Chapter 18: Parkinson's Disease
Drug Treatment |
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Tremor: rhythmic/oscillatory movement -- around a joint
Resting tremor (Parkinson's disease): , associated with:
rigidity
impairment of volitional movement
Essential Tremor:
postural tremor (clearly observable)
Intentional Tremor:
brain stem/cerebellar lesion (particularly with superior cerebellar peduncle involvement
May be associated with alcohol/other drug toxicities
Chorea: involuntary muscle jerks; unpredictable
hereditary
secondary to drug treatment/various physiological disorders
volitional activity impairment
different parts of the body affected
limb proximal muscles-- most severely affected
violent movements -- ballismus
Athetosis:slow, writhing abnormal movement
Dystonia:postural abnormality -- associated with sustained, abnormal movement
Athetosis/dystonias -- causes/characteristics:
brain damage (perinatal)
focal/generalized cortical lesions
adverse effect associated with certain drugs (e.g. antipsychotics)
associated with various neurological disorders:
unknown causes:
idiopathic torsion dystonia
dystonia musculorum deformans
Tics: sudden, abnormal coordinated movements
single/multiple; transient/chronic
Chronic, multiple tics: Gilles de la Tourette's syndrome (Tourette's syndrome)
repetitive (especially around head/face, in children)
voluntary suppression: for limited amount of time
Common tics:
shoulder shrugging
repetitive sniffing
tremor |
bradykinesia |
rigidity |
characteristic gait/postural abnormality |
Chronic, progressive
begins in middle/late life and leads to progressive disability
Affects all ethnic groups
Equal gender distribution
General Population: 1-2 per 1000 people
Population > 65 years: 1 per 100 persons
Age group -- 65-74 years of age: 15%
Age group -- > 85 years of age: > 50%
Neuroanatomical Correlates of Disease
Normal anatomy and physiology:
Cell bodies from the substantia nigra pars compacta provides dopaminergic input to the striatum (basal ganglia)
dopaminergic neurons + cholinergic striatal interneurons modulate monosynaptic GABA inhibitory output to the globus pallidus internus and pars reticulata of the substantia nigra
globus pallidus internus transmits GABA-mediated inhibition to the ventrolateral/ventroanterior thalamic nuclei (direct pathway, striatal D1-mediated)
globus pallidus externus transmits via subthalamic nuclei (indirect pathway, striatal D2-mediated) excitatory (Glutamate) input to the globus pallidus internus.
Neuronal loss in Parkinson's Disease
loss of substantia nigra pars compacta cells cause reduced nigral-striatal dopamine input to the putamen. There are two effects:
loss of an striatal excitatory dopamine input (D1-mediated direct pathway)
loss of dopamine-mediated excitation of an inhibitory GABA pathway (DeLong's model) causes GPi hyperactivity which leads to excessive thalamic inhibition (GPi output is inhibitory (GABA)
loss of an striatal inhibitory dopamine input (D2-mediated, indirect pathway)
loss of dopamine-mediated inhibition of a GABA inhibitory pathway more GABA release and GPe hypoactivity
GPe hypoactivity decreases GABA (inhibitory) output to subthalamic nuclei.
Increased subthalamic nuclei excitatory output (glutamate-mediated) further increases GPi hyperactivity leading to further thalamic inhibition.
GABA -- basal ganglia inhibitory neurotransmitter
Glutamate -- excitatory neurotransmitter (subthalamic nuclei ® thalamus)
Loss of striatal dopamine increases GPi activity by both direct and indirect mechanisms leading to increased thalamic inhibition and reduced thalamic-mediated motor cortex excitation (bradykinesia): see Iacona et al., Am. Surg 60: 777-782, 1994);
Recall dopamine normally activates excitatory D1 receptors (direct pathway) and represses inhibitory D2 receptors (in direct pathway) -- with dopamine depletion:
decreased activity of direct pathway (less GPi inhibition) leads to increased GPi activity which results in increased thalamic inhibition
increased activity of the indirect pathway (more GPe inhibition) leads to less subthalamic nuclei inhibition and increased GPi activity resulting in increased thalamic inhibition
Chemically-Induced: in primates by --
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which is
converted to the active form by monoamine oxidase
active toxin: MPP+ -- N-methyl-4-phenylpyridinium
MPP+:
taken up into nerve terminals by dopamine reuptake system (active transport)
inhibits oxidative phosphorylation (possibly complex I; respiratory chain site)
may also produce oxidative stress/free radicals
Consequence:
nigro-striatal neuronal death
basal ganglia dopamine depletion
Parkinson's disease
unknown
Possibilities include:
environmental toxin
endogenous toxins (perhaps related to free radicals generation)
Genetic Aspect: uncertain
Frequency: usually 4-to 6-Hz
7-8-Hz in about 10%-15% (resembling essential tremor)
resting tremor (worsens with stress)
initially:
rhythmic flexion-extension of: fingers, hand, foot
rhythmic pronation-supination to forearm
may be associated with one limb or to limbs ipsilateral, initially, then becoming more widespread
Rigidity:increased resistance to passive movement
common feature (flexed posture)
Bradykinesia: most disabling disease manifestation
severest form -- akinesia
Characteristics:
voluntary movement: slowness
Flat affect (flat facial expression)
widened palprebral fissures
infrequent blinking
Blepharoclonus: (closed eyelid fluttering)
Blepharospasm: (eyelid closure -- involuntary)
Drooling
Voice: hypophonic/poorly modulated
Handwriting: small, tremulous, perhaps illegible
difficulty in initiation -- patients may increasingly leaned forward to begin movement
small, shuffling steps
no arm-swing
stopping difficulty
festinating gait:
walking with increasing speed to keep from falling (because because of abnormal center of gravity)
Tendon: unaltered
Tapping over the glabella: sustained blink response (Myerson's sign)
may reach dementia in advanced cases
Primary Reference: Aminoff, M. J. Pharmacologic Management of Parkinsonism & Other Movement Disorderslogy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 450-463
Primary Reference: Aminoff, M. J. Parkinson's Disease and Other Extrapyramidal Disorders, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 2356-2362
Iacona et al., Am. Surg 60: 777-782, 1994