ABSTRACT
B. Striatum and Pallidostriatal Connections 1. Main input to the basal ganglion: cerebral cortex
(mainly frontal lobe) 2. Other sources of input to the striatum are from
a. Thalamus: excitatory input b. Dopaminergic neurons of substantia nigra pars compacta
1) Dopaminergic input to spiny striatal neurons with dopamine1 (D1) receptors: dopamine acts on D1 receptors on striatal output neurons projecting to substantia nigra pars reticulata and globus pallidus interna (direct pathway); these output neurons are γ-aminobutyric acid (GABA)ergic, with substance P and dynorphin as cotransmitters
2) Dopaminergic input to spiny striatal neurons with D2 receptors: dopamine acts on D2 receptors on striatal output neurons projecting to globus pallidus externa (indirect pathway); these output neurons are GABAergic, with enkephalin as cotransmitter
3) The substantia nigra pars compacta input facilitates the direct pathway via D1 receptors and inhibits the indirect pathway via D2 receptors
4) Degeneration of dopaminergic substantia nigra pars compacta input (which occurs with idiopathic Parkinson’s disease) leads to relative activation of the indirect pathway and resultant hypokinetic movement disorder (Fig. 8-1 B)
5) Dopaminergic input to both pathways acts to enhance excitatory cortical input
c. Large aspiny striatal interneurons: excitatory (cholinergic) and influenced by cortical input
d. Neighboring medium spiny neurons: collateral inhibition
3. The majority of the neurons are medium spiny projection neurons, which are GABAergic inhibitory cells projecting to globus pallidus and subtantia nigra
4. Main cortical input: excitatory glutaminergic synapses on dendritic spines of GABAergic neurons
5. Output (primarily GABAergic, inhibitory) a. Globus pallidus interna and substantia nigra pars reticu-
lata as a functional unit 1) Receive inhibitory GABAergic input from striatal
projection neurons with substance P and dynorphin as cotransmitters
2) GABAergic cells with projections to ventrolateral and ventroanterior thalamus (excitatory relay to cerebral cortex)
b. Globus pallidus externa 1) Receives inhibitory GABAergic input from striatal
neurons with enkephalin as cotransmitter 2) GABAergic cells with projections to subthalamic
nucleus
C. Subthalamic Nucleus 1. Receives inhibitory GABAergic input from globus pal-
lidus externa 2. Receives excitatory glutaminergic input from cerebral
cortex 3. Contains excitatory neurons with glutamate as the pri-
mary neurotransmitter
4. Output: excitatory and mainly to globus pallidus interna and substantia nigra pars reticulata, some projections to globus pallidus externa as excitatory feedback
D. Intrinsic Circuits 1. Direct pathway (Fig. 8-1 C)
a. Dopaminergic activation of D1 receptors b. Direct phasic inhibition of globus pallidus interna and
substantia nigra pars reticulata (transmitter, GABA; cotransmitters, substance P and dynorphin) by striatal projection neurons, which in turn, reduce inhibition of the thalamus by globus pallidus interna and substantia nigra pars reticulata
c. Activates thalamocortical excitatory pathways and promotes movement
d. Net result: augmentation of movement e. Hyperactive in hyperkinetic disorders
2. Indirect pathway (Fig. 8-1 B) a. Dopaminergic activation of D2 receptors
b. GABAergic inhibition of globus pallidus externa (cotransmitter, enkephalin), causing reduced inhibition of the subthalamic nucleus and subsequent activation of subthalamic nucleus excitatory projections to globus pallidus interna and substantia nigra pars reticulata
c. Indirect excitatory stimulation of the globus pallidus interna and substantia nigra pars reticulata, increasing inhibition of the thalamus and subsequent reduction of excitatory thalamocortical projections
d. Net result: reduction of movement e. Hyperactive in hypokinetic disorders
E. Physiology 1. At rest
a. Low-frequency spontaneous discharge of medium spiny striatal neurons (relatively hyperpolarized because of an inward rectifying potassium current)
b. High-frequency spontaneous discharge of globus pallidus interna and substantia nigra pars reticulata
2. With movement a. Corticostriatal pathway activates a desired motor pro-
gram: excitatory corticostriatal input overcomes the inward rectifying potassium current (requires temporal and spatial summation of excitatory input to multiple dendritic spines simultaneously) activation of striatum stimulates striatal phasic inhibition to globus pallidus interna and substantia nigra pars reticulata (overcoming excitation from subthalamic nucleus), decreasing the frequency of spontaneous discharges of globus pallidus interna and substantia nigra pars reticulata and promoting excitatory thalamocortical input for the desired movement (Fig. 8-1 C)
b. Corticosubthalamic pathway inhibits undesired motor programs: excitatory cortical input to the subthalamus increases subthalamic glutaminergic excitation of inhibitory globus pallidus interna and substantia nigra pars reticulata cells, increasing inhibition of the thalamocortical input for the undesired movement
c. End result: 1) Reduction of undesired movements (excitation of
globus pallidus interna and substantia nigra pars reticulata by cortical stimulation of subthalamic nucleus and release of inhibition of subthalamic nucleus via the indirect pathway)
2) Promotion of the desired motor programs (striatal inhibition of globus pallidus interna and substantia nigra pars reticulata via the direct pathway)
F. Parallel Circuits (Table 8-1) 1. Five parallel circuits have different corticostriatal input
from specific cerebral cortical areas and project back to the same cortical areas via a thalamic relay
2. Responsible for the role of basal ganglia in cognition and affective functions in addition to motor and oculomotor functions
A. Idiopathic Parkinson’s Disease 1. Risk factors
a. Age b. Sex (M > F) c. Family history d. History of exposure to toxins: higher risk with exposure
to pesticides, herbicides, welding (manganese poisoning), or for agricultural workers
e. History of head trauma 2. Inherited parkinsonism (Table 8-2)
a. PARK1 gene 1) Autosomal dominant 2) Missense mutation or triplication of the α-synuclein
gene on chromosome 4q 3) α-Synuclein: role in synaptic function and transmitter
release 4) L-dopa-responsive parkinsonism with young age at
Table 8-1. Basal Ganglia Parallel Circuits
Output Thalamic Circuit Cortical origin of circuit Striatum (GPi/SNr) nucleus Function
onset, associated with dystonia, and more prominent dementia than sporadic Parkinson’s disease
b. PARK2 gene 1) May be responsible for up to half of inherited cases
with early-onset parkinsonism 2) Autosomal recessive 3) Early-onset parkinsonism with early dystonia 4) Mutation of parkin protein (gene on chromosome 6) 5) Parkin protein is required for protein degradation via
the proteasome complex a) Ubiquitination of a protein (no longer needed by
the cell) is the key step in marking that protein for subsequent degradation by the proteasome
b) Ubiquitination requires the action of ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3); Parkin is an E3 ubiquitin ligase
c) Abnormal accumulation of the substrate protein eventually causes selective cell death of dopaminergic neurons
d) Lewy bodies do not form in the absence of ubiquitinated protein inclusions
3. Clinical features a. Tremor
1) Characterized as rest tremor 2) May also be a postural or kinetic tremor (rest tremor
typically dampens with posture or action) 3) Usually unilateral onset in an extremity 4) Tremor may spread to involve contiguous extremities
b. Rigidity 1) Not velocity-dependent or direction-dependent 2) “Cogwheeling”: usually indicative of superimposed
tremor c. Bradykinesia
1) Reduced arm swing 2) Generalized slowness in movements 3) Slowness and difficulty with manual dexterity
(Fig. 8-2) 4) Micrographia 5) Masked facies (hypomimia) 6) Sialorrhea because of bulbar bradykinesia
d. Postural instability 1) Loss of postural reflexes 2) Retropulsion as may be found on the “pull test”
e. Gait disturbance
Table 8-2. Inherited Forms of Parkinson’s Disease
Key Pattern of Chromosome clinical
Gene inheritance of gene locus feature
Cardinal Features of Parkinson’s Disease Tremor
Rigidity
Bradykinesia
Postural instability and gait disturbance
Genetics of Idiopathic Parkinson’s Disease PARK1: autosomal dominant (α-synuclein gene on chromosome 4)
PARK2: Autosomal recessive (parkin gene on chromosome 6)
Both: early parkinsonism and dystonia
1) Stooped posture: characteristic “shuffling” festinating gait with short stride, with tendency to lean forward
2) Propulsion: involuntary and unwanted forward acceleration when patient wants to stop
3) Difficulty initiating gait and gait “freezing” after gait already initiated (sudden inability to take another step)
4) Difficulty with turns f. Associated features
1) Hypokinetic speech: characterized by reduced amplitude and sometimes acceleration of rate
2) Autonomic features a) Most commonly, orthostatism, usually not a pre-
senting feature b) Other less common features: urinary symptoms
(hesitancy, nocturia, incontinence), sexual dysfunction, intermittent increased sweating
3) Behavioral and cognitive features a) Bradyphrenia (mental slowing), with difficulty
with attention, and poor initiation and working memory
b) Depression in up to 2/3 of patients and anxiety (especially associated with akinetic “off” state)
c) Dementia may develop after many years i) Difficulty with frontal lobe executive and
visuospatial functions, with some language deficits ii) Difficulty with attentional tasks and those
involving timed responses 4. Neuroimaging
a. Magnetic resonance imaging (MRI): generally not helpful b. Fluorodopa positron emission tomography (PET):
reduced uptake in dopaminergic striatal and nigrostriatal pathways, proportional to severity of disease and pathology
5. Histopathology (Fig. 8-3) a. Macroscopic pigmentary loss and microscopic neuronal
loss of substantia nigra pars compacta, with microglial activation and cytoplasmic pigmentation of macrophages
b. Locus ceruleus, intermediolateral cell column, and dorsal motor nucleus of the vagus nerve may be affected
c. Lewy bodies in surviving neurons in areas affected (sparing neocortex): cytoplasmic inclusions with dense eosinophilic core containing hyperphosphorylated neurofilament proteins, lipids, iron, ubiquitin, and α-synuclein
6. Treatment (Table 8-3) a. Levodopa
1) Precursor of dopamine 2) Should be taken on empty stomach because it com-
petes with amino acids in crossing the blood-brain barrier by a transporter
3) Formulations a) Immediate release (IR) carbidopa-levodopa
i) More predictable response than controlled release ii) Start at 1 tablet of 25/100 IR 3 times daily and
increase to ceiling dose of 3 1/2 tablets 3 times daily
iii) If not tolerated, may start at 1/4 of 25/100 IR tablet
iv) Should be taken 1 hour before meals b) Controlled-release (CR) carbidopa-levodopa
i) Twice daily regimen: start at 1 tablet of 25/100 CR twice daily and increase to ceiling dose of 4 to 6 tablets twice daily
ii) Should be taken 2 hours before meals iii) Onset of action: usually about 2 hours iv) May be used as initial therapy in absence of
clinical fluctuations v) Disadvantage: delayed and unpredictable
absorption and response, may cause severe dyskinesias
4) Increments in dose should be made weekly because a week is required to determine cumulative effect of drug
5) Inconclusive evidence about potential levodopa toxicity as initial agent
6) Simpler to use and initiate than the agonists 7) Most efficacious and potent medical treatment 8) Greater incidence of motor fluctuations and
dyskinesias than with dopamine agonists 9) Adverse effects
a) Nausea i) Due to premature conversion of levodopa to
dopamine in the circulation by the peripheral dopa decarboxylase enzyme (L-aromatic amino acid decarboxylase)
ii) Dopamine in the circulation does not penetrate blood-brain barrier but can penetrate into brainstem chemoreceptor trigger zone that lacks blood-brain barrier, and this is responsible for nausea
iii) Common cause of nausea at initiation of levodopa therapy is inadequate doses of carbidopa; this drug does not cross blood-brain barrier and acts to inhibit peripheral dopa decarboxylase enzyme; approximately 100 to 150 mg of carbidopa per day is required to saturate this peripheral enzyme
iv) May be treated with dry bread or cracker (low protein), adding carbidopa to each dose, domperidone (Motilium), or trimethobenzamide (Tigan) 250 mg 1 to 3 times daily as needed
b) Dyskinesias i) Dystonia (parkinsonian) ii) Choreiform (levodopa-induced): reduce dose of
levodopa for peak-dose dyskinesias c) Orthostatic hypotension (management discussed
in another chapter) d) Visual hallucinations and psychosis e) Insomnia and vivid dreams (discussed below)
b. Dopamine agonists (Table 8-3) 1) Directly activate dopamine receptors 2) Activation of both D1 and D2 receptors needed for
optimal physiologic response 3) All have high affinity for D3 receptors 4) More likely than levodopa to produce psychosis, hal-
lucinations, and orthostatic hypotention 5) Less likely than levodopa to produce dyskinesias 6) Synergistic effect with concomitant use of levodopa to
exacerbate dyskinesias while reducing the “off” state, necessitating a lower levodopa dose
7) Pergolide and bromocriptine a) Ergot derivatives, higher chance of ergot side
effects such as potential for vasoconstriction (e.g.,
Table 8-3. Medical Treatment for Parkinson’s Disease
Usual Maximal dose Drug starting dose (usual target dose) Adverse effects
Reynaud’s phenomenon), erythromelalgia, pulmonary and retroperitoneal fibrosis (rare)
b) Pergolide: recently reported cases of noninflammatory fibrotic degeneration of cardiac valves is believed to involve serotonin-mediated abnormal fibrogenesis via 5-HT2B receptors in fibroblasts of heart valves
8) Pramipexole and ropinirole: nonergolines, have lower rate of adverse effects than traditional dopamine agonists above; may rarely cause sleep attacks and leg edema
c. COMT inhibitors 1) They inhibit catechol O-methyltransferase (COMT)
and increase plasma level of levodopa 2) Formulations
a) Tolcapone (Tasmar) i) Rarely used because of reported cases of acute
fulminant liver failure, requiring frequent monitoring of liver function enzymes
ii) Reversible central-and peripheral-acting COMT inhibitor
b) Entacapone (Comtan) i) Reversible peripheral-acting (including gastro-
intestinal tract, erythrocytes, and liver) ii) Shorter duration of action than tolcapone iii) Given as 200-mg dose with each dose of
levodopa 3) They do not delay time to reach peak plasma level of
levodopa 4) They do not delay absorption of levodopa 5) They act to prolong “on” time 6) Have predisposition to levodopa-induced dyskinesias
and other adverse effects (e.g., nausea), sometimes requiring decrease in levodopa dose
7) Other adverse effects: abdominal cramps, abdominal pain, severe diarrhea (1.3% of patients) related to allergic hypersensitivity-otherwise, well tolerated
d. Anticholinergic agents 1) Usually less effective than levodopa or dopamine
agonists 2) May be selectively more effective for tremor and dys-
tonia poorly responsive to levodopa or dopamine agonist when added
3) Dose-related therapeutic effect 4) Most commonly used formulations: trihexyphenidyl
(Artane) and benztropine mesylate (Cogentin) 5) Adverse effects: dry mouth, blurred vision, urinary
retention, forgetfulness, hallucinations, psychosis e. Adjunctive therapy
1) Amantadine a) Used in early stages: may delay need for levodopa b) Used as adjunctive therapy: reduce the required
doses of dopaminergic treatment c) May be effective in reducing levodopa-induced
dyskinesias d) Excreted unchanged in the urine: dose needs to be
reduced in patients with renal impairment and in elderly
e) Can cause cognitive impairment 2) Selegiline
a) Selectively inhibits monoamine oxidase (MAO)-B and not MAO-A at doses below 10 mg daily
b) Daily dose above 10 mg can inhibit MAO-A and may induce hypertensive crisis with ingestion of tyramine-containing food
c) Delays the need for levodopa if started early, but no long-term benefit
d) Unclear if it has neuroprotective effect e) Metabolized to amphetamine and
methamphetamine f) May have a synergistic effect with levodopa
f. Sleep disturbance and treatment 1) Parkinsonism-related akathisia (restlessness) or other
motor symptoms: fourth dose of carbidopa-levodopa IR
2) Insomnia and fragmented sleep a) Parkinsonian symptoms: nocturnal awakenings
from rigidity and difficulty turning in bed, nocturnal akathisia, nocturnal leg cramps and dystonias (including early morning dystonias) i) Initial insomnia: use carbidopa-levodopa IR at
bedtime ii) Awakening 2 to 3 hours after sleep onset: use
CR formulation or dopamine agonist before sleep
iii) Awakening after 3 to 5 hours or early morning hours: use carbidopa-levodopa IR on awakening
COMT Inhibitors Tolcapone
A reversible central and peripheral-acting COMT inhibitor
Entacapone A reversible peripheral-acting COMT inhibitor; shorter half-life than tolcapone (usually given with each levodopa-carbidopa [Sinemet] dose)
b) Medication effect: alerting effect, insomnia, hallucinations, vivid dreams, nightmares, or dyskinesias-reduce dopaminergic medications, add hypnotics, or reduce or discontinue causative drug if possible
c) Primary sleep disturbance: restless legs syndrome associated with Parkinson’s disease (treat with dopamine agonist or gabapentin)
d) Depression (may afflict up to 40% of patients with Parkinson’s disease): treat with selective serotonin reuptake inhibitor (SSRI) or a bedtime tricyclic antidepressant
e) Circadian rhythm disturbance: treat with melatonin
3) Hypersomnia and excessive daytime sleepiness a) Secondary to insomnia and fragmented sleep b) Obstructive sleep apnea (primary sleep disorder):
associated with idiopathic Parkinson’s disease c) Depression d) Narcolepsy-like disorder with hallucinations and
sleep attacks 4) Excessive nocturnal motor activity
a) Rapid eye movement (REM) sleep behavior disorder (RBD) i) Up to 30% of patients with Parkinson’s disease
develop RBD at some time ii) Up to 40% of patients with idiopathic RBD
eventually develop Parkinson’s disease at mean of 12.7 years after RBD onset
iii) Loss of skeletal muscle atonia during REM sleep iv) Excessive chin muscle tone and limb motor
activity noted on polysomnography v) Usually associated with dreams of being chased
or threatened, may involve violent and aggressive motor activity
vi) Sporadic in frequency and severity vii) Must distinguish from “sundowning,” (patient
appears awake and confused) viii) Treatment: small doses of clonazepam
(Klonopin) or melatonin at bedtime b) Periodic limb movements of sleep: occurs more
frequently in patients with Parkinson’s disease 5) Hallucinations
a) Medication-induced: levodopa (vivid dreams, nightmares), anxiolytics, anticholinergics, antidepressants
b) Associated with sundowning and dementia c) Associated with RBD d) Treatment
i) Discontinue the weaker antiparkinsonian medi-
cine believed to exacerbate hallucinations (e.g., amantadine)
ii) If continued, treatment options may include clozapine, quetiapine (Seroquel), or olanzapine (Zyprexa)
g. General approach to initial symptomatic treatment in mild to moderate parkinsonism 1) Consider treatment with levodopa or dopamine
agonist if symptoms interfere with daily activity 2) If minimal interference with daily activity: may start
with selegiline, amantadine, or anticholinergic agent 3) Onset of symptoms at young age (<40-50 years):
many prefer to start with dopamine agonist (no motor fluctuations or dyskinesias in absence of levodopa, much less potent than levodopa) or combination therapy (levodopa and dopamine agonist) a) Patients with early onset parkinsonism are more
prone to dyskinesias and fluctuating motor responses and response to levodopa is less predictable
4) Onset of symptoms at older age: start with levodopa IR 25/100 3 times daily 1 hour before meals and titrate weekly or consider an agonist; initial dose may be smaller and titration slower if nausea or other prominent adverse effects
h. General approach to advancing Parkinson’s disease (Fig. 8-4) 1) “Wearing off” effect
a) Most common type of motor fluctuation in advancing disease
b) Recurrence of parkinsonian symptoms and clinical deterioration before next dose
c) If response to levodopa during the “on” phase is adequate, move next dose to an earlier time and shorten the time between doses
d) If response to levodopa during the “on” phase is inadequate, increase individual levodopa dose before making any adjustment in timing of next dose
e) Addition of dopamine agonist after adjustments to levodopa regimen has been made reduces motor fluctuations
f) Addition of COMT inhibitors may also increase the “on” phase but predispose to levodopa-induced adverse effects (e.g., dyskinesias)
2) Dyskinesias a) Dystonic in absence of chorea: usually
parkinsonian (most commonly, early morning or nocturnal dystonia such as painful foot cramps)
b) Choreiform with or without dystonia: usually levodopa-induced
c) Usually peak-dose (Off-On-Dyskinesia-On-Off)
and rarely biphasic (Off-Dyskinesia-OnDyskinesia-Off)
d) Mechanism thought to involve overactivity of direct striatum-globus pallidus interna pathway
e) Peak-dose dyskinesias: reduce amount of levodopa IR and consider discontinuing adjunctive selegiline or COMT inhibitors
f) Consider addition of amantadine g) Rapid motor fluctuations with alternating dys-
kinesias and “off” states, consider addition of an agonist (use adequate dose and avoid rapid titration of dose)
h) Biphasic dykinesias (true biphasic dyskinesias are rare): shortening the time between doses
3) “On-Off” phenomenon a) Unpredictable, abrupt episodes of parkinsonism b) Usually treated with increasing levodopa dose or
addition of dopamine agonists 4) Freezing
a) Usually occurs because of rigidity and bradykinesia, represents difficulty with initiating movements (walking, getting up from a seated position, etc.)
b) “Off” phase, end-dose freezing responds to short-
ening the time between levodopa doses and taking the next dose at earlier time, addition of a COMT inhibitor or agonist
c) If clinical response to levodopa is inadequate, treatment is to increase the respective levodopa dose
d) Liquid levodopa as “rescue therapy” can be effective given relatively short onset of symptoms
e) Rarely, occur as a peak-dose effect (may respond to a slight decrease in the respective levodopa dose)
i. Surgical treatment of Parkinson’s disease 1) Thalamotomy
a) Now obsolete b) Alleviates or abolishes contralateral rest tremor or
rigidity in 80% to 90% of patients c) Also effective for contralateral dyskinesias d) No effect on bradykinesia, postural instability, or
other axial symptoms e) Complications: weakness, numbness, paresthesias,
dysarthria, delayed-onset dystonia (more common with bilateral procedures previously done)
2) Unilateral pallidotomy a) Improves rigidity, postural instability, and brady-
kinesia (as opposed to thalamotomy), although not much greater benefit over L-dopa treatment.
