Dr.

Gowtham Reddy
 Causes of parkinsonism
 Idiopathic Parkinson’s disease
 Secondary parkinsonism
 Drug-induce parkinsonism:
- phenothiazines (eg: Chlorpromazine),
- butyrophenones (eg: haloperidol)
- Metoclopramide
 Stroke
 Tumor
 Exposure to toxin eg: CO, Manganese
 Trauma: eg: repeated head injuries in boxing.
 Encephalitis
 Atypical parkinsonism or Parkinsonism – plus
syndrome:
 Atypical parkinsonism refers to a group of neurodegenerative
conditions that usually are associated with more widespread
neurodegeneration than is found in PD.
 Parkinsonism in these conditions is often characterized by early
Speech and gait impairment,
Absence of rest tremor,
No asymmetry,
Poor or no response to levodopa
An aggressive clinical course.
 Progressive supranuclear palsy
 Multiple system atrophy
 Corticobasal degeneration
 Diffuse Lewy body dementia
 Spinocerebellar ataxia
 Wilson’s disease
 Parkinson’s disease:

 Parkinson’s disease is a progressive neurodegenerative

disorder that is associated with loss of pigmented
dopaminergic neurons in the substantia nigra pars
compacta (SNpc).
 The hallmarks of the disease are its triad of motor
features:
 Resting tremor
 Rigidity
 Akinesia/bradykinesia (inability to initiate movement and
slowness of movement, respectively).
History:
 Idiopathic Parkinson’s disease is named after James
Parkinson, a general practitioner in London who wrote
aboutparalysis agitansas a distinct disease separate from
other causes of tremor in his classic 1817 article, “Essay
on the Shaking Palsy.”
Epidemiology:
 It is the second most common neurodegenerative
disease after Alzheimer’s disease.
 It affects over 1 percent of the population over age
55 and nearly 3 percent of the population over age
70.
 The mean age of onset for Parkinson’s disease is
60 years of age, and 80 percent of individuals
develop the disorder between the ages of 40 and
70 years.
 About 5 percent of patients have symptom onset
before age 40 yrs.
 Men are affected slightly more often than
women.
 The background life time risk of 2 % doubles
where there is a positive family history and a
genetic component is more likely in those whose
symptoms start before the age of 50.
 Genetics:
 At least 18 genes or genetic loci have been associated
with Parkinson’s disease. (Harrison 18th )
 At present these genes account for only a very small
proportion of patients with the disorder.
 The first gene to be identified was α-synuclein on
chromosome 4.
 One of the most prevalent genes associated with familial
and sporadic Parkinson’s disease is leucine-rich repeat
kinase 2 (LRRK2), identified in 2004.
 The locus for LRRK2, called PARK8, is located on
chromosome 12.
Pathology:

 The primary pathology in Parkinson’s disease is death of the

melanin-containing pigmented dopaminergic neurons in the
pars compacta of the substantia nigra (SNpc) is responsible
for the motor signs of this disease.
 But what leads to this selective and progressive cell death is
unknown.
 Most cases of Parkinson’s disease are SPORADIC and
believed to be caused by exogenous environmental factors or
their interactions with genetic vulnerability factors.
 A number of risk factors have been identified, but increasing
age is the only unequivocal risk factor for Parkinson’s
disease.
 Evidence suggests that the death of dopaminergic
neurons begins a decade before symptom
onset.
 When the neuronal loss reaches about 70% of
total neurons, symptoms begin.
 The cause of dopaminergic neuronal death is
unknown, but current theories include exposure
to environment neurotoxins,
 Proposed pathogenic mechanisms in parkinson’s disease
include:
 Free radical-mediated oxidative injury.
 Mitochondrial abnormalities.
 Perturbations of the neuronal cytoskeleton/axonal
transport.
 Calcium-induced injury
 Programmed cell death.
 Microscopically
- loss of small pigmented neurons in the substantia
nigra
- eosinophilic, cytoplasmic inclusion bodies
surrounded by a clear halo (Lewy bodies) in
remaining neurons (aggregations of
neurofilaments and α-synuclein protein).

 Environmental factors or behavior with a reduced

risk to develop parkinson’s disease are:
 Caffeine use
 Cigarette smoking
 Neuronal degeneration with inclusion body formation can
also affect
- cholinergic neurons of the nucleus basalis of Meynert,
- norepinephrine neurons of the locus coeruleus (LC),
- serotonin neurons in the raphe nuclei of the brainstem,
- neurons of the olfactory system, cerebral hemispheres,
spinal cord, and peripheral autonomic nervous system.

This "nondopaminergic" pathology is likely responsible for

- constipation,
- anosmia,
- rapid eye movement (REM) behavior sleep disorder
Pathology
Depletion of pigmented
dopaminergic neurons in
SN

Reduced dopaminergic Inclusion bodies (Lewy Degeneration in

output from SN bodies) develop in other basal
nigral cells ganglia nuclei

↑ firing of neurons in STN resulting

in excessive inhibition of thalamus,
↓ activation of cortex.

Parkinsonian
features
Clinical features:
 Motor manifestations:
 Initially affect one-half of the body.
 Gradually progress to the contralateral side but remain
asymmetric.

 TREMOR:
 Presenting feature in about three-quarters of the idiopathic
cases
 Alternating contractions of opposing muscle groups
(frequency 4–6 Hz).
 20-30% of cases have no tremor at all.
 It is present at rest but ceases during sleep.
 May become less marked when the limb is engaged in
voluntary movement.
 It is worsened by excitement, anxiety and fatigue.
 Most typically it appears in the hands as flexio-extension
movements affecting the metacarpophalangeal joints of the
fingers and thumb.
 BRADYKINESIA & AKINESIA:
 Bradykinesia consists of poverty and slowness of
movement.
 This is the most disabling aspect of Parkinson’s disease
and contribute to problems with dexterity and gait.
 Bradykinesia probably accounts for many of the classic
features of parkinsonism:
- masklike face (hypomimia),
- infrequent blinking,
- monotonous speech, soft voice.
- Lack of prosody due to poor motor control
- clumsiness of fine finger movement,
- crabbed writing, micrographia
 Patients typically walk in a flexed forward posture without
swinging their arms.
 The gait is slow and shuffling, with small steps and a
tendency to fall forward and hasten the rate of walking
(festination = hurry).
 This typical ‘festinant’ gait appears to be a product of the
abnormal posture along with difficulty in controlling the
centre of gravity.
 Postural instability leads to frequent falls.
 The gait is affected in many characteristic ways
- slowness, shuffling,
- difficulty in starting and turning sharply
- impaired equilibrium.
- episodic quality, causing periodic freezing of action or
episodes of complete immobility.
 RIGIDITY:
 Increased muscle tone on examination.
 First indication of rigidity: muscle cramps, weakness or
stiffness.
 Rigidity affects the large and small muscles of the limbs,
trunk and neck, involving agonists and antagonists equally
and through the whole range of passive movement.
 Have a ‘lead pipe’ or ‘plastic’ quality.
 When tremor is also present the rigidity is brokenup
(‘cogwheel rigidity).
 Rigidity, like tremor, can be predominantly unilateral.
 It persists during sleep and is unaffected by emotional
factors
 Other features:
 Excessive salivation: mainly the result of difficulties in
coping with normal quantities of saliva on account of
dysphagia.
 Constipation: is a major symptom of the disease and a cause
of much distress.
 Urinary disturbance
 Infrequent blinking and paresis of convergence may occur.
The glabellar tap reflex is elicited by tapping over the root of
the nose between the eyebrows; parkinsonian patients are
said to blink in response to each tap no matter how often or
at what frequency, and fail to habituate as normal subjects
do.
 Loss of smell: it can predate the onset of motor disturbance
by over a year .
 Cognitive manifestations:
 Some degree of cognitive impairment, ranging from mild
impairment to dementia, affects nearly all patients with
Parkinson’s disease.
 25 to 40% of patients develop dementia.
 The dementia is of SUBCORTICAL type of dementia.
 Executive dysfunction is especially common.
 Compared with patients with Alzheimer’s disease,
recognition memory, aphasia, agnosia, apraxia and higher
language functions are relatively spared.
 Psychiatric manifestations:

 Psychiatric disturbances affect up to 90% of the patients at

some point during the course of Parkinson’s disease and
more than one psychiatric disturbance is often present.
 In up to 30% of patients, adult-onset anxiety disorder and
depressive disorders precede the obvious onset of motor
symptoms.
 Depression:
 Normal psychological reactions to the illness can result in
low mood, grief, demoralization, frustration and
embarrassment.
 Depressive disorders involve more pervasive mood changes
and generally resemble idiopathic forms of depression.
 Prevalence rates range from 20-90%.
 Majority of patients have non-major depressive syndromes
such as minor depression, dysthymia, subsyndromal
depression.
 Anxiety symptoms and co-morbid anxiety disorders are
especially prominent.
 Depression is generally not associated with a family history
of mood disorders.
 Apathy:
 Apathy occurs in at least 25% of patients and often co-
exists with depression.
 Indifference and a lack of motivation, initiative,
perseverance, interest in new things or concern for
one’s health.
 Inactivity, deconditioning and fatigue contribute to
further loss of function and increased disability and
suffering.
 Anxiety:
 Difficulties initiating movements can frequently lead to
anxiety-provoking circumstances.
 Anxiety is more common compared with other parkinsonian
syndromes.
 Particularly common are GAD, social phobia and panic
disorder.
 Anxiety can also be associated with fluctuations in
levodopa levels and motor function.
 Sleep disturbances are very common and seem to aggravate
daytime anxiety.
 Psychosis:
 Psychosis affects approximately 25% of the patients.
 “Visual hallucinations are the most common
psychotic symptoms in Parkinson’s disease and
are related to dopaminergic medication.
 Auditory and tactile hallucinations also occur.
 Aggression, delusional jealousy and other paranoid
accusations are frequent manifestations that may
require hospitalization.
 Hallucinations and delusions also occur with major
depression, mania or anxiety disorders.
 Other disturbances:
 Disinhibited behaviors.
 Hypersexuality is seen in 2-6% of patients and is usually
related to antiparkinsonian therapy.
 Pathological gambling.
 COURSE AND PROGNOSIS:
 Parkinson’s disease is clinically heterogeneous.
 Many cases of Parkinson’s disease can be subdivided
into:
 Tremor-predominant type: more benign course.
 Gait disorder and postural instability prominent type.
 Heterogeneity in onset, progression and levedopa
response also influences the natural history of
Parkinson’s disease.
 Successful treatment of depression improves motor
status, but medical treatment of motor symptoms does
not usually improve depression.
 Mean life expectancy from diagnosis is 14 years.
 A small number, however, show very slow progression and
remain without severe disablement after 20 years or more.
 Factors associated with increased mortality :
- Advanced age
- Dementia,
- Depression
- Lack of levodopa responsiveness.
 Common causes of death:
 Cardiac and cerebral vascular disease,
 Bronchopneumonia and neoplasia.
 Diagnosis:
 Mainly Clinical diagnosis: requires 2 of 3 cardinal signs
 No laboratory markers.
 In Parkinson’s disease, PET studies with radioactive
fluorodopa demonstrate reduced uptake in putamen.
 Rating scales:

 Research studies of PD require a means of rating the

severity of disease
- by measurement of motor manifestations,
- assessment of ability to perform daily functional activities,
- symptomatic response to medication.
The most common rating scales are
- Unified Parkinson Disease Rating Scale (UPDRS),
- Hoehn and Yahr staging,
- Schwab and England rating of activities of daily living.
 TREATMET:
 Motor symptoms:
 Pharmacological treatment:
 Current treatment options provide only symptomatic relief of
the motor symptoms and there are no preventive or
regenerative strategies.
 The gold standard of treatment is Levodopa. Mainstay of
therapy for PD.
 Dopamine does not cross the blood-brain barrier (BBB)
 So levodopa a precursor of dopamine is prescribed which
crosses BBB.
 Levodopa is routinely administered in combination with a
peripheral decarboxylase inhibitor- carbidopa to prevent its
peripheral metabolism to dopamine and the development
of nausea and vomiting due to activation of dopamine
receptors in the area postrema that are not protected by the
BBB.
 No current medical or surgical treatment provides
antiparkinsonian benefits superior to what can be achieved with
levodopa.
 Rigidity and bradykinesia are most improved.
 Dose: carbidopa/levodopa are 10:100,25:100, 25:250 mg 1-3
tablets every 3-5 hrs.
 Important limitations of levodopa therapy.
- Acute dopaminergic side effects include nausea, vomiting, and
orthostatic hypotension.
- These are usually transient and can generally be avoided by
gradual titration.
 Levodopa-induced motor complications consist of fluctuations in
motor response and involuntary movements.
 Wearing-off effect:
 When patients initially take levodopa, benefits are long-
lasting (many hours) even though the drug has a
relatively short half-life (60–90 minutes).
 With continued treatment, however, the duration of
benefit following an individual dose becomes
progressively shorter until it approaches the half-life of
the drug. This loss of benefit is known as the wearing-off
effect.
 Approximately one-third of patients can be expected to
obtain marked relief, one-third moderate benefit, and
the remainder show a modest or disappointing response.
 Perhaps some 15% do not respond at all; in such cases
the possibility of some alternative diagnosis, such as
progressive supra nuclear palsy or multiple system
atrophy, should be considered.
 It may take several months before maximal benefit is
obtained, and it cannot be said to have failed until it has
been tried for 6 months or preferably a year.
 “On” and “Off” phenomenon:
 On long term use, fluctuating motor effects replace
sustained motor benefits, with improved motor function
in response to medication (the “on” state) and reduced
mobility when medication effect subsides (the “off”
state).
 Dopamine Agonists:
 Act directly on dopamine receptors.
 Initial dopamine agonists were ergot derivatives (e.g.,
bromocriptine, pergolide, cabergoline) and were associated
with ergot-related side effects, including cardiac valvular
damage.
 They have largely been replaced by a second generation of
non-ergot dopamine agonists (e.g., pramipexole, ropinirole,
rotigotine).
 In general, dopamine agonists do not have comparable
efficacy to levodopa.
 Acute side effects of dopamine agonists include nausea,
vomiting, and orthostatic hypotension. As with levodopa,
these can usually be avoided by slow titration.
 Hallucinations and cognitive impairment are more
common with dopamine agonists than with levodopa.
 Less frequently causes dyskinesias.
 Dose: 0.25-5mg TID
 MAO-B Inhibitors:
 Inhibitors of monoamine oxidase type B (MAO-B) block
central dopamine metabolism and increase synaptic
concentrations of the dopamine.
 Selegiline and rasagiline
 Selegiline 5mg BD
 COMT Inhibitors:
 Inhibitors of COMT (catechol-O-methyltransferase) 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.
 Very effective in more advanced disease.
 Tolcapone, Entacapone
 Dose: Entacapone 200 mg with each dose of
carbidopa/levodopa
 Increases the on time of levodopa by 90-120 mins.
 It should be always combined with levodopa
 PD patients who fluctuates and who don't fluctuate also improve
 Early use with levodopa will delay or prevent motor fluctuations.
 Severe diarrhea has been described with tolcapone, and to a
lesser degree with entacapone, and necessitates stopping the
medication in 5–10% of individuals.
 Cases of fatal hepatic toxicity have been reported with
tolcapone, and periodic monitoring of liver function is required.
This problem has not been encountered with entacapone.
 Discoloration of urine can be seen with both COMT inhibitors due
to accumulation of a metabolite, but it is of no clinical concern.
 Amantadine:
 Antiparkinsonian effects due to NMDA-receptor antagonism.
 Most widely used as an antidyskinesia agent in patients with
advanced PD.
 Dose: 100-200 mg BD
 Side effects : weight gain, and impaired cognitive function.
 Central-acting anticholinergic drugs:
 Such as trihexyphenidyl and benztropine were used
historically for the treatment for PD, but they lost favor with
the introduction of dopaminergic agents.
 Appropriate for younger patients with tremor
predominant PD.
 Also used to treat sialorrhea and urinary urgency.
 Dose: Trihexyphenidyl: 2mg 3-4 times daily.
 Disease modifying drugs:
 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.
 Treatment strategy:
 During early stages, Anticholinergics (Trihexyphenidyl,
Benztropine, Amantidine, Selegiline) provide mild to
moderate reduction in motor symptoms.
 Postural instability does not usually respond to
antiparkinsonian medications.
 Dopamine agonists (Pramipexole, Ropinirole, Pergolide,
Levodopa) can then be added to address progressive
disability.
 Surgical treatment:
 Stereotactic neurosurgical therapies currently used for
Parkinson’s disease are:
 High frequency deep brain stimulation of the substantia nigra
and Globus pallidus.
 Ablative procedures that target Globus pallidus (pallidotomy)
or thalamus (thalamotomy).
 Both improve motor function because they reduce
hyperactivity of substantia nigra and its efferent targets.
 Thalamotomy and thalamic DBS are indicated for
disabling tremor.
 Cognitive symptoms:
 There are no standard treatments for cognitive deficits in
Parkinson’s disease.
 A few small clinical trials showed cognititve benefits with
Donepezil & Tacrine.
 Education of patients and families about cognitive deficits
may minimize distress.
 Psychiatric manifestations:
 The first step in the treatment of psychiatric disorders is
to evaluate:
 Contribution of antiparkinsonian medication
 Fluctuating medication effects
 Other medical conditions
 Cognitive deficits
 Caregiver and other psychosocial variables.
 Sleep is commonly disturbed in Parkinson’s disease
independent of psychiatric problems and addressing it
alone can reduce daytime mood lability, psychosis and
motor impairments.
 Patient and caregiver education and supportive
psychotherapy are cornerstones of effective treatment.
 Depression:
 Research on their treatment is limited.
 SSRIs improve depressive symptoms.
 SSRIs can aggravate motor symptoms, but this is not
especially common.
 Imipramine, Nortryptiline, Desipramine show little
efficacy.
 ECT is safe and effective for depression in Parkinson’s
disease.
 Anxiety:
 Antidepressants are often effective.
 Buspirone has been used in Parkinson’s disease.

 Apathy:
 No studies on treatment of apathy.
 Treatment of co-morbid depression is an obvious initial
approach.
 Psychosis:
 Treatment of psychosis is challenged by the delicate
balancing act between the use of medications that relieve
psychosis without aggravating motor or cognitive
dysfunction and the treatment of motor symptoms without
exacerbating the mental status.
 The gold standard is CLOZAPINE; it is effective even at low
doses (less than 25 mg).
 Because of the requisite blood monitoring with clozapine,
QUETIAPINE is usually the initial drug of choice.
 ECT can be used to treat psychotic depression as well as
dopamine-induced psychosis.
 References:
 Kaplan & saddock comprehensive textbook of psychiatry
9th edition.
 Lishman ‘s organic psychiatry 4th edition
 Harrison’s principles of internal medicine 18th edition
Thankyou