MANAGEMENT OF PARKINSONS DISEASE

1. Presented by-Dr Sadaf Siddiqui
Moderator-Prof.S.A.Azmi
Management of Parkinson's
disease

2. Introduction
 Parkinson's disease (PD) is the second commonest
neurodegenerative disease, exceeded only by Alzheimer's
disease (AD).
 It is estimated that approximately 1 million persons in the
United States and 5 million persons in the world suffer
from this disorder.
 The mean age of onset is about 60 years, but cases can be
seen in patients in their 20s, and even younger.

3.  Very few studies are available on the prevalence of PD in
India.
 Different studies have shown that the crude prevalence
rate (CPR) of PD is 14 per 100,000 in the north India, 27 per
100,000 in south India and 16 per 100,000 in east India.
However, in one study of Parsis in Mumbai revealed a CPR
of 328 per 100,000.
 The frequency of PD increases with aging, and based on
projected population demographics, it is estimated that
the prevalence will dramatically increase in future
decades.

4.  Clinically, PD is
characterized by rest
tremor, rigidity,
bradykinesia, and gait
impairment, known as the
"cardinal features" of the
disease.

5. Other motor features
 Micrographia
 Masked facies (hypomimia)equalize
 Reduced eye blink
 Soft voice (hypophonia)
 Dysphagia
 Freezing

6. Nonmotor features
 Anosmia
 Sensory disturbances (e.g., pain)
 Mood disorders (e.g., depression)
 Sleep disturbances
 Autonomic disturbances
 Orthostatic hypotension
 Gastrointestinal disturbances
 Genitourinal disturbances
 Sexual dysfunction
 Cognitive impairment/Dementia

7. UK PARKINSON’S DISEASE SOCIETY BRAIN BANK
CLINICAL DIAGNOSTIC CRITERIA
Step 1. Diagnosis of a parkinsonian syndrome
 Bradykinesia and at least one of the following:
• muscular rigidity
• rest tremor (4–6 Hz)
• postural instability unrelated to primary visual,
cerebellar, vestibular or proprioceptive dysfunction.

8. Step 2. Exclusion criteria for Parkinson's disease (PD)
 History of :
• repeated strokes with stepwise progression
• repeated head injury
• antipsychotic or dopamine-depleting drugs
• definite encephalitis and/or oculogyric crises on no drug
treatment
• more than one affected relative
• sustained remission

9. Step 3. Supportive criteria for PD
 Three or more required for diagnosis of definite PD :
 unilateral onset
 excellent response to levodopa
 rest tremor present
 severe levodopa-induced chorea
 progressive disorder
 levodopa response for over 5 years
 persistent asymmetry affecting the side of onset most
 clinical course of over 10 years.

10.  Idiopathic
 Genetic (<50 y/o)
 Exposure to unrecognized neurotoxins
 Oxidation reaction with generation of free radicals
 Reduced level of dopamine in the basal ganglia
PATHOGENESIS:

11.  Pathologically, the hallmark features of PD are
degeneration of dopaminergic neurons in the substantia
nigra pars compacta (SNc), reduced striatal dopamine, and
intracytoplasmic proteinaceous inclusions known as Lewy
bodies.
 Neuronal degeneration with inclusion body formation can
also affect cholinergic neurons of the nucleus basalis of
Meynert (NBM), norepinephrine neurons of the locus
coeruleus (LC), serotonin neurons in the raphe nuclei of
the brainstem, and neurons of the olfactory system,
cerebral hemispheres, spinal cord, and peripheral
autonomic nervous system.

12.  This "nondopaminergic" pathology is likely responsible for
the nondopaminergic clinical features
 Several studies suggest that symptoms reflecting
nondopaminergic degeneration such as constipation,
anosmia, rapid eye movement (REM) behavior sleep
disorder, and cardiac denervation precede the onset of the
classic motor features of the illness.

13. WHAT CAN BE DONE TO HELP
PARKINSON’S SUFFERERS?

14. Objectives
 To Understand the Goals in Management of Parkinson’s
Disease.
 The Pharmacological Intervention in Parkinson’s Disease.
 The Non-Pharmacological Intervention in Parkinson’s
Disease.
 The Surgical Treatments in Parkinson’s Disease.

15. Goals of Management
 Maintain the function
 Avoid drug-induced complications
Bradykinesia
Tremor
Rigidity
Abnormal posture
Respond early in the
illness

16. But…
Cognitive symptoms
Hypophonia
Autonomic dysfunction
Balance difficulties
Respond poorly

17. Pharmacological Management of
Parkinson’s Disease.
Drugs used in PD
1. Levodopa and Carbidopa
2. Dopamine agonist
3. Catechol-O-methyltransferase inhibitors (COMT inhibitors
4. Monoamine oxidase type B (MAO-B)

18. 1-Levadopa
 Levodopa remains the most effective symptomatic
treatment for PD and the gold standard against which new
therapies are compared.
 No current medical or surgical treatment provides
antiparkinsonian benefits superior to what can be
achieved with levodopa.
 It benefits the classic motor features of PD, prolongs
independence and employability, improves quality of life,
and increases life span.

19.  Dose- 200–1000 mg/d,2–4 times/d
 It is routinely administered in combination with the
decarboxylase inhibitor carbidopa (Sinemet),with
benserazide (Madopar).
Carbidopa
 25 mg daily,70-100 mg/day but not to exceed 200 mg/day.

20.  LCD-100/10mg
 LCD (125)-100/25mg
 LCD(250mg)-200/50mg
 LCD (275)-250/25mg

21.  Syndopa (110mg)-100/10mg
 Syndopa (275mg) 250/25mg
 Syndopa CR200/50mg
 Tidomet –CR-200/50mg
 Tidomet Forte- 250/25mg
 Tidomet LS-100/10mg
 Tidomet PlusTorrent-100/10mg

22. Side effects
 Acute dopaminergic side effects include nausea, vomiting,
and orthostatic hypotension.
 These are usually transient and can generally be avoided
by gradual titration
 If they persist, they can be treated with additional doses of
a peripheral decarboxylase inhibitor (e.g., carbidopa) or a
peripheral dopamine-blocking agent such as domperidone.

23.  Levodopa-induced motor complications consist of
fluctuations in motor response and involuntary
movements known as dyskinesias.
 In more advanced states, patients may cycle between "on"
periods complicated by disabling dyskinesias and "off"
periods in which they suffer severe parkinsonism

24.  On/off" Effect Occurs usually after 2 or more years on L
Dopa
 Related with continous destruction of dopaminergic
neurons.
 "On/off" Effect May Be Due to Composite of Amino Acids
that use same Dopamine Transportor , causing extremely
low levels of L Dopa in CNS thereby causing symptoms of
Parkinsonism to reappear.

25. Treatment
 Adding a dopamine agonist, catechol- O -methyltransferase
(COMT) inhibitor, or monoamine oxidase (MAO)-B inhibitor
 Dosing levodopa more frequently
 Increasing the levodopa dose
 Switching from immediate-release (IR) to sustained-release
(CR) levodopa/carbidopa or
levodopa/carbidopa/entacapone

26.  Behavioral alterations can be encountered in levodopa-
treated patients.
 A dopamine dysregulation syndrome has been described
where patients have a craving for levodopa and take
frequent and unnecessary doses of the drug in an
addictive manner.
 PD patients taking high doses of levodopa can also have
purposeless, stereotyped behaviors such as the
meaningless assembly and disassembly or collection and
sorting of objects. This is known as punding.

27. 2-Dopamine Agonists
 ergot derivative
Bromocriptine-D2 agonists
1.25 mg PO q12hr
May increase dose by 2.5 mg/day q2-4Weeks
not to exceed 100 mg/day.
Pergolides-Stimulates both D1 and D2
More effective than bromocriptine
3 mg daily.

28.  non-ergot dopamine agonists
a-Pramipexole
 D2 receptor agonist
 strong affinity for D2 and D3 receptors
 0.125 mg PO q8hr initially,increase at weekly intervals to
target range of 1.5-4.5 mg/day PO divided q8hr.

29. b-Ropinirole
 Potent nonergoline dopamine agonist specific for D2 and
D3 subtypes.
 0.25 mg PO q8hr for 1 week initially, then increased weekly
by 0.75 mg,if necessary after week 4, may be increased
weekly by 1.5 mg/day up to 9 mg/day, then increased
weekly by 3 mg/day up to 24 mg/day.

30. C-Apomorphine-
 It is generally administered SC as a rescue agent for the
treatment of severe "off" episodes.
 It can also be administered by continuous infusion and has
been demonstrated to reduce both "off" time and
dyskinesia in advanced patients.
 2 mg (0.2 mL) SC,If no response, titrate every few days by
1-mg doses up to 6 mg SC q8hr; 3-5 times a day.

31. d-Rotigotine
 Non-ergolinic D3/D2/D1 dopamine agonist.
 Apply 2 mg/24 hr transdermal patch qDay for early-stage
disease or 4 mg/24 hr for advanced-stage disease.
 May be increased as needed but Not to exceed 6 mg/24 hr.

32. Side effects
 Have more adverse effects than levodopa, including
sleepiness, hallucinations, edema, and impulse control
disorders.
 However, these adverse effects resolve upon lowering the
dose or discontinuing the medication.

33. 3-MAO-B inhibitor
 used for early symptomatic treatment of Parkinson
disease.
 These medications provide mild symptomatic benefit, have
excellent adverse effect profiles, and may improve long-
term outcomes.
 These characteristics make MAO-B inhibitors a good choice
as initial treatment for many patients.

34. Selegiline
 indicated as adjunctive therapy
 5 mg every morning,maximum, 10 mg/day
Rasagiline
 indicated as initial monotherapy-1 mg/day
 as adjunctive therapy 0.5-1.0 mg/day to levodopa.
 Potential side effects include nausea, headaches, and dizzines.

35. COMT Inhibitors
 Inhibitors of COMT increase the elimination half-life of
levodopa and enhance its brain availability.
 Combining levodopa with a COMT inhibitor reduces "off"
time and prolongs "on" time in fluctuating patients while
enhancing motor scores.

36. Tolcapone
 central & peripheral metabolism.
 Hepatotoxic : less preferred.
 DOSE : 100 mg TDS

37.  May increase dose to 200 mg.
 Failure to show the expected incremental benefit on the
200-mg dose after a total of 3 weeks of treatment
(regardless of dose), tolcapone should be discontinued.
ENTACAPONE
 200 mg
 Not to exceed 1600 mg/day

38. Side effects
 Postural hypotension
 Fatigue
 Somnolence
 Peripheral edema
 Nausea
 Constipation
 Dyskinesias
 Confusion
 Orange discoloration of urine.

39. Amantadine
 Antiviral agent that has antiparkinsonian activity.
 It appears to potentiate CNS dopaminergic
responses,release dopamine and norepinephrine from
storage sites and inhibit the reuptake of dopamine and
norepinephrine.
 dose of 100 mg per day and slowly increased to an initial
maintenance dose of 100 mg 2 or 3 times daily.

40. side effects
 confusion and hallucinations.
 Other Common side effects include nausea, headache,
dizziness, and insomnia.
 Less frequently reported side effects include anxiety and
irritability, ataxia, livedo reticularis, peripheral edema, and
orthostatic hypotension.

41. ACETYLCHOLINE BLOCKING AGENTS
 Improve tremor & rigidity of parkinsonism but have little
effect in bradykinesia
 Doc for drug induced parkinsonism
 One of the most commonly used anticholinergic is
trihexyphenidyl.
 Dose-1 mg,Dosage can be titrated by 1 mg each week or
so, until a total of 4-6 mg a day.

42. Pharmacological Therapy in early PD
 ‘Early disease’ refers to PD in people who have developed
functional disability and require symptomatic therapy.
 There is no single drug of choice in the initial
pharmacotherapy of early PD.

43. Options for initial pharmacotherapy in early PD

44.  The dose of levodopa should be kept as low as possible to
maintain good function in order to reduce the development of
motor complications.
 Beta blockers used in the symptomatic treatment of selected
people with postural tremor in PD.
 Anticholinergics may be used as a symptomatic treatment
typically in young people with early PD and severe tremor

45. Pharmacological therapy in later PD
 ‘Later disease’ refers to PD in people on levodopa who have
developed motor complications.
 There is no single drug of choice in the pharmacotherapy of later
PD.
 So, Adjuvant drugs are taken alongside with Levodopa for it.
 Ex: COMT inhibitors, MAO-B inhibitors, Dopamine agonist,
Amantadine… etc.

46. Options for adjuvant pharmacotherapy in later PD

47.  Modified-release levodopa preparations may be used to
reduce motor complications in people with later PD, but
should not be drugs of first choice.
 MAO-B & COMT inhibitors may be used to reduce motor
fluctuations and Amantadine may be used to reduce
dyskinesia in people with later PD.

48. Neuroprotection
 Despite the many therapeutic agents available for the
treatment of PD, patients can still experience intolerable
disability due to disease progression and the emergence of
features such as falling and dementia that are not
controlled with dopaminergic therapies.
 Trials of several promising agents such as rasagiline,
selegiline, coenzyme Q10, pramipexole, and ropinirole
have had positive results in clinical trials consistent with
disease-modifying effects.

49.  However, it is not possible to determine if the positive
results are due to neuroprotection with slowed disease
progression or confounding symptomatic or pharmacologic
effects that mask ongoing progression.
 If it could be determined that a drug slowed disease
progression, this would be a major advance in the
treatment of PD.

50. Surgical Treatment
 The surgical treatment for PD is currently considered in
advanced patients when the optimized medical treatment
has failed in treating motor symptoms (such as motor
fluctuations and/or dyskinesia).
 Although pallidotomy and thalamotomy might still be
performed in selected patients, deep brain stimulation
(DBS) is currently the surgical treatment of choice in
advanced PD patients.

51.  The most used current targets for PD are: the thalamus
(Vim nucleus), the subthalamic nucleus (STN), and the
globus pallidus internus (GPi).
 DBS of the STN may be considered as a treatment option
in PD patients to improve motor function and to reduce
motor fluctuations, dyskinesia, and medication usage.

52.  The overall improvement of ADLs and motor UPDRS scores
in the off medication/on stimulation condition has been
reported to be on average 50% when compared to the off
medications condition before surgery.
 Levodopa-induced dyskinesia has also been reduced by
69% on average after surgery

53. Adverse events (AEs) due to the surgical procedure include:
 Infections (6.1%), migration or misplacement of the leads
(5.1%), lead fractures (5%), intracranial hemorrhage (3%),
and skin erosion (1.3%)
 The most reported complications possibly related to the
stimulation (especially STN DBS) and persistent in the long-
term follow-up include: eyelid opening apraxia (1.8-30%),
dysarthria/hypophonia (4-17%), gait disturbances (14%),
postural instability (12.5%) weight gain (8.4%) and verbal
fluency decline.

54.  Age and duration of PD may be considered as factors
predictive of outcome after DBS of the STN.
 Younger patients with shorter disease durations may
possibly have improvement greater than that of older
patients with longer disease durations.

55. Management of the Nonmotor and
Nondopaminergic Features of PD
Depression -
 1. Consider emotional fluctuations associated with “OFF”
periods → Reduce “OFF” time
 2. Involvement of geriatric or neuro-psychiatrist;
 3. SSRIs
 5. Pramipexole may have antidepressant effects over and
above its antiparkinsonian effects.
Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a
randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 Jun. 9(6):573-80

56.  Amitriptyline may be considered in the treatment of
depression associated with PD.
 6. ECT in severe refractory cases

57. Psychotic Symptoms
 R/o secondary (e.g., metabolic) causes.
 PD medications should be eliminated in the following
order: anticholinergics → amantadine → DAs → MAO-B
inhibitors.
 L-dopa has the greatest motor effect with the least mental
SEs; the lowest dose that satisfactorily controls PD
symptoms should be used.

58.  Psychosis in PD often responds to low doses of atypical
neuroleptics.
 Quetiapine is the atypical neuroleptic agent most
commonly used.
 It is usually introduced at a dose of 25 mg at bedtime and
can be increased to 50 mg or more at bedtime as
necessary.

59.  Clozapine is the most effective
 Dose is 12.5–50 mg/d
 It can be associated with agranulocytosis, and regular
monitoring is required.
 ECT in severe refractory cases.

60. Dementia
 Dementia in PD (PDD) is common, affecting as many as
80% of patients
 These patients are particularly prone to have
hallucinations and diurnal fluctuations.
 Levodopa and other dopaminergic drugs can aggravate
cognitive function in demented patients and should be
stopped or reduced to try and provide a compromise
between antiparkinsonian benefit and preserved cognitive
function.

61.  Drugs are usually discontinued in the following sequence:
anticholinergics, amantadine, dopamine agonists, COMT
inhibitors, and MAO-B inhibitors.
 Eventually, patients with cognitive impairment should be
managed with the lowest dose of standard levodopa that
provides meaningful antiparkinsonian effects and does not
aggravate mental functions.

62.  Anticholinesterase agents such as rivastigmine and
donepezil reduce the rate of deterioration of measures of
cognitive function in controlled studies and can improve
attention.
 Memantine, an antiglutamatergic agent, may also provide
benefit for some PDD patient.

63. Sleep Disorders-
 Good sleep hygiene should be advised in people with PD
with any sleep disturbance.
 Care should be taken to identify and manage restless legs
syndrome (RLS) and rapid eye movement (REM) sleep
behaviour disorder in people with PD and sleep
disturbance.
 Low doses of clonazepam are usually effective in
controlling this problem
 Modafinil may be considered for daytime
hypersomnolence in people with PD.

64. Autonomic dysfunction
 General measures for treating urinary urgency and
incontinence include avoiding coffee before bedtime, limit
water ingestion before bedtime, etc
 Add peripherally acting anticholinergic drugs

65. Constipation
 Apply general measures for treating constipation.
 These include diet, laxatives, etc
 Reduce or discontinue drugs with anticholinergics
activity.
 Add domperidone.

66. Orthostatic hypotension (OH)
1. Non-pharmacological: ↑ fluid intake, ↑ dietary salt,
avoid alcohol / large meals (frequent small meals
instead) / excessive warmth, elevate head of bed.
 Patients should be advised to rise slowly, especially in
morning or after sitting/lying for a period of time
2.Discontinue unnecessary medications, e.g.,
antihypertensives
3. Fludrocortisone
4. Domperidone
5. Midodrin
6. Consider pyridostigmine

67. Non-Pharmacological Management of
Parkinson’s Disease.
 It includes,
 Rehabilitation.
Diet.
Physiotherapy
Speech & Language therapy
Occupational therapy

68. Rehabilitation
 Physiotherapy
It helps to improve the,
a. Mobility.
b. Flexibility.
c. Strength.
d. Gait speed.
e. Aerobic capacity.
f. Quality of life.

69.  Speech and language therapy
 Particular consideration should be given to :
 improvement of vocal loudness and pitch range.
 Ensuring an effective means of communication is
maintained throughout the course of the disease.
 review and management to support safety and
efficiency of swallowing and to minimise the risk of
aspiration.

70.  Occupational therapy
 Particular consideration should be given to :
 maintenance of work and family roles, home care
and leisure activities.
 improvement and maintenance of transfers and
mobility.
 improvement of personal self-care activities, such as
eating, drinking, washing and dressing.

71. Diet
 Diet should include high fibre foods and plenty of water.
 When levodopa is introduced excessive proteins are
discouraged due to competition between them to cross
the BBB and intestine.
 So, To minimize interaction with proteins, levodopa is
recommended to be taken 30 minutes before meals.

72. Future Treatments for Parkinson's Disease
 A2a antagonists
 new class of nondopaminergic medications
 Thought to provide antiparkinsonian benefit by reducing
the overactivity of the striatopallidalpathway.
 levodopa formulations
 Levodopa/carbidopa intestinal gel (LCIG; Duodopa) is an
aqueous gel that contains 20 mg/ml levodopa and 5 mg/ml
carbidopa
 effective to reduce motor fluctuations and dyskinesia in
advanced

73.  Antidyskinesia medications
 AFQ056 is a selective antagonist of the metabotropic
glutamate receptor 5 (mGluR5).
 A robust antidyskinetic medication would be very helpful
for the management of advanced PD, both to reduce the
unwanted effects of dyskinesia and to allow more liberal
use of dopaminergic medications.

74.  Gene therapy
 Glutamic Acid Decarboxylase (GAD) Gene Transfer-GAD
gene transfer in the STN modifies the phenotype of STN
neurons from predominantly excitatory to predominantly
inhibitory, thereby reversing excessive drive onGPi and SNr,
and returning their output to a more normal state.
Hauser RA. Future treatments for Parkinson's disease: surfing the PD pipeline. Int J Neurosci. 2011

76. CASE VIGNETTE
 A tremor and stiffness develop in the left leg of a 49-year-
old woman with a past history of anxiety and panic attacks;
the diagnosis is PD. She has no history of neuroleptic use,
toxin exposure, or other secondary causes of
parkinsonism. She is treated with carbidopa/levodopa,
entacapone, and clonazepam, and she does well for
several years.
 Five years after the onset of PD, a death in the family
triggers depression. Her motor symptoms worsen during
this period, and a dopamine agonist (ropinirole) and
selegiline are added.

77.  Over the next year, her personality changes and she
becomes increasingly irritable and begins to exhibit
strange behaviors; she becomes delusional, falsely
accusing her husband of infidelity. She becomes sexually
promiscuous and begins to spend money frivolously. She
separates from her husband. She is seen by a psychiatrist
and is briefly hospitalized. She receives paroxetine,
clonazepam, lithium, and risperidone in addition to her
usual PD medications. Her tremors and stiffness worsen.
The treating physician increases the ropinirole dosage from
6 mg to 12 mg daily, and eventually the risperidone is
stopped.

78.  The patient is referred for a second neurological opinion;
the diagnosis is psychosis and impulse control disorders,
which are a consequence of the dopaminergic therapies
used to treat the PD. Entacapone and selegiline are
discontinued; ropinirole is gradually tapered and
discontinued. The patient is treated with
carbidopa/levodopa 25 mg/100 mg before meals and at
bedtime, which controls the motor symptoms. Quetiapine
25 mg at bedtime is added, and she continues on
clonazepam 0.5 mg 3 times daily. Over the ensuing 9
months, the hallucinations and delusions stop and
problems with impulse control are diminished

79. References
 Kaplan and sadock's comprehensive textbook of psychiatry
9th edition
 Harrisons principles of internal medicine
 P D samanta j, hauser ra. duodenal levodopa infusion for
the treatment of parkinson’s disease. expert opin
pharmacother. 2007;8:657–864.
 Hauser ra. future treatments for parkinson's disease:
surfing the pd pipeline. int j neurosci. 2011