Download Neurodegenerative Disorders: Parkinson`s Disease

NEUROLOGY BOARD REVIEW MANUAL
Neurodegenerative Disorders:
Parkinson’s Disease
Catherine L. Gallagher, MD
INTRODUCTION
As the population ages, adult-onset neurodegenerative disorders will be encountered even more frequently by clinical neurologists. New treatments will continue
to emerge as scientific understanding of the molecular
genetic and pathophysiologic basis of these disorders
evolves.
Volume 8 of the Hospital Physician Neurology Board
Review Manual will focus on the diagnosis and management of neurodegenerative disorders. Because many
excellent comprehensive reviews of these topics have
been written, the goal is to provide an outline for review
of basic concepts and to stimulate critical thinking. This
manual is devoted to a discussion of Parkinson’s disease.
Future manuals in this volume will address parkinsonian
syndromes, dementia, and neurodegenerative conditions of the peripheral nervous system and muscle.
CLINICAL AND PATHOLOGIC FEATURES
Movement disorders are classified as hyperkinetic (ie,
abnormal forms of excess movement are the dominant
feature) or hypokinetic (ie, decreased movement is the
essential feature). Parkinson’s disease is the most common hypokinetic disorder and the second most common late-life neurodegenerative disease, affecting 1%
of persons older than 65 years.1 Idiopathic Parkinson’s
disease is characterized clinically by the triad of resting
tremor, bradykinesia, and rigidity and pathologically by
loss of dopaminergic neurons in the pars compacta
(dorsal portion) of the substantia nigra.
CLINICAL PRESENTATION
The clinical presentation of Parkinson’s disease is heterogeneous. As in many neurodegenerative conditions,
clinical signs of disease appear when cerebral reserve has
been exhausted. Several prodromal symptoms seem to
occur more frequently in individuals who develop Parkinson’s disease. These symptoms include late-life depres-
2 Hospital Physician Board Review Manual
sion,2 rapid eye movement sleep (REMS) behavior disorder,3 constipation,4 and anosmia. At initial presentation,
patients may describe classic symptoms of tremor, micrographia, extreme slowness in completing activities of
daily living, voice changes, or difficulty maneuvering in
bed. They also may present with nonspecific complaints,
such as stiffness, pain, weakness, fatigability, mild incoordination, or poor balance.5
Motor Symptoms
A clinical diagnosis of Parkinson’s disease is based on
the presence of 3 of 4 cardinal signs (tremor, rigidity,
bradykinesia, and impaired postural reflexes) or the
presence of 2 signs if tremor, rigidity, or bradykinesia is
asymmetric.6 The classic tremor is a unilateral pillrolling 3- to 5-Hz rest tremor that is most evident when
the patient is walking or seated with hands relaxed. However, leg tremor that improves with weight bearing and
action (postural) tremor that dampens transiently with
assumption of a new posture (reemergent rest tremor)
are frequently observed. Chin tremor is common.
The essential change in muscle tone in patients
with Parkinson’s disease is rigidity. Rigidity is velocityindependent resistance to passive movement about a
joint. Paratonia, in contrast, implies inability to voluntarily relax. Although the tone change in Parkinson’s
disease may be termed cogwheeling, a physician flexing
and extending the arm of any patient with tremor may
note a ratcheting quality to the movement. In patients
with Parkinson’s disease, rigidity should be detectable
in addition to cogwheeling. Rigidity may be confirmed
by asking the patient to perform a voluntary (“mirror”)
movement in the contralateral limb.
Parkinson’s disease causes slowness and reduced
amplitude of movements, appearing in the spectrum
of hypokinesia, bradykinesia, and akinesia. Specific
manifestations include bradyphrenia (slow verbal
responses), hypophonia, hypomimia (masked facies),
micrographia, digital impedance (tendency for rapid
alternating movements to “block” or assume the rhythm
of the tremor),6 and decreased arm swing. Later, more
severe symptoms appear, including freezing (inability to
Neurodegenerative Disorders: Parkinson’s Disease
Table 1. Modified Hoehn and Yahr Staging Scale for
Parkinson’s Disease
Stage
0
1
1.5
2
2.5
Description
No signs of disease
Unilateral disease
Unilateral disease with axial involvement
A
B
Bilateral disease without postural instability
Early signs of postural instability (recovery on
“pull test”)
3
Bilateral disease with postural instability, physically
independent
4
Severe disability but still able to stand or walk
unassisted
5
Confinement to wheelchair or bed
Adapted from Hoehn MM. The natural history of Parkinson’s disease
in the pre-levodopa and post-levodopa eras. Neurol Clin 1992;10:
331–9. Reprinted with permission from Elsevier Science.
initiate gait, especially when turning or passing through
a doorway), retropulsion (more than 2 steps required for
recovery on the “pull test”),7 and difficulty arising from a
chair without rocking back and forth or using the arms.
Although slightly flexed posture is normal in elderly
persons, the flexed position is more exaggerated in
Parkinson’s disease. Dystonia—especially involving the
brow (blepharospasm), toes, or feet—is common. Oculomotor findings may include slow saccades, insufficient
convergence, and reduced blink rate. Glabellar reflex
(Myerson’s sign) is frequently present.
Nonmotor Symptoms
Approximately 30% of patients develop cognitive dysfunction that has been characterized as subcortical,
because the affected individuals predominantly display
elements of poor motivation, slow thought, and executive dysfunction, with relative preservation of language
and memory. The cognitive abilities of patients with
advanced Parkinson’s disease are frequently underestimated due to bradyphrenia. Additional nonmotor symptoms include dysautonomia (resulting in excessive sweating, orthostatic hypotension, sexual dysfunction, urinary
dysfunction, and constipation), sialorrhea, dysphagia,
sleep disorders (restless legs syndrome, excessive daytime
sleepiness, REMS behavior disorder, and obstructive and
central sleep apnea), neuropsychiatric symptoms (depression, psychosis, and anxiety), and anosmia. Subjective sensory symptoms—such as pain, numbness, tingling, and burning—occur in 40% of patients.8
Figure 1. Gross pathology of Parkinson’s disease. Comparison
between normal (A) and Parkinson’s (B) midbrain, showing depigmentation of the substantia nigra with maximal cell loss in the lateral nigra (inset, arrow). (Photograph courtesy of M. Shahriar
Salamat, MD, PhD.)
Clinical Staging
The most widely used disability/disease progression
scales include the Hoehn and Yahr9 staging system
(Table 1) and the Unified Parkinson’s Disease Rating
Scale (UPDRS).10 The 6 subsections of the UPDRS comprise the Hoehn and Yahr staging system and the Schwab
and England Activities of Daily Living Scale. Although
time consuming to administer, the UPDRS is the principal outcome measure used in many clinical studies.
PATHOLOGY
Characteristic pathologic features of Parkinson’s disease are cell loss and Lewy body formation in the substantia nigra and other pigmented brainstem nuclei.
The pattern of neuronal loss in the substantia nigra is
opposite (beginning in the lateral ventral pars compacta) to the pattern seen in normal aging (Figure 1).11
Functional imaging and autopsy studies suggest that at
least 30% of nigral dopaminergic neurons are lost
before disease expression occurs.12 Degeneration of
other neuronal populations occurs, including neurons
of the nucleus basalis of Meynert; hypothalamic neurons; small cortical neurons in the cingulate gyrus and
entorhinal cortex; neurons of the olfactory bulb, sympathetic ganglia, and dorsal motor nucleus of the vagus;
and parasympathetic neurons in the gastrointestinal
tract.13 Lewy bodies (ie, neuronal cytoplasmic inclusions consisting of radially arranged, intermediate filaments [Figure 2]) accumulate in neurons of the substantia nigra, brainstem nuclei, hippocampus, cerebral
cortex, myenteric plexus, and olfactory bulb. Typically,
a hematoxylin and eosin stain is used to reveal these
round, eosinophilic, cytoplasmic inclusions that are surrounded by a pale halo. Lewy bodies are ubiquitinpositive. The presence of Lewy bodies is nonspecific for
Neurology Volume 8, Part 1 3
Neurodegenerative Disorders: Parkinson’s Disease
Table 2. Exclusion Criteria for Parkinson’s Disease
Figure 2. Hematoxylin and eosin stain demonstrating Lewy
bodies (arrows) within pigmented nigral neurons. (Photograph
courtesy of M. Shahriar Salamat, MD, PhD.)
idiopathic Parkinson’s disease; they also are found in
multiple system atrophy, progressive supranuclear palsy,
corticobasal degeneration, and other neurodegenerative syndromes with additional pathologic features. A
few Lewy bodies are found incidentally in 4% to 13% of
aged brains.11
PREMORBID DIAGNOSTIC ACCURACY
Clinicopathologic studies published in the 1990s reported that a neurologist’s clinical diagnosis of idiopathic Parkinson’s disease corresponded with the pathologic diagnosis in only 76% of cases.14,15 However, a
more recent assessment of 73 pathologic cases revealed
considerably higher accuracy of diagnosis in movement
disorders clinics.16 Features that improve diagnostic accuracy include asymmetric onset, resting tremor, and
clinical response to levodopa. Features that suggest an
alternative diagnosis include history or signs suggestive
of another hypokinetic-rigid syndrome or druginduced parkinsonism (Table 2).8
ETIOLOGY
LOSS OF NIGRAL DOPAMINERGIC OUTPUT
Catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine) are synthesized from
tyrosine in tissues that express the necessary biosynthetic enzymes (Figure 3). For example, dopamine
β-hydroxylase is expressed in locus ceruleus and postganglionic sympathetic neurons, whereas phenylethanolamine-N-methyltransferase (PNMT) is expressed
4 Hospital Physician Board Review Manual
Disease
Criteria
Vascular parkinsonism
Step-wise progression, gait apraxia
MPTP toxicity
Abrupt onset of symptoms
Medication-induced
parkinsonism
Remitting course, neuroleptic
therapy within the previous year
Postencephalitic
parkinsonism
History of encephalitis
Progressive supranuclear palsy
Supranuclear gaze palsy
Multiple system
atrophy
Cerebellar signs, severe autonomic
failure, unexplained pyramidal
(upper motor neuron) signs
Pantothenate kinase–
associated disorders
Unexplained pyramidal signs
Lewy body dementia
Early dementia, hallucinations
Corticobasal
degeneration
Unilateral apraxia with cortical
sensory loss
MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. (Adapted
with permission from Koller WC. How accurately can Parkinson’s disease be diagnosed? Neurology 1992;42[Suppl 1]:6–16.)
in the adrenal medulla. Melanin also is synthesized
from tyrosine (not surprising when one considers that
both melanocytes and neurons are neural crest derivatives), accumulates in mesencephalic catecholaminesynthesizing reticular neurons with age, and is present
even in albinos.17
Central and peripheral dopamine receptors are classified differently. Peripheral receptors include DA1 and DA2
subtypes. DA1 receptors mediate vasodilation of mesenteric, renal, and coronary beds, whereas DA2 receptors
mediate reduction of norepinephrine and aldosterone
release. Central nervous system (CNS) dopamine receptors include the D1,D5 family and the D2,D3,D4 family. D1and D2-receptor activation have opposite effects on adenylate cyclase activity and thus on levels of intracellular
cyclic adenosine monophosphate.18
Of the 4 major dopaminergic CNS tracts, 3 arise in the
substantia nigra; the fourth is the projection from the
hypothalamic arcuate nucleus to the pituitary gland.19
The substantia nigra gives rise to mesolimbic and mesocortical tracts (implicated in schizophrenia) and the
nigrostriatal pathway (implicated in Parkinson’s disease).
Loss of nigral dopaminergic projections produces
Neurodegenerative Disorders: Parkinson’s Disease
Tyrosine
Norepinephrine
Dopamine
Levodopa
TH
DDC
DBH
Epinephrine
PNMT
Figure 3. Catecholamine synthesis from tyrosine. DBH = dopamine β-hydroxylase; DDC = dihydroxyphenylalanine decarboxylase
(ie, DOPA decarboxylase or aromatic amino acid decarboxylase); PNMT = phenyl-ethanolamine-N-methyltransferase; TH = tyrosine
hydroxylase (rate-limiting step).
symptoms of Parkinson’s disease. Circuitry of the basal
nuclei (ganglia) is complex and has been reproduced in
multiple diagrams that are modified frequently as understanding evolves (Figure 4). Some simplified rules follow:
CONTRIBUTING FACTORS
Cumulative genetic and environmental factors
probably play a role in the pathogenesis of Parkinson’s
disease.
1. The striatum (caudate and putamen) is the
main recipient of excitatory (glutamatergic)
inputs from the cerebral cortex. Of striatal
neurons, 90% to 95% are medium-spiny projection neurons. A few striatal neurons are
inhibitory interneurons, some of which synthesize acetylcholine.
Environmental Factors
The environmental toxin most directly linked to
Parkinson’s disease is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This substance was discovered accidentally in the late 1970s, when illegally synthesized
meperidine containing MPTP produced clinical and
pathologic features of Parkinson’s disease (with the
exception of Lewy bodies) in young persons who used
the substance. When infused, lipophilic MPTP readily
crosses the blood-brain barrier and is metabolized to
1-methyl-4-phenylpyridinium (MPP+) in astrocytes and
serotonergic neurons that contain monoamine oxidase B (MAOB). Subsequently, MPP+ is transported into
the extracellular space, where it is selectively taken up by
dopaminergic neurons via the plasma membrane dopamine transporter. Intracellularly, MPP+ inhibits mitochondrial complex I and α-ketoglutarate dehydrogenase
of the tricarboxylic acid cycle; this results in energy failure, with its sequelae—intraneuronal calcium overload,
glutamate release, and impaired detoxification of reactive oxygen and nitrogen species—leading to cell death
in a dose-dependent manner.20 Therefore, inhibition of
either MAOB or dopamine transporter function is protective against MPTP-induced parkinsonism. Under normal conditions, reactive oxygen species generated during metabolism of dopamine via MAOB are “detoxified”
by reduced glutathione and superoxide dismutase.
These observations have led to the evaluation of MAOB
inhibitors as neuroprotective agents.
Other factors that have been shown in animal models or through epidemiologic studies to be potentially
related to the development of Parkinson’s disease include exposure to pesticides (particularly organophosphates and rotenone, which is a mitochondrial complex I inhibitor), rural living, well water, and exposure
to metals (aluminum, copper, iron, and manganese).21
Occupational welders exposed to volatilized metals for
10 or more years develop Parkinson’s disease at a
younger age than controls.22 Other substances that may
2. Major output nuclei include the functionally
related internal segment of globus pallidus
(GPi) and substantia nigra reticularis (SNr). In
the resting state, these nuclei are tonically
active, maintaining cortical inhibition.
3. Within the subcortical circuit, almost all nuclei
have inhibitory outputs mediated by the neurotransmitter γ-aminobutyric acid. Notable
excitatory projections include the substantia
nigra dopaminergic D1-receptor pathway and
the subthalamic nucleus (STN) glutamatergic
pathway.
4. Increased activity of the STN augments inhibitory output from the GPi and SNr.
5. Dopaminergic projections from the substantia nigra pars compacta (dorsal nigra) influence output from the basal nuclei via a direct
(D1-receptor mediated) and an indirect
(D2 -receptor mediated) pathway.
Direct: Striatum → GPi
Indirect: Striatum → GPe (globus pallidus
externa) → STN → GPi
The direct and indirect pathways have inverse influences on GPi and thus on thalamocortical activation. In
Parkinson’s disease, decreased dopaminergic output
from the substantia nigra pars compacta produces
decreased excitation of the direct pathway and decreased inhibition of the indirect pathway, overactivity
of both STN and GPi, and thus akinesia.
Neurology Volume 8, Part 1 5
Neurodegenerative Disorders: Parkinson’s Disease
Permission to electronically reproduce
this figure not granted by copyright holder.
produce parkinsonism through specific toxic effects on
the globus pallidus include carbon monoxide, manganese, carbon disulfide, and cyanide.6
Genetic Factors
Genetic susceptibility is suggested by the observation
that not all persons exposed to MPTP develop parkinsonism.23 Familial aggregation of both early-onset and
late-onset Parkinson’s disease is observed.24 However, a
large twin study found that concordance for Parkinson’s
disease was higher for monozygotic twins than for dizygotic twins only when symptom onset occurred at an age
younger than 50 years.25 Early-onset familial Parkinson’s
disease has been linked to mutations in genes encoding
α-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCHL1).26 The ubiquitin-proteasomal pathway
(UPP) provides controlled degradation of proteins
tagged with ubiquitin within eukaryotic cells. Ubiquitinpositive inclusions are found in several neurodegenerative disorders, suggesting that alterations in the structure
or quantity of the substrate proteins or alterations in the
6 Hospital Physician Board Review Manual
Figure 4. A simplified version of basal nuclear (ganglia) connections. Black projections
are excitatory; white connections are inhibitory. D1, D2 = dopamine receptors;
DA = dopamine; ENK = enkephalin; GABA =
γ-aminobutyric acid; GLU = glutamatergic
inputs; GPe = external segment of the globus
pallidus; GPi = internal segment of the globus
pallidus; SNc = substantia nigra compacta;
SNr = substantia nigra reticularis; STN = subthalamic nucleus; SubstP = substance P;
VA/VL = ventral anterior/ventral lateral nuclei
of the thalamus. (Adapted from Riley DE,
Lang AE. Movement disorders. In: Bradley
WG, Daroff RB, Fenichel GM, Janikovic J, editors. Neurology in clinical practice: principles
of diagnosis and management. Vol 2. 2nd ed.
Butterworth-Heinemann; 1996:1892. Reprinted with permission from Elsevier Ltd.)
efficiency of UPP function lead to abnormal protein accumulation (Table 3).27 α-Synuclein is degraded via the UPP
pathway; ubiquitin, parkin, and UCHL1 are involved in
the degradation of α-synuclein.
Additional genetic factors that seem to play a role in
Parkinson’s disease include deficient mitochondrial complex I function28 and polymorphisms in enzymes that
degrade dopamine, including N-acetyltransferase 2,29
MAOB, and catechol-O-methyltransferase (COMT).30
Other Causes of Parkinsonism
Postinfectious parkinsonism. In 1917, von Economo
described parkinsonism as a complication of encephalitis
lethargica. Postencephalitic parkinsonism differed from
idiopathic Parkinson’s disease in its slow progression, tendency to produce associated hyperkinetic movements,
pyramidal tract signs, behavioral features, and response
to anticholinergics.31 West Nile encephalitis may cause
parkinsonism and other movement disorders.
Iatrogenic parkinsonism. Iatrogenic parkinsonism is
associated with use of neuroleptics (most of which are
Neurodegenerative Disorders: Parkinson’s Disease
Table 3. Representative Neurodegenerative Diseases with Ubiquitin-Positive Inclusion Bodies
Disease
Gene
Mutations
Pathology
AD
APP, PS1, PS2
Missense
Amyloid plaques, neurofibrillary tangles
FTDP
MAPT
Missense
Tau inclusions
Pick’s
MAPT
ALS
SOD
Missense
Lewy body–like inclusions
PD
α-Synuclein, UCHL1, Parkin
Missense
Lewy bodies
DLB
α-Synuclein
Lewy bodies
MSA
α-Synuclein
GCIs
Prion*
Prion
Missense
PrP plaques
DRPLA
Atrophin 1
Polyglutamine
Nuclear inclusions
HD
Huntington
Polyglutamine
Nuclear inclusions
SCA1
Ataxin 1
Polyglutamine
Nuclear inclusions
SCA3/MJD
Ataxin 3
Polyglutamine
Nuclear inclusions
SCA7
Ataxin 7
Polyglutamine
Nuclear inclusions
Pick bodies
AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; APP = amyloid precursor protein; DLB = dementia with Lewy bodies; DRPLA
= dentatorubral-pallidolluysian atrophy; FTDP = frontotemporal dementia with parkinsonism; GCIs = glial cytoplasmic inclusions; HD =
Huntington’s disease; MAPT = microtubule-associated protein tau; MJD = Machado-Joseph disease; MSA = multiple system atrophy; PD =
Parkinson’s disease; PrP = prion protein; PS = presenilin; SCA = spinocerebellar ataxia; SOD = superoxide dismutase; UCHL1 = ubiquitin
C-terminal hydrolase L1.
*Data regarding prion from Dagher A. Functional imaging in Parkinson’s disease. Semin Neurol 2001;21:23–32.
antagonists of D1 or D2 receptors), reserpine, amiodarone, metoclopramide, divalproex, pyridostigmine, cyclosporine, lithium, and fluoxetine. Iatrogenic parkinsonism
may be distinguished from Parkinson’s disease by subacute onset, symmetry, response to anticholinergics, and
resolution of symptoms usually within weeks to months
after discontinuation of the offending agent.32
MANAGEMENT
NONPHARMACOLOGIC THERAPY
There is good evidence that regular exercise and
physical therapy improve UPDRS scores.33 Interventions
that help control freezing include use of targets near the
floor (eg, a specialized cane), marching to music, and
counting. Many devices have been invented to assist with
activities of daily living as well.
PHARMACOLOGIC THERAPY
Motor Symptoms
Medications available in the United States for treatment of motor symptoms are shown in Figure 5. In
humans, these medications have been shown to provide
symptomatic relief rather than to delay progression of
the disease. Dopamine replacement improves bradykinesia, tremor, and rigidity; it is less effective for cognitive
changes, dysarthria, sialorrhea, postural instability, and
dysautonomia.34
Levodopa is taken up into the brain by the amino acid
transporter, so restriction of oral protein intake when taking levodopa enhances bioavailability. Taking levodopa
with acid and without protein also enhances absorption
from the gastrointestinal tract. Bioavailability of extendedrelease levodopa is approximately 80% of immediaterelease levodopa. Levodopa is administered with a DOPA
(dihydroxyphenylalanine) decarboxylase (DDC) inhibitor to enhance passage into the CNS. Initially, 75 mg of
carbidopa was felt to be sufficient to inhibit peripheral
DDC in all patients; however, it now appears that patients
with significant peripheral side effects may benefit from a
higher dose. Doses higher than 150 mg may cross the
blood-brain barrier, inhibiting central DDC and limiting
levodopa central bioavailability.34
The dopamine agonists (pergolide, bromocriptine,
pramipexole, ropinirole) have highest agonist activity for
D2 and D3 receptors. Bromocriptine is also a D1-receptor
antagonist.35 Amantadine has various proposed mechanisms of action, including enhancement of dopamine
Neurology Volume 8, Part 1 7
Neurodegenerative Disorders: Parkinson’s Disease
BRAIN
D1, D2 receptors
(striatum)
Pramipexole
Ropinirole
Bromocriptine
Pergolide
Cholinergic interneurons (striatum)
Trihexyphenidyl
Benztropine
Tolcapone
Dopamine
MAOB
Selegiline
Levodopa
3-O-methyl-dopa
COMT
DDC
(substantia nigra)
Free radicals
BLOOD-BRAIN BARRIER
LNAA transporter
Tolcapone
Entacapone
BODY
Levodopa
COMT
DDC
Methylated
levodopa
Carbidopa
Dopamine
Figure 5. A schematic diagram of standard pharmacologic options for treating Parkinson’s motor symptoms. Note: Amantadine is not
shown because it has several mechanisms of action. COMT = catechol-O-methyltransferase; DDC = dihydroxyphenylalanine decarboxylase; LNAA = large neutral amino acid; MAOB = monoamine oxidase B.
Table 4. Side Effects of Levodopa
Side Effect
Proposed Cause
Nausea
Stimulation of peripheral dopamine receptors in the area postrema
Dyskinetic movements
Unbalanced stimulation of the direct pathway and inhibition of
the indirect pathway
Psychological symptoms ranging from vivid dreams and
“benign visual hallucinations” to psychosis
Possibly related to stimulation of the mesolimbic and
mesocortical dopaminergic pathways
Orthostatic hypotension
Vasodilation, norepinephrine antagonism
Spontaneous erections and possibly hypersexual behavior
Central D2-receptor agonism, oxytocin release
Cardiac arrhythmias
Stimulation of cardiac α1, α2, and β1 receptors
release from central stores, inhibition of dopamine reuptake, and glutamate antagonism. COMT inhibitors block
a different dopamine degradation pathway than that
blocked by carbidopa; tolcapone has both central and
peripheral action (but has been associated with severe
hepatotoxicity); entacapone acts peripherally.
All medications except anticholinergics and possibly
amantadine have side effect profiles similar to levodopa
(Table 4). Muscarinic cholinergic antagonists (trihexyphenidyl, benztropine) may produce dry mucous
membranes, constipation, blurred vision (due to paralysis of accommodation), decreased sweating, and psy-
8 Hospital Physician Board Review Manual
chosis, particularly in elderly persons. Amantadine may
cause peripheral edema, livedo reticularis, and visual
dysfunction. COMT inhibitors may turn the urine
orange. In addition, certain medications have potential
idiosyncratic side effects. Bromocriptine and pergolide
are ergot-derived dopamine agonists, posing a small
risk of retroperitoneal fibrosis. Some studies have
shown a higher incidence of hallucinations and daytime sleepiness in patients taking dopamine agonists
when compared with those taking levodopa.36,37
Pergolide also has been associated with an increased
risk of cardiac valvular abnormalities.
Neurodegenerative Disorders: Parkinson’s Disease
Table 5. Treatment of Nonmotor Symptoms in Patients with Parkinson’s Disease
Condition
Symptom
Pharmacologic
Therapy
Nonpharmacologic
Therapy
Dysautonomia
Constipation
Usual interventions
Orthostatic
hypotension
Sialorrhea
Eliminate antihypertensives
Midodrine
Fludrocortisone
Second-line agents (eg, erythropoietin)*
Eliminate offending medications,
treat depression
Yohimbine*
Sildenafil
β-Blockers*
Focal botulinum toxin injections*
Oxybutynin
Tolterodine
Parotid botulinum toxin injections*
Oral atropine drops*
Increase exercise and fluid
and fiber intake
Increase salt and fluid intake
Elevate head at night
Compression stockings
Dysphagia
Treatment of bradykinesia
Swallowing evaluation and
technique instruction
Depression
SSRIs, others
Exercise
Counseling
Anxiety
Dementia
SSRIs, benzodiazepines
Donepezil,* rivastigmine,*
galantamine*
Decrease levodopa equivalent dose
Clozapine
Quetiapine
?Donepezil*
Aripiprazole
Impotence
Excessive sweating
Urinary frequency
Neuropsychiatric
symptoms
Psychosis
Sleep disorders
Restless legs/PLMS
REMS behavior
disorder
Daytime sleepiness
Modify fluid intake
Bedtime dopamine agonist or
CR* levodopa
Clonazepam*
Modafinil,* methylphenidate*
Pain
Tricyclic antidepressants*
Anticonvulsants*
Seborrhea
Steroid cream
Improve sleep hygiene
CR = controlled release; PLMS = periodic limb movements during sleep; REMS = rapid eye movement sleep; SSRIs = selective serotonin reuptake inhibitors; ? = questionable because only one study indicates improvement.
*These agents are not approved by the Food and Drug Administration for this indication.
Nonmotor Symptoms
A variety of nonmotor symptoms afflict patients with
Parkinson’s disease. Potential therapies for these symptoms are outlined in Table 5.38,39
Natural History of Medically Treated Disease
The introduction of levodopa therapy in the early
1960s revolutionized treatment of Parkinson’s disease.
However, it is now clear that in most patients, response
Neurology Volume 8, Part 1 9
Neurodegenerative Disorders: Parkinson’s Disease
On
dyskinesia
Off
bradykinesia
6–8 hr
3–5 hr
0.5–2 hr
Early
Moderate
Advanced
Parkinson’s disease
Figure 6. Motor fluctuations in treated Parkinson’s disease.
Dark grey = therapeutic window. (Adapted with permission
from Jankovic J. Levodopa strengths and weaknesses. Neurology
2002;58[4 Suppl 1]:S23.)
to pharmacologic therapy ultimately becomes inadequate because of the emergence of motor fluctuations.
Motor fluctuations include wearing off (a shorter duration of medication efficacy), dyskinesias (hyperkinetic
writhing movements typically involving limbs, face, and
neck), and freezing. Rarely, dyskinesias affect ocular,
respiratory, and abdominal muscles. Dyskinesias are
classified as peak dose (monophasic, present at maximum levodopa serum level) or as diphasic (present with
wearing on and wearing off of medication effect).
Patients become painfully aware of the disparity in their
motor abilities in the on state (ie, during times of maximum medication efficacy) versus the off state (ie, when
the medication is depleted). As motor fluctuations
progress, time spent in the on state becomes shorter,
and the transition from on to off becomes more precipitous and less predictable (Figure 6).
Careful observation reveals that most patients treated
with levodopa develop some motor fluctuations within
1 year of starting therapy.40 With progressive attrition of
dopaminergic neurons, the ability of the substantia nigra
to metabolize and store dopamine declines; therapeutic
response to the levodopa more and more closely reflects
its serum half-life (about 60 minutes). Whether the
administration of levodopa alters disease progression is a
matter of debate; however, several studies have shown that
the use of longer-acting dopamine receptor agonists is
associated with a lower risk of developing motor fluctuations.36,37 As a result, the American Academy of Neurology
now recommends dopamine agonists as first-line therapy
for patients with Parkinson’s disease.41 However, the wisdom of this recommendation for all patients remains controversial among neurologists because (1) levodopa produces the greatest improvement in UPDRS scores,36,37
(2) dopamine agonists require prolonged titration sched-
10 Hospital Physician Board Review Manual
ules, (3) dopamine agonists are still under patent protection and therefore are more expensive than levodopa,
and (4) patients with late-onset Parkinson’s disease may
not live long enough for motor fluctuations to produce
significant disability. Therefore, choice of initial therapy
should be individualized.
SURGICAL INTERVENTION
Indications
Between 1939 and the early 1960s, ablative surgeries
of the globus pallidus and thalamus were used to control symptoms of Parkinson’s disease. With growing
awareness of the natural history of pharmacologically
treated Parkinson’s disease, interest in surgical treatment of patients with disabling motor complications
has reemerged. Patients should be considered for surgical intervention if they develop medication-refractory
motor complications, their symptoms are responsive to
levodopa, they are cognitively intact, and they are good
surgical candidates.
Surgical Procedures
Ablative therapy refers to stereotactic lesioning of a
target structure within the basal nuclei (typically thalamus or GPi). Ablative procedures are seldom used bilaterally because of the potential complications of dysarthria and dysphagia. The intraoperative risk of ablative
procedures is generally higher than that of deep brain
stimulator (DBS) placement. However, postoperative
risks with DBS include wire breakage, erosion of the
overlying skin, and infection of the implanted hardware.
The DBS electrode has several contacts within the target
structure, allowing some flexibility in subsequent therapy. Patients usually require numerous postoperative visits for “tuning” of the device and medication adjustment. The subcutaneous battery pack must be replaced
approximately every 5 years.
Surgical Targets and Expected Outcomes
Stimulation or lesioning of the GPi and STN benefits
most symptoms of Parkinson’s disease. GPi procedures
directly suppress dyskinesia, whereas STN procedures
suppress dyskinesia both directly and indirectly by allowing reduction in the levodopa dose (≥ 60%).
A recent multicenter prospective randomized trial of
STN versus GPi stimulation for Parkinson’s disease
found that the median UPDRS motor score improved
by 49% with STN stimulation and by 37% with GPi stimulation.42 The decrease in the UPDRS motor off score
for STN DBS is typically greater than 50%.43 However,
dramatic improvements in motor on function should
not be expected. DBS (Figure 7) appears to suppress or
Neurodegenerative Disorders: Parkinson’s Disease
restore a more normal pattern of output from GPi and
STN, allowing medication doses to be decreased accordingly. Stimulation also has an additive effect with
levodopa in terms of producing dyskinetic side effects.
Surgical Procedures in Development
Transplantation of dopamine-producing progenitor
cells into the striatum has been tried using several different procedures. Allogeneic transplantation of fetal
ventral mesencephalic tissue into the striatum of Parkinson’s patients produced long-term graft survival
(demonstrated by positron emission tomography [PET]
and autopsy), a 20% reduction in levodopa dose, a 44%
reduction in off time, and a 26% improvement in
UPDRS off motor score 2 years after transplantation.44
Unilateral transplants may provide some benefit for
motor symptoms in ipsilateral limbs and do not seem to
require lifelong immunosuppression.44 However, disabling dyskinesias have consistently appeared in a few
patients even when not taking medication. Additional
potential sources of tissue include porcine mesencephalon, human carotid body, adrenal chromaffin
cells, retinal pigment epithelium, and bone marrow. Intraventricular infusion of growth factors intended to encourage precursor cells to differentiate into dopamineproducing neurons have not produced significant
clinical benefit.43 However, direct infusion into the putamen appears more promising (trials ongoing).
NEUROPROTECTIVE THERAPIES
Distinction should be made between the terms neuroprotection and neurorescue.12 Neurorescue implies restoring
the organism to its former healthy state (thus, restoring
function of lost cells); neuroprotection implies slowing
the disease course or preventing things from getting
worse. So far, none of the medications used to treat motor
symptoms of Parkinson’s disease has been conclusively
proven to offer neuroprotection. The Deprenyl and
Tocopherol Antioxidative Therapy of Parkinson’s
(DATATOP)45 study seems to indicate a modest protective role for selegiline. However, subsequent analysis has
suggested that the apparent benefit may have been related to residual symptomatic improvement; the washout
period may have been too short to allow full regeneration
of central MAOB activity. Dopamine agonists have several
theoretical neuroprotective activities. A recent study using
oral coenzyme Q 10 (which is intended to bolster mitochondrial function) showed that patients given coenzyme Q 10 during a period of 16 months experienced
dose-dependent protection against decline in UPDRS
scores, especially activities of daily living.46 Other potential
neuroprotective therapies currently under investigation
Figure 7. Sagittal T1-weighted magnetic resonance image of a
patient with a deep brain stimulator (arrow) in the subthalamic
nucleus.
include antiglutamatergic agents (remacemide, rilutek,
amantadine), trophic factors (glial-derived neurotrophic
factor), MAOB inhibitors (rasagiline), adenosine receptor antagonists, and dopamine agonists.47 Smoking and
caffeine ingestion are associated with a decreased risk for
developing Parkinson’s disease.48
CASE STUDIES FOR SELF-ASSESSMENT
CASE 1
Presentation
A 34-year-old right-handed man presents for evaluation of a 2-year history of left hand and left leg resting
tremor that has slightly increased in amplitude since
onset. The patient also describes symptoms of poor
coordination in his left hand, mild solid dysphagia, and
increased tremor when he is nervous or during physical
exertion. He denies any slowness, weakness, hallucinations, falls, change in facial expression or voice amplitude, or difficulty turning in bed. His medical history is
unremarkable. He has no history of depression, constipation, sexual dysfunction, orthostasis, or urinary urgency. The patient was raised in a rural community; he
denies any history of using illegal substances. His family history is negative for neurodegenerative disorders
and tremor.
Examination reveals a normally developed, intelligent, cooperative patient. His weight is 189 lb. His
Neurology Volume 8, Part 1 11
Neurodegenerative Disorders: Parkinson’s Disease
A
B
Figure 8. Fluorodopa positron emission tomography scan of
(A) normal control and (B) case 1 patient. The scan shows
markedly decreased tracer in the striatum (arrow) compared
with the control, a finding consistent with significant loss of
dopaminergic neurons.
blood pressure is 132/84 mm Hg when sitting and
128/82 mm Hg when standing. Pulse is 64 bpm. Mental
status and cranial nerve examinations are normal with
the exception of mild masking of facial expressions. No
chin tremor is present. Motor examination shows mild
rigidity of left wrist and elbow flexion/extension. the
patient also has decreased amplitude and loss of rhythmicity of rapid movements when using his left hand.
Left hand and left leg resting tremor occurs intermittently. Deep tendon reflexes are 2+ and symmetrical.
Sensory examination is intact to pinprick, vibration,
and proprioception. Coordination testing is normal
with finger-to-nose and heel-shin maneuvers. Gait examination demonstrates decreased left arm swing.
• What is the most likely diagnosis?
A) Essential tremor
B) Parkinson’s disease
C) Iatrogenic parkinsonism
D) Wilson’s disease
Discussion
The best answer is B. Parkinson’s disease with onset
before age 20 years is considered juvenile Parkinson’s
disease; onset before age 40 years is considered early-
12 Hospital Physician Board Review Manual
onset Parkinson’s disease. In a patient with early-onset
parkinsonism, exclusion of Wilson’s disease (slit lamp
examination for Kayser-Fleischer rings, serum ceruloplasmin, 24-hour urine copper, and liver function
tests) and Huntington’s disease (family history, evaluation of chromosome for trinucleotide repeat) is recommended. However, this patient’s neurologic examination and the lack of psychiatric symptoms are
inconsistent with these diagnoses. Essential tremor is
distinguished from idiopathic Parkinson’s disease by
symmetry, postural rather than resting tremor, and the
absence of tone changes and bradykinesia. Recent use
of antidopaminergic therapies would suggest iatrogenic parkinsonism.
• What diagnostic test is most likely to be helpful in
confirming the diagnosis?
A) α-Synuclein gene mutation
B) Ceruloplasmin and 24-hour urine copper
C) Fluorodopa PET scan
D) Magnetic resonance imaging (MRI) of the
brain
Discussion
The best answer is C. Several radiotracers have been
developed to evaluate the function of nigral projections
and dopamine receptors. After intravenous injection,
fluorodopa crosses the blood-brain barrier and is taken
up by nigral neurons, metabolized to [18F]-dopamine by
DDC, and stored in nerve terminals.49 The fluorodopa
PET scan done in this patient shows markedly decreased
and asymmetric tracer uptake in the striatum compared
with the control, a finding consistent with significant loss
of nigral dopaminergic projections (Figure 8). Relative
preservation of tracer uptake in the caudate head compared with the posterior putamen distinguishes idiopathic Parkinson’s disease from other forms of parkinsonism. Although functional MRI is under development
for use in Parkinson’s disease, anatomic images are typically without diagnostic structural characteristics.
Mutations in parkin, α-synuclein, or UCHL1 genes have
only been found in a small fraction of patients with
familial Parkinson’s disease and, therefore, are unlikely
to harbor a mutation.
• What is the best initial therapy for this patient?
A) Acetazolamide 250 mg twice daily (BID)
B) Carbidopa/levodopa 25/100 mg three times
daily (TID)
C) Pramipexole 0.125 mg TID
D) Propranolol 20 mg TID
Neurodegenerative Disorders: Parkinson’s Disease
Discussion
The best answer is C. Especially in young patients,
best options for initial symptomatic therapy include
selegiline and dopamine agonists because of the decreased risk of producing motor fluctuations when
compared with levodopa. Propranolol and acetazolamide are used in the treatment of essential tremor.
CASE 2
Presentation
A 70-year-old man has an 11-year history of resting
tremor, bradykinesia, and rigidity. Although his symptoms are responsive to dopamine replacement therapy,
the duration of therapeutic benefit has become shorter
and shorter over time. His medications include
carbidopa/levodopa 25/100 mg every 2 hours, pramipexole 1.5 mg TID, and selegiline 5 mg BID.
About 30 minutes after a carbidopa/levodopa dose,
the patient develops writhing movements of his face,
arms, and torso. He is able to move fluidly, and his gait
stability is unaffected. These movements resolve approximately 1 hour later, at which time the patient
develops predictable freezing. When in the off state, he
is unable to arise from a chair.
The patient is examined 40 minutes after a dose
of carbidopa/levodopa. His blood pressure is
125/70 mm Hg when sitting, and his pulse is 75 bpm.
Choreic movements of his face, arms, and legs are pronounced. Mental status and language are normal. No
tremor and only minimal rigidity of wrist flexion/
extension are detected. The patient is able to arise from
a chair and walk unassisted without freezing, festination, or loss of balance. During the gait examination,
however, choreic movements of his upper limbs persist.
• What is the correct term for this patient’s excess
movement?
A) Diphasic dyskinesia
B) Peak-dose dyskinesia
C) Latent Huntington’s disease
D) Freezing
Discussion
The best answer is B. Peak-dose dyskinesia is characteristically asymmetric and choreic in nature and parallels
the motor response to levodopa. Diphasic dyskinesia
occurs at transition times between levodopa effectiveness
and wearing off and thus is characterized by a pattern of
dyskinesia-improvement-dyskinesia. Diphasic dyskinesia
may incorporate dystonic elements and be more disabling than peak-dose dyskinesia. In some cases, dyskinesia can be treated by adding amantadine, a dopamine
agonist, or clozapine.34 Huntington’s disease causes unremitting chorea. Freezing implies inability to initiate
movement.
• What is the best initial therapeutic intervention to
prolong the effective half-life of levodopa for this
patient?
A) Apomorphine rescue
B) Add entacapone 200 mg BID
C) Discontinue selegiline
D) Deep brain stimulation (DBS)
Discussion
The best answer is B. An excellent initial intervention for this patient would be to slightly reduce the dose
of levodopa and to prolong its activity by adding a
COMT inhibitor. Another acceptable option would be
to replace some doses of immediate-release carbidopa/
levodopa with a slightly larger dose of extended-release
levodopa. Parenteral apomorphine (2 to 5 mg subcutaneously) has been used to “rescue” Parkinson’s patients
who are frozen. If modification of the medical regimen
is unsuccessful in treating the patient’s motor fluctuations, DBS should be considered.
CASE 3
Presentation
A 73-year-old man with a history of ischemic cardiomyopathy, congestive heart failure, and Parkinson’s disease presents for evaluation of hallucinations
and freezing episodes. The patient developed unilateral levodopa-responsive hand tremor 5 years ago.
Since that time, he has developed bilateral hand
tremor and mild postural instability with infrequent
falls. However, he is plagued by daily visual hallucinations. He does not experience these hallucinations as
distressing and may express insight into their illusory
nature. He frequently describes “smoking men in the
curtains” and “monkeys crossing the lawn.” His motor
symptoms are fairly well controlled, although he develops freezing if he misses a medication dose. Ambulation also is limited by marked orthostatic dizziness that
is so severe at times that he has “blacked out,” precipitating a fall with injury. His medications include
controlled-release carbidopa/levodopa 50/200 mg
TID, carbidopa/levodopa 10/100 mg every 3 hours,
and ropinirole 1 mg TID.
Physical examination reveals an alert patient.
After 3 minutes of standing, his blood pressure is
100/65 mm Hg and his pulse is 80 bpm. His supine
blood pressure and pulse are 150/70 mm Hg and
80 bpm, respectively. Mini-mental status examination
Neurology Volume 8, Part 1 13
Neurodegenerative Disorders: Parkinson’s Disease
score is 27 out of 30. Cranial nerve and motor examinations are significant for mild dyskinetic movements of
the face and arms. Muscle tone is normal. No tremor is
present. His gait is fluid, with mildly decreased left arm
swing. Deep tendon reflexes and plantar responses are
normal.
• What is the best option for treatment of this patient’s
hallucinations?
A) Quetiapine 25 mg at night
B) Haloperidol 1 mg TID
C) Risperidone 0.5 mg BID
D) Olanzapine 5 mg daily
Discussion
The best answer is A. The best initial intervention
would be a reduction in the ropinirole or levodopa
dose. If this intervention produced intolerable motor
decline, one of the atypical antipsychotic medications
(ie, clozapine or quetiapine) could be added, as these
agents do not exacerbate parkinsonism. However, quetiapine may exacerbate orthostatic hypotension, and
clozapine requires lifelong weekly monitoring for
agranulocytosis. Risperidone and olanzapine may exacerbate parkinsonism.
• What would you recommend for treatment of this
patient’s orthostatic hypotension?
A) Alprazolam 0.5 mg BID
B) Fludrocortisone 0.2 mg every morning
C) Midodrine 2.5 mg in the morning and at noon
D) Salt tablets
Discussion
The best answer is C. Neurogenic orthostatic hypotension can be successfully treated with behavior modification, compression stockings, liberalization of fluid
and salt intake, and mineralocorticoid analogs (fludrocortisone). However, some of these therapies would be
a poor choice in this patient because of his history of
congestive heart failure. Vasoconstricting agents, such
as midodrine (a peripheral α1-receptor agonist),
should be taken early in the day because of the risk of
supine hypertension.
SUMMARY POINTS
• Parkinson’s disease is the most common akineticrigid syndrome and the second most common adult
neurodegenerative disease, affecting 1% of persons
older than 65 years.
14 Hospital Physician Board Review Manual
• Parkinson’s disease is characterized by selective loss
of cells and accumulation of Lewy bodies in pigmented brainstem nuclei, especially substantia nigra,
with resulting insufficient function of nigrostriatal
dopaminergic projections. The ultimate consequence is bradykinesia, rigidity, and tremor.
• Most neurodegenerative disorders, including Parkinson’s disease, have a long preclinical phase. By the
time symptoms emerge, significant cerebral reserve
has been lost.
• Environmental factors appear to influence development of Parkinson’s disease in genetically susceptible individuals.
• Replacement of central dopamine is the mainstay of
Parkinson’s disease treatment but is an imperfect
solution because of continued attrition of dopaminergic neurons and emergence of motor fluctuations.
Several pharmacologic and surgical interventions are
available as palliative therapy for Parkinson’s disease
• Especially in young patients, best options for initial
symptomatic therapy include selegiline and dopamine
agonists because of the decreased risk of producing
motor fluctuations when compared with levodopa.
ACKNOWLEDGMENT
Figures 1 and 2 are courtesy of M. Shahriar Salamat,
MD, PhD, Department of Pathology, University of Wisconsin, Madison, WI.
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16 Hospital Physician Board Review Manual