day time sleepiness in some patients.
• 4.Postural hypotension.

34. • Currently, Levodopa is practically always used along with a
decarboxylase inhibitors except in patients who develop marked
involuntary movements with the combination
• Combined preparation of Levodopa and carbidopa-
• Carbidopa Levodopa
• 10mg + 100mg
• 25mg + 100mg
• 25mg + 250 mg
• Benserazide 25mg + 100mg
• Therapy is started at low dose and suitable preparations are chosen
according to needs of individual patients.

35. • Dopaminergic Agonists –
• This class of drugs include Ropinirole and Premipexole.
• The DA agonists can act on striatal DA receptors even in advanced
patients who have largely lost capacity to synthesize, store and and
release DA from administered Levodopa.
• They are longer acting and can exert selective activation of DA
receptors involved in parkinsonism.
• Ropinirole and Pramipexole-
-These are two non-ergoline selective D2/D3 receptor agonists with
negligible affinity for D1 and nondopaminergic receptors.
- Ropinirole and Pramipexole are now frequently used for monotherapy
in early PD as well as to supplement Levodopa-carbidopa in advanced
cases.

36. • There is some indirect evidence that use of Ropinirole/Pramipexole in
place of Levodopa-carbidopa may be associated with slower rate of
neuronal degeneration.
• Ropinirole is rapidly absorbed orally, terminal t1/2 is hours.Thus it is
longer acting than Levodopa useful in management of motor
fluctuations and reducing frequency of on-off effect.
• Side effects-
• The Parkinson study group trial has noted lower incidence of
dyskinesias and motor fluctuations among patients treated with these
drugs than those treated with Levodopa.
• Nausea, dizziness, hallucinations and postural hypotension.
• Behavioral side effects like impulsive shopping,betting, gambling and

37. • Inappropriate sexual overactivity has been observed.
• Overall psychiatric side effects are more with DA agonists than with
Levodopa
• Higher incidence of Hallucinations and sleepiness may disfavour their
use in the elderly.
• Patient should be advised not to drive if they suffer excessive
sleepiness and especially day time sleepiness.
• Dose-
• Ropinirole- starting dose is 0.25mg TDS titrated to maximumof 4-8
mg.Early cases generally require 1-2 mg TDS.
• Available in the strength of .25, .50. 1.0 and 2 mg tablets.

38. Pramipexole-
• It is twice as potent as Ropinirole but comparable in efficacy and
tolerability.
• Starting dose is 0.125 mg TDS titrate to 0.5mg-1.5 mg TDS.
• Available in dose of 0.125, 0.25mg , 0.5, 1.0, 1.5 mg Tablets.
• It is to be noted that Ropinirole is FDA approved drug for use in
Restless Legs Syndrome(RLS)
• RLS is peculiar sensory motor disorder affecting the legs during the
periods of relaxation especially sleep.
• The affected subject feels an irresistible urge to constantly move the
legs,usually associated with tingling,discomfort,itching or
cramps.Genetic basis and mild dopaminergic hypofunction in the
brain have been implicated.Relative low doses Ropinirole ( 0.25- 1.0
mg) or Pramipexole(0.125 to 0.5mg taken 2-3 hours before bedtime
can offer dramatic relief in many cases.

39. • MAO-B Inhibitor-
• Selegiline(Deprenyl) and Rasagiline are drugs of this class.
• Selegiline(Deprenyl)- It is selective and irreversible MAO-B inhibitor.
• MAO-B preferentially oxidizes DA. MAO-B retards intracerebral
degradation of DA. This is responsible for therapeutic effect in
Parkinsonism.
• Selegiline alone has mild antiparkinsonism action in early
cases.Administered with Levodopa, prolongs and enhances with
Levosopa action.
• Clinical benefits derived from selegiline are short lived( 6 to 26
months)
• Adverse Effects include Postural hypotension , nausea ,confusion

40. •
• Accentuation of levodopa induced involuntary movements and
psychosis.
• It is contra-indicated in convulsive disorders.
• Dose- 5mg with breakfast and with lunch, with alone( in early
cases)or with levodopa/carbidopa. Reduce the dose of levodopa by ¼
after 2-3 days adding selegiline.
• Rasagiline-
• Newer selective MAO-B Inhibitor which is 5 times more potent,longer
acting and not metabolised to amphetamine. With these advantages
it is preferred drug over selegiline.
• Dose 1 mg OD in the morning. Tab available in 0.5mg and 1mg.