PARKINSON DISEASE - SPECT [123I]-beta CIT scans – used to measure presynaptic

Noreen T. Trinidad, MD, FPCP, FPNA dopaminergic activity

- Functional MRI and MR spectroscopy
James Parkinson (1755-1824)
1817… ESSAY ON THE SHAKING PALSY
“…involuntary tremulous motion, with lessened muscular power, in
parts not in actionand even when supported; with a propensity to
bend the trunk forward, and to pass from a walking to a running
pace, the senses and intellect being uninjured.”
CLINICAL DIAGNOSIS
- TETRAD:
o Resting tremor,
o bradykinesia,
o rigidity,
o loss of postural reflexes
- Prototype parkinsonian disorder; parkinsonism occurs in
isolation without other evidence of neuropathologic change
- Distinguishing Parkinson disease clinically from other
parkinsonian disorders:
o Asymmetry of parkinsonian signs
o marked rest tremor
o clinically significant response to levodopa
o little or no balance problems in the first months
and years of the disease
ETIOLOGY
- The cause of Parkinson disease is unknown.
- Current research efforts:
o Hereditary factors (including several genetic
defects)
o Environmental toxins that could damage
substantia nigra cells selectively
INITIAL SYMPTOMS IN PD
Tremor 70%
Gait disturbance 11%
Stiffness 10% (Left) Horizontal sections through the midbrain and pons of a 79-
Slowness 10% year-old male (control) and (right) 79-year-old male patient with
Muscle aches 8% Parkinson disease. Note the difference in pigmentation of the
Loss of dexterity 7% substantia nigra and locus ceruleus.
Handwriting disturbance 5%
Depression, nervousness, psychiatric disturbance 4%
Speech disturbance 3%
PATHOGENESIS AND PATHOPHYSIOLOGY
- Degeneration of dopamine producing cells in the pars
compacta of the substantia nigra
- Cell loss in other pigmented brainstem nuclei, autonomic
nuclei, and pyramidal cells in the presupplementary cortex
- Glial cells do not regenerate Low-power photomicrographs of substantia nigra. Note
o Activation in the midst of neuronal loss may play a
difference of neuronal density between the normal
protective role through the release of trophic
factors substantia nigra (left) and the patient with Parkinson
- Free radical toxicity from oxidative reactions disease (right). (Hematoxylin-eosin; x31.25)
o Oxidative stress
o Anti-oxidant therapy may slow down nigral DIFFERENTIAL DIAGNOSES
degeneration in PD - Essential tremor
- PET – one of the most important tools for studying the - Parkinsonism-plus syndromes – additional neurologic signs
pathogenesis and pathophysiology of changes in dopamine beside parkinsonism
neurochemistry in sporadic Parkinson disease and familial o PSP (conjugate gaze paresis)
parkinsonism o MSA (ataxia, dyssynergia, kinetic tremor)
o SND (pyramidal signs)
 o CBD (apraxia and cortical sensory dysfunction)
o Shy-Drager syndrome (marked dysautonomia)
o DLB (early dementia and hallucinations)
o Primary progressive freezing gait
- Hemiatrophy-hemiparkinsonism
- Iatrogenically-induced or exacerbated parkinsonism
- Amyotrophic lateral sclerosis-parkinsonism-dementia
complex
- X-linked Lubag syndrome
- Rigid form of Huntington disease
- Wilson disease
- Ischemic vascular disease
- Post-encephalitic parkinsonism
- Vascular parkinsonism
Parkinson Disease Cont
- diagnosis may be difficult in early stage
- tremor, rigidity and bradykinesia
- features that best predict pathological changes of
idiopathic PD
o resting tremor
o asymmetric presentation
o good response to levodopa
TREATMENT OF EARLY PARKINSON’S DISEASE
- Patients with early untreated disease
- even above criteria may not permit an accurate diagnosis
because of the mild nature of parkinsonian features
- may show no observable effect with levodopa especially if
with tremor dominant form of disease
- may still be reasonable to introduce pharmacological
treatment in any parkinsonian patient with functional
disability
o Atypical parkinsonism patients – may have initial
benefit with dopaminergic replacement
***APPENDIX A
PHARMACOLOGIC INTERVENTION: NEUROPROTECTION
- An intervention that
o protects vulnerable neurons
o slows or stops disease progression
- Selegiline
o selective monoamine oxidase (MAO)-B inhibitor
o capacity to block formation of free radicals derived
from oxidative metabolism of dopamine
o can prevent development of parkinsonian
syndrome induced by MPTP (experimental
animals)
o doses of 5 mg bid delays emergence of disability
and progression of signs and symptoms in
previously untreated PD patients
 Consistent with neuroprotective effect
- Advantages
o As adjunct to levodopa provides reduced motor
fluctuations and increased “on” time
o Levodopa-sparing effect
o Neuroprotective in laboratory models
o May be neuroprotective in PD
Disadvantages
o Minimal antiparkinson effect
o Neuroprotection in PD not definitively established
o Does not stop disease progression
o One unconfirmed report of increased mortality in
patients receiving levodopa plus selegiline
- Vitamin E (α-tocopherol)
o No delay in disease progression detected
(DATATOP study)
o No basis for recommending megadoses of Vit E to
PD patients at this time
***APPENDIX B
PHARMACOLOGIC INTERVENTION: SYMPTOMATIC THERAPY
When to initiate symptomatic therapy?
- Early treatment to provide maximal clinical benefit
or
- Delay initiation of treatment to minimize risk of developing
motor complications or accelerating disease progression
consequent to oxidant radicals derived from levodopa
metabolism
General Agreement
- Appropriate to start treatment when patient begins to
experience functional impairment
- Functional impairment
o Impairment in managing activities of daily living
 ADL subscale of UPDRS is a most useful
way to assess disability
o Threatened loss of employability
 Same degree of dysfunction is more likely
to cause disability in a patient who is
working
o Development of gait disturbance with falling
 Can lead to serious injuries
Factors that influence determination of whether a patient has
functional impairment
- whether symptoms affect the dominant or nondominant
hand
- whether patient is employed or employable
- type of parkinsonian symptoms present (e.g. bradykinesia
tends to be more disabling than tremor)
- individual patient sentiment
- philosophy of the treating physician
PHARMACOLOGIC INTERVENTION: DRUG THERAPIES***APPENDIX C
DOPAMINE AGONISTS
- Group of drugs w/ diverse physical and chemical properties
- Directly stimulate dopamine receptors
- Bromocriptine, pergolide, lisuride, apomorphine
- Cabergoline, pramipexole, ropinirole
o Pramipexole and ropinirole – non-ergot dopamine
agonists that avoid ergot-related side-effects
Advantages
- Some antiparkinson effect
- Reduced incidence of levodopa-related adverse events
- Selective stimulation of dopamine receptor subtypes
- Do not generate oxidative metabolites
- Levodopa-sparing effect
- Potential neuroprotective benefits
Disadvantages
- Limited antiparkinson efficacy
- Specific side effects
 - Do not completely prevent development of levodopa-
related adverse events
- Do not treat all features of PD, such as freezing, postural
instability, autonomic dysfunction, dementia
- Do not stop disease progression
***APPENDIX D
LEVODOPA
- Most effective drug in the treatment of PD
- Treatment is associated with decreased morbidity and
mortality
- Virtually all patients benefit from treatment
- Routinely administered in combination with a
decarboxylase inhibitor to prevent peripheral conversion of
levodopa to dopamine resulting in nausea, vomiting and
hypotension
- Employ lowest dose of levodopa that will provide a
satisfactory clinical response
- Early stages of PD 300 – 500 mg/day of levodopa usually
provides a satisfactory clinical response
- Sustained-release formulations of levodopa are less well
absorbed than the regular formulation; doses 20 to 30%
higher may be needed to achieve the same clinical effect as
the regular preparation of levodopa
- Chronic treatment with levodopa is associated with
development of adverse events in majority of patients
(motor fluctuations, dyskinesias, neuropsychiatric
problems)
- With time, new features develop that do not respond to
levodopa therapy (falling, postural instability, freezing,
autonomic dysfunction, and dementia)
- Levodopa treatment may promote oxidative stress and
accelerate neuronal degeneration in PD because of
potential to generate reactive oxidant species
- Pulsatile stimulation of dopamine receptors is believed to
induce postsynaptic changes, resulting in development of
motor fluctuations and dyskinesia
- Pharmacologic Intervention:
Drug therapies
COMT (Catechol-O-methyltransferase) inhibitors
- Entacapone and tolcapone
- extends plasma half-life and duration of L-dopa
- prevents breakdown of levodopa
COMT inhibitors as an adjunct to levodopa
Advantages
- Decreased “off” time in fluctuators and improved ADL
scores in nonfluctuators
- Easy to administer
- Increases levodopa availability to the brain
- Smoother levodopa plasma levels may reduce risk of
levodopa-related adverse events
Disadvantages
- Dopaminergic side effects, especially dyskinesia
- Intolerable diarrhea in 5 to 6% of tolcapone-treated
patients
- Tolcapone patients require monitoring of liver function
***APPENDIX E
ANTICHOLINERGICS
- In PD, dopamine depletion results in a state of relative
cholinergic sensitivity
- Cholinergic drugs exacerbate and anticholinergic drugs
improve parkinsonian symptoms
- Typically used in younger PD patients (<70 yrs) in whom
tremor is the dominant clinical feature and cognitive
function is preserved
- Useful for treating resting tremor but of lesser value in
treatment of akinesia or impaired postural reflexes
- Adverse effects are common and often limit their use
- Most important side effects
o Memory impairment
o Acute confusion
o Hallucinations
- Adverse events most likely to occur in older individuals but
even younger parkinsonian patients without evident
cognitive impairment can experience neuropsychiatric
dysfunction during anticholinergic treatment
- Other CNS side effects: sedation, dysphoria
- Peripheral antimuscarinic side effects: dry mouth, blurred
vision, constipation, nausea, urinary retention, impaired
sweating and tachycardia
AMANTADINE
- Antiviral agent discovered by chance to have antiparkinson
activity
- Principal mechanism of action has not been established
- Known to increase dopamine release, block dopamine reuptake,
stimulate dopamine receptors and, possibly to have peripheral
anticholinergic properties
- Appears to be more effective than anticholinergic drugs with
regard to akinesia and rigidity but is less effective with regard to
tremor
- Most important side effects: confusion, hallucinations, insomnia
and nightmares (more common in older patients but can be seen
in patients of any age)
TREATMENT OF EARLY PARKINSON’S DISEASE
1. Ensure that the correct diagnosis has been made.
2. Consider neuroprotective therapy as soon as diagnosis is made.
3. Initiate symptomatic therapy with a dopamine agonist in
appropriate patients.
4. Supplement with levodopa when dopamine agonist monotherapy
can no longer provide satisfactory clinical control.
5. Consider introducing supplemental levodopa therapy in
combination with a COMT inhibitor to extend its elimination half-
life and further reduce the risk of motor complications.
FACTORS THAT MIGHT INFLUENCE CHOICE OF INITIAL THERAPY
Age Dopamine agonists in younger pxs (<70 yrs)
- Levodopa + decarboxylaxe inhibitor in older pxs
o Concerns about cognitive dysfunction
o Older pxs less likely to develop levodopa-related motor
complications
- Anticholinergic drugs and amantadine
o Specifically discouraged in older patients (risk of
aggravating underlying mental function)
- Factors that might influence choice of initial therapy in PD
Cognitive impairment
- Most favor initiating treatment of PD sxs with levodopa +
decarboxylase inhibitor in pxs with cognitive impairment
regardless of age
- Immediate-release formulation
o Simpler to initiate
o Easier to adjust
o Can avoid cumulative effects associated with controlled
release preparations and psychiatric problems
associated with DA antagonist