Practice Essentials

Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1%
of individuals older than 6 years and causing progressive disa!ility that can !e slo"ed, !ut not
halted, !y treatment# $he % ma&or neuropathologic findings in Parkinson disease are loss of
pigmented dopaminergic neurons of the su!stantia nigra pars compacta and the presence of 'e"y
!odies and 'e"y neurites#
Essential update: Study finds possible benefit of naltrexone for impulse control disorders
in patients with Parkinson disease
(n a place!o)controlled pilot study of * patients "ith idiopathic PD "ho developed impulse control
disorder ((+D) symptoms "hile receiving dopamine agonist treatment, Papay and colleagues found
that the opioid antagonist naltrexone improved (+D symptoms, as measured on a PD)specific rating
scale#
,1, %-
.altrexone "as administered at * mg daily for / "eeks and then increased to 1 mg daily for /
"eeks in nonresponders# $he difference in response rate on the +linical 0lo!al (mpression)+hange
(+0()+) scale !et"een the naltrexone (*/#*%) and place!o (1/#2%) groups "as not significant (P 3
#%1)# Estimated changes on the patient)completed 4uestionnaire for (mpulsive)+ompulsive
Disorders in Parkinson5s Disease)6ating 7cale (48(P)67) from !aseline to "eek 2, ho"ever,
significantly favored naltrexone9 a change of 1/#: points for naltrexone vs ;#* points for place!o (P 3
#/)# .ausea and headache "ere the most common side effects of naltrexone treatment#
,1, %-
Signs and symptoms
(nitial clinical symptoms of Parkinson disease include the follo"ing9
$remor
7u!tle decrease in dexterity
Decreased arm s"ing on the first)involved side
7oft voice
Decreased facial expression
7leep distur!ances
6apid eye movement (6E<) !ehavior disorder (6=D> a loss of normal atonia during 6E<
sleep)
Decreased sense of smell
7ymptoms of autonomic dysfunction (eg, constipation, s"eating a!normalities, sexual
dysfunction, se!orrheic dermatitis)
? general feeling of "eakness, malaise, or lassitude
Depression or anhedonia
7lo"ness in thinking
@nset of motor signs include the follo"ing9
$ypically asymmetric
$he most common initial finding is a resting tremor in an upper extremity
@ver time, patients experience progressive !radykinesia, rigidity, and gait difficulty
?xial posture !ecomes progressively flexed and strides !ecome shorter
Postural insta!ility (!alance impairment) is a late phenomenon
Nonmotor symptoms
.onmotor symptoms are common in early Parkinson disease# 6ecognition of the com!ination of
nonmotor and motor symptoms can promote early diagnosis and thus early intervention, "hich often
results in a !etter Auality of life#
7ee +linical Presentation for more detail#
Diagnosis
Parkinson disease is a clinical diagnosis# .o la!oratory !iomarkers exist for the condition, and
findings on routine magnetic resonance imaging and computed tomography scans are unremarka!le#
+linical diagnosis reAuires the presence of % of 1 cardinal signs9
6esting tremor
6igidity
=radykinesia
7ee Borkup for more detail#
Management
$he goal of medical management of Parkinson disease is to provide control of signs and symptoms
for as long as possi!le "hile minimiCing adverse effects#
Symptomatic drug therapy
8sually provides good control of motor signs of Parkinson disease for /)6 years
'evodopaDcar!idopa9 $he gold standard of symptomatic treatment
<onoamine oxidase (<?@)E= inhi!itors9 +an !e considered for initial treatment of early
disease
@ther dopamine agonists (eg, ropinirole, pramipexole)9 <onotherapy in early disease and
ad&unctive therapy in moderate to advanced disease
?nticholinergic agents (eg, trihexyphenidyl, !enCtropine)9 7econd)line drugs for tremor only
Treatment for nonmotor symptoms
7ildenafil citrate (Fiagra)9 Gor erectile dysfunction
Polyethylene glycol9 Gor constipation
<odafinil9 Gor excessive daytime somnolence
<ethylphenidate9 Gor fatigue (potential for a!use and addiction)
Deep brain stimulation

7urgical procedure of choice for Parkinson disease

Does not involve destruction of !rain tissue

6eversi!le

+an !e ad&usted as the disease progresses or adverse events occur

=ilateral procedures can !e performed "ithout a significant increase in adverse events

Parkinson disease is recogniCed as one of the most common neurologic disorders, affecting
approximately 1% of individuals older than 6 years# $here are % ma&or neuropathologic
findings9 the loss of pigmented dopaminergic neurons in the su!stantia nigra pars compacta
(7.pc) and the presence of 'e"y !odies (see the follo"ing image)# <ost cases of Parkinson
disease (idiopathic Parkinson disease ,(PD-) are hypothesiCed to !e due to a com!ination of
genetic and environmental factors# Ho"ever, no environmental cause of Parkinson disease
has yet !een proven# ? kno"n genetic cause can !e identified in approximately 1% of cases,
and these are more common in younger)onset patients#

0ross comparison of the appearance of the su!stantia nigra !et"een

a normal !rain and a !rain affected !y Parkinson disease# .ote the "ell)pigmented su!stantia nigra in the
normal !rain specimen on the left# (n the !rain of a Parkinson disease patient on the right, loss of pigmented
su!stantia nigra due to depopulation of pigmented neurons is o!served#

$he classic motor features of Parkinson disease typically start insidiously and emerge slo"ly
over "eeks or months, "ith tremor !eing the most common initial symptom# $he 1 cardinal
signs of Parkinson disease are resting tremor, rigidity, and !radykinesia# Postural insta!ility
(!alance impairment) is sometimes listed as the fourth cardinal feature# Ho"ever, !alance
impairment in Parkinson disease is a late phenomenon, and in fact, prominent !alance
impairment in the first fe" years suggests that Parkinson disease is not the correct diagnosis#
(7ee Presentation#)

Bhen a patient presents "ith tremor, the clinician evaluates the patient5s history and physical
examination findings to differentiate Parkinson disease tremor from other types of tremor# (n
patients "ith parkinsonism, careful attention to the history is necessary to exclude causes
such as drugs, toxins, or trauma# (7ee Differential Diagnosis#) @ther common causes of
tremor include essential tremor, physiologic tremor, and dystonic tremor#

.o la!oratory or imaging study is reAuired in patients "ith a typical presentation of Parkinson

disease# 7uch patients are aged ** years or older and have a slo"ly progressive and
asymmetric parkinsonism "ith resting tremor and !radykinesia or rigidity# $here are no red
flags such as prominent autonomic dysfunction, !alance impairment, dementia, or eye)
movement a!normalities# (n such cases, the diagnosis is ultimately considered confirmed
once the patient goes on dopaminergic therapy (levodopa or a dopamine agonist) as needed
for motor symptom control and exhi!its a ro!ust and sustained !enefit# (7ee Borkup#)

(maging studies can !e considered, depending on the differential diagnosis# <agnetic

resonance imaging (<6() of the !rain can !e considered to evaluate possi!le cere!rovascular
disease (including multi)infarct state), space)occupying lesions, normal)pressure
hydrocephalus, and other disorders#

(odine)1%1Ela!eled fluoropropyl)%!eta)car!omethoxy)1!eta)/)iodophenyl)nortroptane (GP)

+($ (
1%1
) ((oflupane, Da$scan) single)photon emission computed tomography (7PE+$) can !e
considered in cases of uncertain parkinsonism to help differentiate disorders associated "ith
a loss of dopamine neurons (Parkinson disease and atypical parkinsonisms, including
multiple system atrophy ,<7?- and progressive supranuclear palsy ,P7P-) from those
disorders not associated "ith a loss of dopamine neurons (eg, essential tremor, dystonic
tremor, vascular parkinsonism, medication)induced parkinsonism or tremor, psychogenic
conditions)#
,1-

'evodopa coupled "ith a peripheral decar!oxylase inhi!itor (PD(), such as car!idopa,

remains the gold standard of symptomatic treatment of motor features of Parkinson disease#
(t provides the greatest antiparkinsonian !enefit "ith the fe"est adverse effects in the short
term# Ho"ever, its long)term use is associated "ith the development of fluctuations and
dyskinesias# <oreover, the disease continues to progress, and patients accumulate long)term
disa!ility# (7ee $reatment#)

Dopamine agonists such as pramipexole (<irapex) and ropinirole (6eAuip) can !e used as
monotherapy to improve symptoms in early Parkinson disease or as ad&uncts to levodopa in
patients "ho are experiencing motor fluctuations# <onoamine oxidase (<?@))= inhi!itors,
such as selegiline (Eldepryl) and rasagiline (?Cilect) provide mild !enefit as monotherapy in
early disease and as ad&uncts to levodopa in patients "ith motor fluctuations# (7ee
<edication#) Entacapone (+omtan), a catechol)o)methyltransferase (+@<$) inhi!itor, reduces
the peripheral meta!olism of levodopa, there!y making more levodopa availa!le to enter the
!rain over a longer period> this agent is used as an ad&unct to levodopa in patients "ith motor
fluctuations#

Parkinson disease is predominantly a disorder of the !asal ganglia, "hich are a group of
nuclei situated at the !ase of the fore!rain# $he striatum, composed of the caudate and
putamen, is the largest nuclear complex of the !asal ganglia# $he striatum receives excitatory
input from several areas of the cere!ral cortex, as "ell as inhi!itory and excitatory input from
the dopaminergic cells of the su!stantia nigra pars compacta (7.c)# $hese cortical and nigral
inputs are received !y the spiny pro&ection neurons, "hich are of % types9 those that pro&ect
directly to the internal segment of the glo!us pallidus (0Pi), the ma&or output site of the !asal
ganglia> and those that pro&ect to the external segment of the glo!us pallidus (0Pe),
esta!lishing an indirect path"ay to the 0Pi via the su!thalamic nucleus (7$.)#

Gor an illustration of the su!thalamic nucleus, see the image !elo"#

7agittal section, 1% mm lateral of the midline, demonstrating the

su!thalamic nucleus (7$.) (lavender)# $he 7$. is one of the preferred surgical targets for deep !rain
stimulation to treat symptoms of advanced Parkinson disease#

$he actions of the direct and indirect path"ays regulate the neuronal output from the 0Pi,
"hich provides tonic inhi!itory input to the thalamic nuclei that pro&ect to the primary and
supplementary motor areas#
.o specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the
specificity and sensitivity of its characteristic findings have not !een clearly esta!lished# Ho"ever, the
follo"ing are the % ma&or neuropathologic findings in Parkinson disease9
'oss of pigmented dopaminergic neurons of the su!stantia nigra pars compacta
$he presence of 'e"y !odies and 'e"y neurites
$he loss of dopamine neurons occurs most prominently in the ventral lateral su!stantia nigra#
?pproximately 6)2% of dopaminergic neurons are lost !efore the motor signs of Parkinson disease
emerge#
7ome individuals "ho "ere thought to !e normal neurologically at the time of their deaths are found to
have 'e"y !odies on autopsy examination# $hese incidental 'e"y !odies have !een hypothesiCed to
represent the presymptomatic phase of Parkinson disease# $he prevalence of incidental 'e"y !odies
increases "ith age# .ote that 'e"y !odies are not specific to Parkinson disease, as they are found in
some cases of atypical parkinsonism, Hallervorden)7patC disease, and other disorders# .onetheless,
they are a characteristic pathology finding of Parkinson disease#
Motor circuit in Parkinson disease
$he !asal ganglia motor circuit modulates the cortical output necessary for normal movement (see the
follo"ing image)#
7chematic representation of the !asal ganglia ) thalamocortical motor circuit and its
neurotransmitters in the normal state# Grom Fitek I# 7tereotaxic surgery and deep !rain stimulation for Parkinson
disease and movement disorders# (n9 Batts 6', Joller B+, eds# <ovement Disorders9 .eurologic Principles and
Practice# .e" Kork9 <c0ra")Hill, 1::;9%/# +opyright, <c0ra")Hill +ompanies, (nc# 8sed "ith permission#
7ignals from the cere!ral cortex are processed through the !asal ganglia)thalamocortical motor circuit
and return to the same area via a feed!ack path"ay# @utput from the motor circuit is directed through
the internal segment of the glo!us pallidus (0Pi) and the su!stantia nigra pars reticulata (7.r)# $his
inhi!itory output is directed to the thalamocortical path"ay and suppresses movement#
$"o path"ays exist "ithin the !asal ganglia circuit, the direct and indirect path"ays, as follo"s9
(n the direct path"ay, outflo" from the striatum directly inhi!its the 0Pi and 7.r> striatal
neurons containing D1 receptors constitute the direct path"ay and pro&ect to the 0PiD7.r
$he indirect path"ay contains inhi!itory connections !et"een the striatum and the external
segment of the glo!us pallidus (0Pe) and !et"een the 0Pe and the su!thalamic nucleus (7$.)>
striatal neurons "ith D% receptors are part of the indirect path"ay and pro&ect to the 0Pe
$he 7$. exerts an excitatory influence on the 0Pi and 7.r# $he 0PiD7.r sends inhi!itory output to
the ventral lateral nucleus (F') of the thalamus# Dopamine is released from nigrostriatal (su!stantia
nigra pars compacta ,7.pc-) neurons to activate the direct path"ay and inhi!it the indirect path"ay# (n
Parkinson disease, decreased striatal dopamine causes increased inhi!itory output from the 0PiD7.r
via !oth the direct and indirect path"ays (see the follo"ing image)#
7chematic representation of the !asal ganglia ) thalamocortical motor circuit and the
relative change in neuronal activity in Parkinson disease# Grom Fitek I# 7tereotaxic surgery and deep !rain stimulation
for Parkinson disease and movement disorders# (n9 Batts 6', Joller B+, eds# <ovement Disorders9 .eurologic
Principles and Practice# .e" Kork9 <c0ra")Hill, 1::;9%/1# 8sed "ith kind permission# +opyright, <c0ra")Hill
+ompanies, (nc#
$he increased inhi!ition of the thalamocortical path"ay suppresses movement# Fia the direct
path"ay, decreased striatal dopamine stimulation causes decreased inhi!ition of the 0PiD7.r# Fia the
indirect path"ay, decreased dopamine inhi!ition causes increased inhi!ition of the 0Pe, resulting in
disinhi!ition of the 7$.# (ncreased 7$. output increases 0PiD7.r inhi!itory output to the thalamus#
?lthough the etiology of Parkinson disease is still unclear, most cases are hypothesiCed to !e due to a
com!ination of genetic and environmental factors# +urrently kno"n genetic causes of Parkinson
disease account for approximately 1% of cases#
Environmental causes
Environmental risk factors commonly associated "ith the development of Parkinson disease include
use of pesticides, living in a rural environment, consumption of "ell "ater, exposure to her!icides, and
proximity to industrial plants or Auarries#
,/-
? meta)analysis of 2: studies, including 6 prospective and 21 case)control studies, found that
exposure to pesticides may increase the risk for PD !y as much as 2%#
,*, 6-
Exposure to the "eed
killer paraAuat or to the fungicides mane! or mancoCe! is particularly toxic, increasing the risk for PD
a!out %)fold# <any of the agents studied are no longer used in the 8nited 7tates and Europe>
ho"ever, some are still found in developing parts of the "orld#
,*, 6-
(n case)control studies, PD "as associated "ith exposure to any type of pesticide, her!icide,
insecticide, and solvent, "ith risks ranging from 11% to 2%#
,*, 6-
(ncreased PD risk "as also associated
"ith proxy conditions of exposure to organic pollutants, such as farming, "ell)"ater drinking, and rural
living# (n addition, risk seemed to increase "ith length of exposure#
,*, 6-
$he .ational (nstitutes of Health)??6P Diet and Health 7tudy, as "ell as a meta)analysis of
prospective studies, found that higher caffeine intake "as associated "ith lo"er risk of Parkinson
disease in !oth men and "omen# ? similar association "as found for smoking and Parkinson disease
risk#
,;-
$he !iological mechanisms underlying the inverse relationship !et"een caffeine or smoking and
Parkinson disease risk are not "ell elucidated#
MPTP interference with mitochondrial function
7everal individuals "ere identified "ho developed parkinsonism after self)in&ection of 1)methyl)/)
phenyl)1,%,1,6)tetrahydropyridine (<P$P)# $hese patients developed !radykinesia, rigidity, and
tremor, "hich progressed over several "eeks and improved "ith dopamine replacement therapy#
<P$P crosses the !lood)!rain !arrier and is oxidiCed to 1)methyl)/)phenylpyridinium (<PPL) !y
monoamine oxidase (<?@))=#
,2-
<PPL accumulates in mitochondria and interferes "ith the function of complex ( of the respiratory
chain# ? chemical resem!lance !et"een <P$P and some her!icides and pesticides suggested that
an <P$P)like environmental toxin might !e a cause of Parkinson disease, !ut no specific agent has
!een identified# .onetheless, mitochondrial complex ( activity is reduced in Parkinson disease,
suggesting a common path"ay "ith <P$P)induced parkinsonism#
xidation hypothesis
$he oxidation hypothesis suggests that free radical damage, resulting from dopamine5s oxidative
meta!olism, plays a role in the development or progression of Parkinson disease# $he oxidative
meta!olism of dopamine !y <?@ leads to the formation of hydrogen peroxide# .ormally, hydrogen
peroxide is cleared rapidly !y glutathione, !ut if hydrogen peroxide is not cleared adeAuately, it may
lead to the formation of highly reactive hydroxyl radicals that can react "ith cell mem!rane lipids to
cause lipid peroxidation and cell damage# (n Parkinson disease, levels of reduced glutathione are
decreased, suggesting a loss of protection against formation of free radicals# (ron is increased in the
su!stantia nigra and may serve as a source of donor electrons, there!y promoting the formation of
free radicals#
Parkinson disease is associated "ith increased dopamine turnover, decreased protective
mechanisms (glutathione), increased iron (a pro)oxidation molecule), and evidence of increased lipid
peroxidation# $his hypothesis has raised concern that increased dopamine turnover due to levodopa
administration could increase oxidative damage and accelerate loss of dopamine neurons# Ho"ever,
there is no clear evidence that levodopa accelerates disease progression#
!enetic factors
(f genetic factors are important in a particular disease, concordance in genetically identical
monoCygotic (<M) t"ins "ill !e greater than in diCygotic (DM) t"ins, "ho share only a!out *% of
genes# Early Parkinson disease t"in studies generally found lo" and similar concordance rates for
<M and DM pairs#
Ho"ever, genetic factors in Parkinson disease appear to !e very important "hen the disease !egins
at or !efore age * years# (n a study of 1:1 t"ins, overall concordance for <M and DM pairs "as
similar, !ut in 16 pairs of t"ins in "hom Parkinson disease "as diagnosed at or !efore age * years,
all / <M pairs, !ut only % of 1% DM pairs, "ere concordant#
,:-
$he identification of a fe" families "ith familial Parkinson disease sparked further interest in the
genetics of the disease# (n one large family in 7alerno, (taly, * of *:% mem!ers had Parkinson
disease> linkage analysis incriminated a region in !ands /A%1)%1, and seAuencing revealed an ?)for)
0 su!stitution at !ase %: of the alpha)synuclein gene#
,1-
$ermed PD-1, this mutation codes for a
su!stitution of threonine for alanine at amino acid *1# $hese individuals "ere characteriCed !y early
age of disease onset (mean age, /;#* years), rapid progression (mean age at death, *6#1 years), lack
of tremor, and good response to levodopa therapy#
,1-
Give small 0reek kindreds "ere also found to
have the PD-1 mutation#
(n a 0erman family, a different point mutation in the alpha)synuclein gene (a su!stitution of + for 0 at
!ase 22, producing a su!stitution of proline for alanine at amino acid 1) confirmed that mutations in
the alpha)synuclein gene can cause Parkinson disease#
,11-
? fe" additional familial mutations in the
alpha)synuclein gene have !een identified and are collectively called PARK1# (t is no" clear that
these mutations are an exceedingly rare cause of Parkinson disease#
? total of 12 loci in various genes have no" !een proposed for Parkinson disease# <utations "ithin 6
of these loci (SNCA, RRK!, PRKN, D"1, P#NK1, and ATP 1$A!) are "ell)validated causes of familial
parkinsonism#
,1%-
(nheritance is autosomal dominant for SNCA and RRK! (although RRK! mutations
exhi!it varia!le penetrance)# (nheritance is autosomal recessive for PRKN, D"1, P#NK1,
and ATP1$A!# (n addition, polymorphisms "ithin SNCA and RRK!, as "ell as variations
in %APT and &'A( are risk factors for Parkinson disease#
,1%-
(Gor more information on genesDloci underlying monogenic parkinsonism and suscepti!ility genesDloci
for Parkinson disease, see $a!les 1 and %, respectively, inThe &enetics of Par)inson Disease#
,1%-
)
(n one study of :*1 patients "ith Parkinson disease "ith age at onset of * years or younger, 6/
patients (6#;%) had a PRKN mutation, 1 patient (#%%) had a D"1mutation, 1* patients (1#6%) had
an RRK! mutation, and 6/ patients (6#;%) had a&'A mutation#
,11-
# <utations "ere more common in
patients "ith age at onset of 1 years or younger (/#6%) than in those "ith age at onset !et"een 11
and * years (1/#6%)> more common in patients of Ie"ish ancestry (1%#/%) than in non)Ie"ish
patients (11#;%)> and more common in patients reporting a first)degree family history of Parkinson
disease (%1#:%) than in those "ithout such a family history (1*#1%)#
,11-
?lthough the mechanisms !y "hich genetic mutations cause Parkinson disease is not kno"n,
evidence to date converges on mechanisms related to a!normal protein aggregation, defective
u!iAuitin)mediated protein degradation, mitochondrial dysfunction, and oxidative damage#
"lpha#synuclein conformational changes and aggregation
?!normally aggregated alpha)synuclein is the ma&or component of 'e"y !odies and 'e"y neurites,
"hich are characteristic pathologic findings in Parkinson disease# <issense mutations and
multiplications in the SNCA gene that encodes alpha)synuclein, although rare, cause autosomal
dominant Parkinson disease# Ho"ever, genome)"ide association studies have also demonstrated a
link !et"een SNCAand sporadic Parkinson disease#
Dysfunction of alpha)synuclein appears to play a central role in the pathogenesis of Parkinson
disease, and understanding its relationship to the disease process holds ma&or promise for the
development of a cure#
?lpha)synuclein is a 1/)amino)acid protein that is unfolded at neutral pH# Ho"ever, "hen !ound to
mem!ranes or vesicles containing acidic phospholipids, it takes on an alpha)helical structure#
.ormally, alpha)synuclein is found mainly in neuronal presynaptic terminals and may play a role in
assem!ly and function of 7.?6E (solu!le .)ethylmaleimide)sensitive factor activating protein
receptor) proteins that are involved in neurotransmitter release#
8nder certain conditions, alpha)synuclein aggregates into oligomers that are gradually converted to
the !etaEsheet)rich fi!rillary structures that form 'e"y !odies and neurites in Parkinson disease# <ost
evidence currently suggests that it is the intermediate solu!le oligomers that are toxic to neurons#
<ultiple mechanisms have !een suggested as to ho" a!normally aggregated alpha)synuclein could
exert neurotoxicity#
,1/-
@ne hypothesis suggests that oligomeric alpha)synuclein can promote formation
of ion)permea!le pores on neuronal mem!ranes, leading to increased calcium influx# ?!errant pore
formation could also lead to neurotransmitter leaks from synaptic vesicles into the cytosol# (n addition,
overexpression of alpha)synuclein has !een demonstrated to impair mitochondrial complex ( activity,
and oligomeric alpha)synuclein may have a direct effect on mitochondrial mem!ranes# @ther lines of
evidence suggest that oligomeriCation of alpha)synuclein could cause cytoskeletal disruption, possi!ly
!y an effect on the microtu!ule)sta!iliCing protein, tau#
,1*-
Elevated levels of alpha)synuclein promote a!normal aggregation# levels are normally regulated !y a
!alance !et"een synthesis and degradation# SNCAmultiplications lead to increased synthesis of
alpha)synuclein and can cause Parkinson disease# ?lpha)synuclein appears to !e degraded !y the
u!iAuitin proteasome system and the autophagy)lysosome path"ay# 7everal genetic mutations
associated "ith Parkinson disease may lead to decreased alpha)synuclein degradation# Gor example,
increased risk of Parkinson disease in carriers of &'A (!eta)glucocere!rosidase gene) mutations,
"hich encode for the lysosomal enCyme glucocere!rosidase, may !e due to lysosomal dysfunction
and conseAuent alpha)synuclein accumulation and oligomeriCation#
Ho" the Parkinson disease process !egins is not kno"n# @nce it is initiated, ho"ever, it may
propagate !y a prionlike process in "hich misconformed proteins induce the templated misfolding of
other protein molecules# (n Parkinson disease, synuclein pathology !egins in the lo"er !rainstem and
olfactory !ul!, ascends up the mid!rain, and eventually affects the neocortex# @ne set of o!servations
in support of a prionlike process comes from experience "ith fetal dopaminergic grafts transplanted
into the striata of patients "ith Parkinson disease, !ecause these grafts develop 'e"y !odies,
suggesting host)graft transmission of disease#
,16-
Preventing the propagation of a!normal alpha)synuclein aggregation may !e the key to slo"ing or
stopping Parkinson disease progression#
=efore the introduction of levodopa, Parkinson disease caused severe disa!ility or death in %*% of
patients "ithin * years of onset, 6*% "ithin 1 years, and 2:% "ithin 1* years# $he mortality rate
from Parkinson disease "as 1 times that of the general population matched for age, sex, and racial
origin# Bith the introduction of levodopa, the mortality rate dropped approximately *%, and longevity
"as extended !y many years# $his is thought to !e due to the symptomatic effects of levodopa, as no
clear evidence suggests that levodopa stems the progressive nature of the disease#
,12, 1:-
$he ?merican ?cademy of .eurology notes that the follo"ing clinical features may help predict the
rate of progression of Parkinson disease
,%-
9
@lder age at onset and initial rigidityDhypokinesia can !e used to predict (1) a more rapid rate
of motor progression in those "ith ne"ly diagnosed Parkinson disease and (%) earlier development
of cognitive decline and dementia> ho"ever, initially presenting "ith tremor may predict a more
!enign disease course and longer therapeutic !enefit from levodopa
? faster rate of motor progression may also !e predicted if the patient is male, has associated
comor!idities, and has postural insta!ilityDgait difficulty (P(0D)
@lder age at onset, dementia, and decreased responsiveness to dopaminergic therapy may
predict earlier nursing home placement and decreased survival
Patient Education
Patients "ith Parkinson disease should !e encouraged to participate in decision making
regarding their condition#
,%1-
(n addition, individuals and their caregivers should !e provided
"ith information that is appropriate for their disease state and expected or ongoing
challenges#
,1:-
Psychosocial support and concerns should !e addressed andDor referred to a
social "orker or psychologist as needed#
Prevention of falls should !e discussed# $he 8J .ational (nstitute for Health and +linical
Excellence has several guidance documents including those for patients and caregivers#
@ther issues that commonly need to !e addressed at appropriate times in the disease course
include cognitive decline, personality changes, depression, dysphagia, sleepiness and
fatigue, and impulse control disorders# ?dditional information is also often needed for financial
planning, insurance issues, disa!ility application, and placement (assisted living facility,
nursing home)#
Gor patient education information, see the =rain N .ervous 7ystem +enter, as "ell
as Parkinson5s Disease Dementia#
Previous
History
@nset of motor signs in Parkinson disease is typically asymmetric, "ith the most common initial
finding !eing an asymmetric resting tremor in an upper extremity# @ver time, patients notice
symptoms related to progressive !radykinesia, rigidity, and gait difficulty# $he first affected arm may
not s"ing fully "hen "alking, and the foot on the same side may scrape the floor# @ver time, axial
posture !ecomes progressively flexed and strides !ecome shorter#
7ome nonmotor symptoms commonly precede motor signs in Parkinson disease# <ost Parkinson
disease patients have a su!stantial reduction in olfactory function (smell) !y the time motor signs
emerge# Ho"ever, either this is not noticed !y the patients or patients may not realiCe that it is part of
the disease# ?nother common premotor symptom is rapid eye movement (6E<) !ehavior disorder
(6=D)# (n this condition, individuals exhi!it movements during 6E< sleep that are often descri!ed as
hitting or kicking motions# $here are also a num!er of midlife risk factors for the later development of
Parkinson disease# $hese include constipation and excessive daytime sleepiness, although they are
far from specific for Parkinson disease#
(n a =ritish study, the freAuency of nonmotor symptoms in 1*: patients "ith ne"ly diagnosed
ParkinsonOs disease "as found to !e significantly greater than that in :: healthy age)matched control
patients (mean, 2#/ vs %#2)#
,%%-
$he most commonly experienced nonmotor symptoms in patients "ith
early Parkinson disease in this study included the follo"ing
,%1-
9
Excessive saliva
Gorgetfulness
8rinary urgency
Hyposmia
+onstipation
(nitial clinical symptoms in Parkinson disease include the follo"ing9
$remor
? su!tle decrease in dexterity> for example, a lack of coordination "ith activities such as
playing golf or dressing (a!out %% of patients first experience clumsiness in one hand)
Decreased arm s"ing on the first)involved side
7oft voice
Decreased facial expression
7leep distur!ances
6=D, in "hich there is a loss of normal atonia during 6E< sleep9 (n one study, 12% of *)
year)old men "ith 6=D and no neurologic signs "ent on to develop parkinsonism
,%/-
> patients Pact
out their dreamsQ and may kick, hit, talk, or cry out in their sleep
Decreased sense of smell
7ymptoms of autonomic dysfunction, including constipation, s"eating a!normalities, sexual
dysfunction, and se!orrheic dermatitis
? general feeling of "eakness, malaise, or lassitude
Depression or anhedonia
7lo"ness in thinking
+ommon early motor signs of Parkinson disease include tremor, !radykinesia, rigidity, and dystonia#
Tremor
?lthough tremor is the most common initial symptom in Parkinson disease, occurring in approximately
;% of patients, it does not have to !e present to make the diagnosis# $remor is most often descri!ed
!y patients as shakiness or nervousness and usually !egins in one upper extremity and initially may
!e intermittent# 8pper extremity tremor generally !egins in the fingers or thum!, !ut it can also start in
the forearm or "rist# ?fter several months or years, the tremor may spread to the ipsilateral lo"er
extremity or the contralateral upper extremity !efore !ecoming more generaliCed> ho"ever,
asymmetry is usually maintained#
$remor can vary considera!ly, emerging only "ith stress, anxiety, or fatigue# +lassically, the tremor of
Parkinson disease is a resting tremor (occurring "ith the lim! in a resting position) and disappears
"ith action or use of the lim!, !ut this is not seen in all patients# (nitially, the tremor may !e noticed
during activities such as eating or reading a ne"spaper# ?lthough Parkinson disease is a rare cause
of tremor affecting the head or neck, tremors of the chin, lip, or tongue are not uncommon# ?s "ith
other tremors, the amplitude increases "ith stress and resolves during sleep#
$radykinesia
=radykinesia refers to slo"ness of movement# 7ymptoms of !radykinesia are varied and can !e
descri!ed !y patients in different "ays# $hese may include a su!&ective sense of "eakness, "ithout
true "eakness on physical examination> loss of dexterity, sometimes descri!ed !y patients as the
Rmessage not getting to the lim!R> fatiga!ility> or achiness "hen performing repeated actions#
Gacial !radykinesia is characteriCed !y decreased !link rate and facial expression# 7peech may
!ecome softer, less distinct, or more monotonal# (n more advanced cases, speech is slurred, poorly
articulated, and difficult to understand# Drooling is an uncommon initial symptom in isolation !ut is
reported commonly (especially nighttime drooling) later in the disease course#
$runcal !radykinesia results in slo"ness or difficulty in rising from a chair, turning in !ed, or "alking# (f
"alking is affected, patients may take smaller steps and gait cadence is reduced# 7ome patients
experience a transient ina!ility to "alk, as though their feet are froCen to the floor# $his RfreeCingR is
seen commonly in patients "ith more advanced disease> it is more prominent as patients attempt to
navigate door"ays or narro" areas and can result in patients getting trapped !ehind furniture or !eing
una!le to cross a door threshold easily#
(n the upper extremities, !radykinesia can cause small, effortful hand"riting (ie, micrographia) and
difficulty using the hand for fine dexterous activities such as using a key or kitchen utensils# (n the
lo"er extremities, unilateral !radykinesia commonly causes scuffing of that foot on the ground, as it is
not picked up during leg s"ing# $his may also !e descri!ed as dragging of one leg#
%igidity
7ome patients may descri!e stiffness in the lim!s, !ut this may reflect !radykinesia more than rigidity#
@ccasionally, individuals may descri!e a feeling of ratchety stiffness "hen moving a lim!, "hich may
!e a manifestation of cog"heel rigidity#
Dystonia
Dystonia is a common initial symptom in young)onset Parkinson disease, "hich is defined as
symptom onset !efore age / years# Dystonia in Parkinson disease commonly consists of a foot
involuntary turning in (inversion) or do"n (plantar flexion), often associated "ith cramping or aching in
the leg# Dorsiflexion of the !ig toe may also occur# ?nother common dystonia in Parkinson disease is
adduction of the arm and el!o", causing the hand to rest in front of the a!domen or chest# Dystonic
postures can "ax and "ane, occurring "ith fatigue or exertion#
Bhether stooped posture is due to truncal dystonia is a matter of de!ate# @ne study suggests that the
stooped posture may !e due to verte!ral fractures resulting from vitamin D deficiency "ith
compensatory hyperparathyroidism#
,%*-
Fitamin D supplementation may reduce the risk for stooped
posture#
$here are / cardinal signs of Parkinson disease, "ith % of the first 1 listed !elo" reAuired to make the
clinical diagnosis# $he fourth cardinal sign, postural insta!ility (!alance difficulty), emerges late in the
disease, usually after 2 years or more#
6esting tremor
6igidity
=radykinesia
Postural insta!ility
%esting tremor
6esting tremor is assessed !y having patients relax their arms in their lap "hile in a seated position#
Having patients count aloud !ack"ard from 1 may help !ring out the tremor# $he arms should also
!e o!served in an outstretched position to assess postural tremor, and kinetic tremor (tremor "ith
voluntary movement) can !e o!served during the finger)to)nose test# ?lthough a resting tremor is the
tremor characteristic of Parkinson disease, many Parkinson disease patients also have some postural
andDor kinetic tremor#
%igidity
6igidity refers to an increase in resistance to passive movement a!out a &oint# $he resistance can !e
either smooth (lead pipe) or oscillating (cog"heeling)# +og"heeling is thought to reflect tremor rather
than rigidity and may !e present "ith tremors not associated "ith an increase in tone (ie, essential
tremor)# 6igidity is usually tested !y flexing and extending the patient5s relaxed "rist and can !e made
more o!vious !y having the patient perform voluntary movements, such as tapping, "ith the
contralateral lim!#
$radykinesia
=radykinesia refers to slo"ness of movement !ut also includes reduced spontaneous movements and
decreased amplitude of movement# =radykinesia is also expressed as micrographia (small
hand"riting), hypomimia (decreased facial expression), decreased !link rate, and hypophonia (soft
speech)# $hus, the patientOs !link rate and facial expression should !e o!served#
(n addition, speed and amplitude of movements are assessed !y having the patient open his or her
hand (each lim! is assessed individually) and tap his or her thum! and index finger repetitively, trying
to perform the movement as !ig and as fast as possi!le# 7imilarly, the patient should !e asked to tap
the toes of each foot as !ig and as fast as possi!le# Ginally, the patient should !e asked to arise from
a seated position "ith the arms crossed to assess the a!ility to arise from a chair# $he patient is then
o!served "hile "alking to assess stride length and speed, as "ell as arm s"ing#
Postural instability
Postural insta!ility refers to im!alance and loss of righting reflexes# (ts emergence in a patient "ith
Parkinson disease is an important milestone, !ecause it is poorly amena!le to treatment and a
common source of disa!ility in late disease# Postural sta!ility is typically assessed !y having patients
stand "ith their eyes open and then pulling their shoulders !ack to"ard the examiner# Patients are
told to !e ready for the displacement and to regain their !alance as Auickly as possi!le# $aking 1 or %
steps !ack"ard to regain !alance is considered normal# $he examiner should !e ready to catch
patients if they are una!le to regain !alance#
&aryngeal dysfunction and dysphagia
?s the patient is speaking, the vocal loudness, intonation, and Auality, including fluidity of speech and
articulation, should !e assessed# 7ustaining vo"el phonation (eg, RahR) for maximum duration,
counting to *, and reading a passage that tests articulation (eg, the rain!o" passage) provide
reasona!le speech samples# +losely listening for reduced or diminishing loudness and intonation and
increasing !reathiness and hoarseness helps differentiate Parkinson disease from hyperkinetic
disorders such as spasmodic dysphonia#
,%6-
? soft, monotone voice, vocal tremor, poor articulation, varia!le speech rate, trou!le "ith the initiation
of speech, and stuttering)like Aualities are all characteristics of Parkinson disease# Perhaps the most
telling vocal symptom is the marked contrast !et"een ha!itual vocal volume (soft and diminishing)
and the patient5s response to a reAuest to increase loudness# ? reAuest to Rsay that again, t"ice as
loudR often results in increased loudness, improved voice Auality, and a dramatic improvement in
speech intelligi!ility#
Dysphagia is common, especially in advanced Parkinson disease# <anifestations may range from
drooling to aspiration#
?n otolaryngologist can perform a more detailed assessment of laryngeal dysfunction in patients "ith
Parkinson disease, using neurolaryngeal examination and stro!oscopy# =ecause distortion can occur
"hen the tongue is held for"ard during rigid stro!oscopy, the neurolaryngeal examination is !est
performed !y vie"ing the larynx "ith a flexi!le laryngoscope# $he larynx is evaluated for vocal fold
mo!ility, paresis or paralysis, coordination of movement, agility, fatiga!ility, flexi!ility, and use of
accessory muscles during phonation "hile the patient says various phrases and sylla!les#
Hyperfunctional and hypofunctional disorders can often !e differentiated !y isolating the a!ductor and
adductor muscle groups# $he larynx is also visualiCed at rest#
6igid stro!oscopy plays a key role in the assessment of the vi!ratory characteristics of the vocal folds,
including the presence of masses, lesions, or scar and glottic configuration a!normalities, including an
elliptical closure pattern, phase asymmetry, and a!normal phase closure# 7tro!oscopy and
neurolaryngeal examination are complementary in the evaluation of the patient "ith Parkinson
disease# +ommon stro!oscopy findings in Parkinson disease include true vocal fold atrophy or other
evidence of glottal incompetence, including a chasing "ave or a shorter closed phase#
Pooling of secretions, decreased sensation, and aspiration are also characteriCations of the Parkinson
disease larynx# ? paralyCed vocal fold suggestsParkinson)plus syndrome (PP7) as the etiology for the
parkinsonism if other aspects of the diagnosis are present#
PereC et al found that vocal tremor is present in **% of patients "ith Parkinson disease#
,%;-
(nterestingly, only 1*% of patients "ith Parkinson disease exhi!ited a resting vocal cord tremor,
"hereas the remainder exhi!ited kinetic tremor# $he tremor is primarily a vertical laryngeal movement#
PP7 "as found to carry a higher incidence of vocal tremor (6/%), "ith most tremors located in the
arytenoids# $he authors found no vertical laryngeal tremor in patients "ith PP7#
,%;-
"utonomic dysfunction
?utonomic dysfunction is common in patients "ith Parkinson disease# @rthostatic hypotension often
!ecomes a concern in late disease, and impaired intestinal motility can lead to constipation and,
sometimes, vomiting or impaired a!sorption# 8rinary symptoms, retention, and !ladder infection can
occur, and erectile dysfunction is not uncommon# (n addition, many patients note episodes of
s"eating#
Prominent autonomic dysfunction, especially frank urinary incontinence or profound orthostatic
hypotension, may suggest multiple system atrophy (<7?) rather than Parkinson disease#
'ardiopulmonary impairment
$he flexed posture of patients "ith Parkinson disease can lead to kyphosis, cause a reduction in
pulmonary capacity, and produce a restrictive lung disease pattern#
STAGING
(nvestigators have proposed a staging system to improve the assessment of overall Parkinson
disease severity# (n an o!servational, cross)sectional study of :11 patients "ith Parkinson disease,
6ay +haudhuri and colleagues found a "ide discrepancy !et"een the severity of nonmotor symptoms
as measured !y the .on<otor 7ymptoms 7cale (.<77) and motor symptoms as measured !y the
Hoehn and Kahr scale#
,%2, %:-
$he investigators proposed a staging system for nonmotor symptom
!urden !ased on .<77 scores, "hich "as correlated "ith measures of disa!ility and Auality of life#
$he staging system rates nonmotor symptom !urden (.<7=) on a scale of (no .<7=) to / (very
severe .<7=)#
,%2, %:-
0iven the high prevalence of mood disorders in Parkinson disease, these
patients should !e screened regularly for depression# Ho"ever, assessment of depression in patients
"ith Parkinson disease is complicated !y the fact that some symptoms of Parkinson disease overlap
"ith those of depression (eg, masklike facies, insomnia, psychomotor slo"ing, difficulty concentrating,
fatigue)# 0uilt and self)reproach are less prominent in depression in patients "ith Parkinson disease,
"hereas anxiety and pessimism are more prominent#
Hoops et al found that in Parkinson disease, the Montreal Cognitive Assessment (MoCA) is
superior to the Mini-Mental State Examination (MMSE) for sreening for mild ognitive
impairment or dementia!
"#$%
MoCA and MMSE demonstrated similar overall disriminant
validit& for detetion of an& ognitive disorder, 'ut as a sreening instrument, MoCA (as
'etter than MMSE ()*+ vs ,*+ orret diagnoses)!
"#$%
-he prevalene of dementia in Parkinson disease ranges from .$-*$+, (ith the disease
onferring a .- to )-fold inreased risk ompared (ith ontrol populations!
"#/%
Man& patients
(ith Parkinson disease have some exeutive funtion impairment, even earl& in the disease!
"#/%
Su'stantial ognitive impairment and dementia t&piall& our 0 &ears or more after the
onset of motor features!
1ementia generall& ours late in Parkinson disease2 su'stantial ognitive d&sfuntion (ithin
/ &ear of onset of motor features suggests a diagnosis of 3e(& 'od& disease, a disease losel&
related to Parkinson disease and marked '& the presene of ortial 3e(& 'odies! 4n the
affeted age group, omor'idit& (ith other neurodegenerative disorders,
partiularl& Al5heimer disease and ere'rovasular disease, is ommon! -he relativel& high
prevalene of depression in patients (ith Parkinson disease is another onfounder in the
diagnosis of Parkinson disease dementia!
Exeutive funtion, short-term memor&, and visuospatial a'ilit& ma& 'e impaired in patients
(ith Parkinson disease dementia, 'ut aphasia is not present! 4n a long-term Australian stud&
that ompared neurops&hologi measures 'et(een patients (ith Parkinson disease (ho had
earl& dementia (6 /$ &ears of disease onset) and those (ith late dementia, investigators
reported that dementia in parkinsonism appears to our at a'out age 7$ &ears regardless of
the time of onset of Parkinson disease!
"#.%
Ho(ever, although earl& and late dementia had
similar effets in ognitive domains, individuals (ith earl& onset of parkinsonism had a
preserved linguisti a'ilit& 'efore the onset of dementia!
"#.%
Previous
?typical parkinsonisms, or Parkinson)plus syndromes, are primary neurodegenerative disorders that
have parkinsonian features and are associated "ith complex clinical presentations that reflect
degeneration in various neuronal systems# Patients "ith atypical parkinsonisms typically have a "orse
prognosis than those "ith Parkinson disease, and atypical parkinsonisms respond poorly to standard
anti)Parkinson disease treatments#
(Gor more information, see Parkinson)Plus 7yndromes for detailed information regarding clinical
clues, "orkup, differential diagnosis, and treatment of atypical parkinsonisms, including multiple
system atrophy, progressive supranuclear palsy, parkinsonism)dementia)amyotrophic lateral
sclerosis complex, cortico!asal ganglionic degeneration, and diffuse 'e"y !ody disease#)
Previous
Proceed to Differential Diagnoses
$he most common tremor disorders are Parkinson disease and essential tremor# Bhen a patient
presents "ith tremor, the clinician should pay particular attention to the !ody parts involved,
positionsDconditions in "hich the tremor occurs (ie, resting, postural, kinetic, intention), and the
freAuency of the tremor# (t is also critical to look for potential associated signs# $he patient should !e
examined for evidence of parkinsonism (!radykinesia, rigidity, postural insta!ility), dystonia, and other
neurologic signs#
?n 2)1% HC action (posturalDkinetic) tremor of the upper extremities that is temporarily relieved !y
drinking alcohol is characteristic of essential tremor, "hereas the presence of a pill)rolling rest tremor,
!radykinesia, and rigidity is consistent "ith Parkinson disease and argues against essential tremor#
(n patients "ith parkinsonism, careful attention to the history is necessary to exclude secondary
causes such as medications, toxins, or trauma# <edications that !lock striatal dopamine receptors,
such as metoclopramide and neuroleptics, can cause drug)induced parkinsonism# +ertain toxins such
as <P$P (1)methyl)/)phenyl)1,%,1,6)tetrahydropyridine) and manganese (at high levels of exposure)
can also cause parkinsonism#
+onsider evaluating patients "ith parkinsonism for osteoporosis and osteopenia# (n a meta)analysis of
%1 studies, $ornsey and colleagues found evidence that individuals "ith Parkinson disease have an
increased risk for osteoporosis and osteopenia#
,11, 1/-
? pooled analysis of % of the studies, for example,
indicated that in patients "ith Parkinson disease, the odds ratio for developing osteoporosis, "hen
compared "ith healthy controls, "as %#61, although the increase "as lo"er in men than in "omen#
?nalysis of 1/ studies found !one mineral densities in patients "ith Parkinson disease to !e
significantly lo"er at the hip, lum!ar spine, and femoral neck, "hereas, after an examination of :
studies, the investigators estimated that !one fracture risk is dou!led in Parkinson patients#
,11, 1/-
Early clinical features that suggest an atypical parkinsonism rather than Parkinson disease include the
follo"ing
,%-
9
Galls at presentation or early in the disease
Poor response to levodopa
7ymmetry at disease onset
6apid disease progression
.o tremor
Dysautonomia (eg, urinary incontinence, fecal incontinence, catheteriCation for urinary
retention, persistent erectile failure, prominent symptomatic orthostatic hypotension)
$he atypical parkinsonisms are usually associated "ith little or no tremor, relatively early speech and
!alance difficulty, and little or no response to dopaminergic medications# <ultiple system atrophy
(<7?) is relatively symmetric and characteriCed !y parkinsonism, often "ith some com!ination of
autonomic, corticospinal, and cere!ellar dysfunction# Progressive supranuclear palsy (P7P) is
relatively symmetric and characteriCed !y parkinsonism "ith early falls (often in the first year) and a
supranuclear gaCe palsy in "hich the patient has difficulty "ith voluntary do"n)gaCe# +ortico!asal
ganglionic degeneration (+=D) is typically very asymmetric and characteriCed !y !oth cortical
(difficulty identifying o!&ects, apraxias) and !asal ganglionic (usually marked rigidity in an arm)
features#
'e"y !ody disease is characteriCed !y su!stantial cognitive dysfunction "ithin 1 year of onset of
parkinsonism# Hallucinations are common#
Patients "ith onset of parkinsonism !efore age / years should !e tested for Bilson disease, starting
"ith serum ceruloplasmin measurement and ophthalmologic evaluation for Jayser)Gleischer rings#
Differential Diagnoses
?lCheimer Disease
+ardioem!olic 7troke
+horea in ?dults
+ortical =asal 0anglionic Degeneration
Dementia Bith 'e"y =odies
Dopamine)6esponsive Dystonia
Essential $remor
Hallervorden)7patC Disease
Huntington Disease
'acunar 7yndromes
<ultiple 7ystem ?trophy
.euroacanthocytosis
.ormal Pressure Hydrocephalus
@livopontocere!ellar ?trophy
Parkinson)Plus 7yndromes
Progressive 7upranuclear Palsy
7triatonigral Degeneration
Fascular Dementia
Bilson Disease
?pproach +onsiderations
Parkinson disease is a clinical diagnosis# .o la!oratory !iomarkers exist for the condition, and
findings on routine magnetic resonance imaging (<6() and computed tomography (+$) scan are
unremarka!le# Positron emission tomography (PE$) and single)photon emission +$ (7PE+$) may
sho" findings consistent "ith Parkinson disease, and olfactory testing may provide evidence pointing
to"ard Parkinson disease, !ut these studies are not routinely needed# (@lfactory testing can reveal
hyposmia, "hich may precede the motor signs of Parkinson disease !y several years#
,1*-
Ho"ever,
olfactory loss is not specific and can also occur in ?lCheimer disease#)
.o la!oratory or imaging study is reAuired in patients "ith a typical presentation# 7uch patients are
aged ** years or older and have a slo"ly progressive and asymmetric parkinsonism "ith resting
tremor and !radykinesia or rigidity# Patients "ho do not have tremor should generally !e considered
for <6( evaluation to exclude !rain lesions such as stroke, tumor, or demyelination#
(n patients "ith an unusual presentation, diagnostic testing may !e indicated to exclude other
disorders in the differential diagnosis# 7uch tests may include serum ceruloplasmin, sphincter
electromyography, or lum!ar puncture#
7erum ceruloplasmin concentration is o!tained as a screening test for Bilson disease in patients
younger than / years "ho present "ith parkinsonian signs# (f the ceruloplasmin level is lo",
measurement of %/)hour urinary copper excretion and slit)lamp examination for Jayser)Gleischer
rings must !e performed# ?!normal results on urinary sphincter electromyography have !een noted in
patients "ith multiple system atrophy (<7?)#
? su!stantial and sustained response to dopamine medications (dopamine agonists or levodopa)
helps confirm a diagnosis of Parkinson disease# (t is unclear "hether acute levodopa or apomorphine
challenge has any advantage over clinical diagnostic criteria#
,%-
@ver time, diagnostic accuracy
improves as the progression of signs and symptoms and response to medications unfolds#
(n the general community, there is a high diagnosis error rate !et"een Parkinson disease and
essential tremor# Gor movement disorder neurologists, "hen an erroneous diagnosis of Parkinson
disease is made, the most likely correct diagnoses are the atypical parkinsonisms (<7?, progressive
supranuclear palsy ,P7P-, cortico!asal ganglionic degeneration ,+=D-)# Early in the disease course, it
may !e very difficult to distinguish !et"een Parkinson disease and the atypical parkinsonisms# $hese
disorders also do not have la!oratory !iomarkers, and, therefore, distinguishing among them is !ased
on clinical criteria# @lfactory testing may help differentiate Parkinson disease from P7P and +=D, !ut
olfaction is also reduced in <7?#
Magnetic resonance imaging
<agnetic resonance imaging (<6() is useful to exclude strokes, tumors, multi)infarct state,
hydrocephalus, and the lesions of Bilson disease# <6( should !e o!tained in patients "hose clinical
presentation does not allo" a high degree of diagnostic certainty, including those "ho lack tremor,
have an acute or step"ise progression, or are younger than ** years#
$he follo"ing <6( indicates "here a thalamic stimulator is typically placed#
?xial, fast spin)echo inversion recovery magnetic resonance image at the level
of the posterior commissure# $he typical target for placing a thalamic stimulator is demonstrated (cross)hairs)#
=elo" is a coronal <6( follo"ing !ilateral su!thalamic nuclei deep !rain stimulation#
Postoperative coronal magnetic resonance image (<6() demonstrating desired
placement of !ilateral su!thalamic nuclei)deep !rain stimulation (7$.)D=7) leads#
PET and SPE'T scanning
Positron emission tomography (PE$) and single)photon emission computed tomography (7PE+$)
scanning are useful diagnostic imaging studies, !ut these are not routinely reAuired# Different
radioligands permit imaging of different components or a!normalities "ithin the !rain#
?t the onset of motor signs, patients "ith Parkinson disease sho" an approximately 1% decrease
in
12
G)dopa (fluorodopa) uptake on PE$ imaging in the contralateral putamen#
12
G)Dopa is taken up !y
the terminals of dopamine neurons and converted to
12
G)dopamine# $he rate of striatal
12
G
accumulation reflects transport of
12
G)dopa into dopamine neurons and its decar!oxylation to
12
G)
dopamine, "hich is stored in dopamine nerve terminals in the striatum# $hus,
12
G)dopa PE$ imaging
provides an index of remaining dopamine neurons# Ho"ever, this study is not "idely availa!le, is
usually not covered !y insurance, and is currently generally considered a research tool#
+ar!on)11 (
11
+))nomifensine and cocaine analogues such as
1%1
()!eta)+($ (iodine)1%1)la!eled
car!oxymethoxy)1!eta)/)iodophenyl)nortropane) and
1%1
()GP)+($ (fluoropropyl)+($) !ind to dopamine
reuptake sites on nigrostriatal terminals and provide an index of the remaining dopamine neurons#
(oflupane (
1%1
() (Da$scan) is a radiopharmaceutical agent that is indicated for striatal dopamine
transporter visualiCation using 7PE+$ !rain imaging to assist in the evaluation of adults "ith
suspected Parkinsonian syndromes (P7s)# $his agent may !e used to help differentiate essential
tremor from tremor due to P7s (idiopathic Parkinson disease ,(PD- and Parkinson)plus syndromes
,PP7-)#
,1-
?nalysis of data from % clinical trials demonstrated that the use of ioflupane "ith iodine)1%1
and single)photon emission computed tomography (7PE+$) scanning to diagnose early)stage
Parkinson5s disease performed as "ell as clinical assessment at 1)year follo")up#
,16, 1;-
Deficits on
1%1
( 7PE+$ scans indicate a dopamine deficiency syndrome !ut do not differentiate
Parkinson disease from atypical parkinsonisms, including multiple system atrophy (<7?)
and progressive supranuclear palsy (P7P)# (oflupane 7PE+$ imaging reveals a dopamine deficiency
in Parkinson disease, <7?, P7P, cortico!asal ganglionic degeneration, and 'e"y !ody disease# $his
study is normal in essential tremor, dystonic tremor, medication)induced parkinsonism or tremor,
psychogenic disorders, and in normal individuals#
HISTOLOGI
Classi pathologi findings in Parkinson disease inlude degeneration of the neurons
ontaining neuromelanin, espeiall& in the su'stantia nigra and the lous eruleus! Surviving
neurons often ontain eosinophili &toplasmi inlusions alled 3e(& 'odies (see the
follo(ing image)! -he primar& 'iohemial defets are loss of striatal dopamine, (hih
results from degeneration of dopamine-produing ells in the su'stantia nigra, as (ell as
h&perativit& of the holinergi neurons in the audate nuleus!
3e(& 'odies are intra&toplasmi eosinophili inlusions, often (ith halos, that are easil& seen in
pigmented neurons, as sho(n in this histologi slide! -he& ontain pol&meri5ed alpha-s&nulein2 therefore, Parkinson disease is a
s&nuleinopath&! 3e(& 'odies in the lous oeruleus from a patient (ith Parkinson
disease!
Alpha-s&nulein is a ma8or strutural omponent of 3e(& 'odies2 all 3e(& 'odies stain for
alpha-s&nulein, and most also stain for u'i9uitin! 3e(& 'odies are onentri, eosinophili,
&toplasmi inlusions (ith peripheral halos and dense ores! -he presene of 3e(& 'odies
(ithin pigmented neurons of the su'stantia nigra is harateristi, 'ut not pathognomoni, of
Parkinson disease! 3e(& 'odies are also found in the ortex, nuleus 'asalis, lous eruleus,
intermediolateral olumn of the spinal ord, and other areas!
Aording to the :raak h&pothesis, 3e(& 'od& patholog& in the 'rain 'egins in the olfator&
'ul' and lo(er 'rainstem and slo(l& asends to affet dopamine neurons in the su'stantia
nigra and, ultimatel&, the ere'ral ortex!
"#0%
3e(& 'od& patholog& is also o'served in
autonomi nerves of the gut and heart!
Previous
'um!ar puncture should !e considered if signs of normal)pressure hydrocephalus (.PH) are
o!served (eg, incontinence, ataxia, dementia)# (n .PH, clinical signs characteristically improve after
removal of a!out % m' of cere!rospinal fluid#
Dopa)responsive dystonia should !e considered in patients "ith &uvenile)onset dystonia and
parkinsonism, particularly "ith diurnal fluctuations in symptoms# (n such patients, a trial of levodopa is
critical# ?dditional tests for this condition include measurement of +7G concentrations of !iopterin,
neopterin, and the neurotransmitter meta!olites homovanillic acid (HF?), *)hydroxyindoleacetic acid
(*)H(??), and 1)methoxy)/)hydroxyphenylglycol (<HP0)# (n !oth forms of dopa)responsive dystonia,
an altered pattern of decreases in these compounds is o!served#
(n the RParkinson5s Progression <arkers (nitiativeR cross)sectional study of 61 drug)naive patients "ith
early)stage PD and 1: healthy controls, +7G levels of the ?lCheimer5s !iomarkers S)amyloid 1)/%
(?S1)/%), total tau ($)tau), tau phosphorylated at threonine 121 (P)tau121), and T)synuclein "ere
lo"er in the PD patients than in the controls# ?S1)/% and P)tau121 "ere significant predictors of
Parkinson5s disease, and $)tau and T)synuclein "ere associated "ith the severity of motor
dysfunction# (n particular, lo"er ?S1)/% and P)tau121 concentrations "ere associated "ith the
postural insta!ilityEgait distur!anceEdominant PD phenotype, !ut "ere not associated "ith the
tremor)dominant or intermediate phenotypes#
,1:, /-
7ee 'um!ar Puncture for detailed information on indications for the procedure, contraindications, and
a step)!y)step discussion containing images and video on ho" to perform the procedure#
Previous
$he goal of medical management of Parkinson disease is to provide control of signs and symptoms
for as long as possi!le "hile minimiCing adverse effects# 7tudies demonstrate that a patient5s Auality
of life deteriorates Auickly if treatment is not instituted at or shortly after diagnosis#
,/1-
Symptomatic and neuroprotective therapy
Pharmacologic treatment of Parkinson disease can !e divided into symptomatic and neuroprotective
(disease modifying) therapy# ?t this time, there is no proven neuroprotective or disease)modifying
therapy#
'evodopa, coupled "ith car!idopa, a peripheral decar!oxylase inhi!itor (PD(), remains the gold
standard of symptomatic treatment for Parkinson disease# +ar!idopa inhi!its the decar!oxylation of
levodopa to dopamine in the systemic circulation, allo"ing for greater levodopa distri!ution into the
central nervous system# 'evodopa provides the greatest antiparkinsonian !enefit for motor signs and
symptoms, "ith the fe"est adverse effects in the short term> ho"ever, its long)term use is associated
"ith the development of motor fluctuations (P"earing)offQ) and dyskinesias# @nce fluctuations and
dyskinesias !ecome pro!lematic, they are difficult to resolve#
<onoamine oxidase (<?@))= inhi!itors can !e considered for initial treatment of early disease# $hese
drugs provide mild symptomatic !enefit, have excellent adverse effect profiles, and, according to a
+ochrane revie", have improved long)term outcomes in Auality)of)life indicators !y %)%*%#
,/%-
Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic !enefit and delay the
development of dyskinesia compared "ith levodopa# Proactively screen patients receiving oral
dopamine agonists for adverse events# ? revie" of the +ochrane and Pu!<ed data!ases from 1::
to %2 found that these agents caused a 1*% increase in adverse events such as somnolence,
sudden)onset sleep, hallucinations, edema, and impulse control disorders (eg, pathologic gam!ling,
shopping, and (nternet use> hypersexuality> and hoarding)#
,/1-
.ote that patients may !e reluctant to
mention these events or may not attri!ute them to their treatment#
7ymptomatic anti)Parkinson disease medications usually provide good control of motor signs of
Parkinson disease for /)6 years# ?fter this, disa!ility often progresses despite !est medical
management, and many patients develop long)term motor complications, including fluctuations and
dyskinesias# ?dditional causes of disa!ility in late disease include postural insta!ility (!alance
difficulty) and dementia# $hus, symptomatic therapy for late disease reAuires different strategies#
.europrotective therapy aims to slo", !lock, or reverse disease progression> such therapies are
defined as those that slo" underlying loss of dopamine neurons# ?lthough no therapy has !een
proven to !e neuroprotective, there remains interest in the long)term effects of <?@)= inhi!itors#
@ther agents currently under investigation include creatine and isradipine#
$he younger the patient, the more emphasis the authors place on long)term considerations to guide
early treatment# Koung patients have a longer life expectancy and are more likely to develop motor
fluctuations and dyskinesias# Gor older patients and those "ith cognitive impairment, less emphasis is
placed on long)term considerations> instead, the focus is on providing adeAuate symptomatic !enefit
in the near term, "ith as fe" adverse effects as possi!le#
Gor patients "ho have motor fluctuations and dyskinesias that cannot !e adeAuately managed "ith
medication manipulation, surgery is considered# $he principal surgical option is deep !rain stimulation
(D=7), "hich has largely replaced neuroa!lative lesion surgeries# 'evodopaDcar!idopa intestinal gel
infusion is availa!le in some countries and is in clinical trials in others, including the 8nited 7tates#
,1/-
(onmotor symptoms
(t is no" recogniCed that in Parkinson disease, nonmotor symptoms may !e as trou!lesome as, or
more trou!lesome than, motor symptoms# .onmotor symptoms can !e categoriCed as autonomic,
cognitiveDpsychiatric, and sensory
,//-
and may include depression, dementia, hallucinations, rapid eye
movement (6E<) sleep !ehavior disorder (6<D), orthostatic hypotension, and constipation#
.onmotor symptoms can also fluctuate, especially depression, pain, num!ness,
paresthesiaDdysesthesia, akathisia, and restless)legs syndrome# 6ecognition of nonmotor symptoms
of Parkinson disease is essential for appropriate management#
,//-
7creen Parkinson disease patients for depression, and treat it "hen present# ?n evidence)!ased
guideline from the ?merican ?cademy of .eurology (??.) reports that physician recognition of
depression is lo" in Parkinson disease, at less than 1% of clinically proven cases# $here are many
factors that confound its diagnosis in these patients> and depression has the single largest effect on
the Auality of life of patients "ith Parkinson disease#
,%/, /*-
(n %1, the ??. released guidelines on the treatment of nonmotor symptoms of Parkinson disease#
6ecommendations included the follo"ing
,/6-
9

7ildenafil citrate (Fiagra) may !e considered to treat erectile dysfunction

Polyethylene glycol may !e considered to treat constipation

<odafinil should !e considered for patients "ho su!&ectively experience excessive daytime
somnolence

Gor insomnia, evidence is insufficient to support or refute the use of levodopa to improve
o!&ective sleep parameters that are not affected !y motor symptoms> evidence is also insufficient to
support or refute the use of melatonin for poor sleep Auality

'evodopaDcar!idopa should !e considered to treat periodic lim! movements of sleep in

Parkinson disease, !ut there are insufficient data to support or refute the use of nonergot dopamine
agonists to treat this condition or that of restless)legs syndrome

<ethylphenidate may !e considered for fatigue (note9 methylphenidate has the potential for
a!use and addiction)

Evidence is insufficient to support or refute specific treatments of orthostatic hypotension,

urinary incontinence, anxiety, and 6<D

<edications commonly used for symptomatic !enefit of motor symptoms in early Parkinson
disease include levodopa, monoamine oxidase (<?@))= inhi!itors, and dopamine agonists#

&evodopa

'evodopa, coupled "ith a peripheral dopa decar!oxylase inhi!itor such as car!idopa,

remains the standard of symptomatic treatment for Parkinson disease# (t provides the greatest
antiparkinsonian !enefit "ith the fe"est adverse effects in the short term# Ho"ever, long)term
use of levodopa is associated "ith the development of fluctuations and dyskinesias# @nce
fluctuations and dyskinesias !ecome pro!lematic, they are difficult to resolve# $hese adverse
effects are the reason to consider delaying the initiation of levodopa if other alternatives are
a!le to control symptoms#

'evodopaDcar!idopa is introduced at a lo" dose and escalated slo"ly# +ar!idopa inhi!its the
decar!oxylation of levodopa to dopamine in the systemic circulation, allo"ing for greater
levodopa delivery into the central nervous system#

+urrently availa!le levodopa preparations in the 8nited 7tates include levodopaDcar!idopa

immediate)release ((6) ta!lets (7inemet), levodopaDcar!idopa controlled)release (+6) ta!lets
(7inemet +6), and levodopaDcar!idopa orally disintegrating ta!lets (Parcopa)# $he orally
disintegrating ta!let is !ioeAuivalent to oral levodopaDcar!idopa (6, !ut it dissolves on the
tongue "ithout the need to s"allo" it "ith "ater# $he orally disintegrating ta!let is not
a!sor!ed in the mouth !ut travels in the saliva to a!sorption sites in the proximal small !o"el
("here other levodopa preparations are also a!sor!ed)#

'evodopaDcar!idopa is also availa!le in com!ination "ith entacapone, a catechol)@)

methyltransferase (+@<$) inhi!itor# Bhen entacapone is given in con&unction "ith levodopa
and car!idopa, plasma levels of levodopa are higher and more sustained than after
administration of levodopa and car!idopa alone# 'evodopaDcar!idopaDentacapone is useful in
advanced Parkinson disease in patients "ith motor fluctuations# (n the 7$6(DE)PD (7$alevo
6eduction (n Dyskinesia Evaluation) study, patients "ith early Parkinson disease treated "ith
levodopaDcar!idopaDentacapone (7talevo) developed more dyskinesia than patients treated
"ith levodopaDcar!idopa> therefore, levodopaDcar!idopaDentacapone is not recommended for
treatment of early disease#
,/;-

'evodopa in com!ination "ith a dopa decar!oxylase inhi!itor is started at a lo" dose and
slo"ly titrated to control clinical symptoms# <ost patients experience a good response on a
daily levodopa dosage of 1)6 mgDday (usually divided 1 or / times daily) for 1)* years or
longer# Doses higher than those necessary to control symptoms adeAuately should !e
avoided, !ecause higher doses increase the risk for the development of dyskinesia#
,/2-
(f
nausea occurs, the levodopa dose can !e taken immediately follo"ing a meal# ?dditional
measures to alleviate nausea include adding extra car!idopa or introducing domperidone
(availa!le outside the 8nited 7tates)# @ther side effects include diCCiness and headache# (n
elderly patients, confusion, delusions, agitation, hallucinations, and psychosis may !e more
commonly seen#

M"#$ inhibitors

<?@)= inhi!itors, such as selegiline and rasagiline, may !e used for early symptomatic
treatment of Parkinson disease# $hese medications provide mild symptomatic !enefit, have
excellent adverse effect profiles, and may improve long)term outcomes# $hese characteristics
make <?@)= inhi!itors a good choice as initial treatment for many patients# Bhen the <?@)=
inhi!itor alone is not sufficient to provide good control of motor symptoms, another medication
(eg, a dopamine agonist or levodopa) can !e added#

7elegiline is indicated as ad&unctive therapy (* mg every morning> maximum, 1 mgDday) in

the treatment of Parkinson disease in patients !eing treated "ith levodopaDcar!idopa#
6asagiline is indicated for the treatment of the signs and symptoms of Parkinson disease as
initial monotherapy (1 mgDday) and as ad&unctive therapy (#*)1# mgDday) to levodopa#
Potential side effects include nausea, headaches, and diCCiness#

Dopamine agonists

(nitial treatment "ith a dopamine agonist, to "hich levodopa can !e added as necessary, is
associated "ith fe"er motor fluctuations and dyskinesias than levodopa alone in prospective,
dou!le)!lind studies# 7u!seAuent analyses of these studies indicate that the !enefit of
dopamine agonists in delaying motor symptoms is due to their a!ility to delay the need for
levodopaDcar!idopa#
,/:, *-
+ommonly used dopamine agonists include pramipexole and
ropinirole#

Dopamine agonists provide symptomatic !enefit that is compara!le to that "ith

levodopaDcar!idopa in early disease, !ut these agents lack sufficient efficacy to control signs
and symptoms !y themselves in more advanced disease# Dopamine agonists provide
moderate symptomatic !enefit and rarely cause fluctuations and dyskinesias !y themselves,
!ut they have more adverse effects than levodopa, including sleepiness, hallucinations,
edema, and impulse control disorders# Ho"ever, these adverse effects resolve upon lo"ering
the dose or discontinuing the medication#

Dopamine agonists are commonly reserved for younger individuals (U 6*); years) "ho are
cognitively intact# Bhen the dopamine agonist ("ith or "ithout an <?@)= inhi!itor) no longer
provides good control of motor symptoms, levodopa can !e added# Ho"ever, dopamine
agonists may provide good symptom control for several years !efore levodopa is reAuired#

Gor patients aged 6*); years, the authors make a &udgment !ased on general health and
cognitive status# $he more ro!ust and cognitively intact the patient, the more likely the
authors are to treat "ith a dopamine agonist !efore levodopa and add levodopaDcar!idopa
"hen necessary# Gor patients "ith cognitive impairment and those older than ; yearsV"ho
may !e prone to adverse effects, such as hallucinations, from dopamine agonistsVand for
those likely to reAuire treatment for only a fe" years, the authors may elect not to use a
dopamine agonist and instead depend on levodopaDPD( (peripheral decar!oxylase inhi!itor)
as primary symptomatic therapy#

Bhen introducing a dopamine agonist, it is important to start at a lo" dose and escalate
slo"ly# $he dose should !e titrated up"ard until symptoms are controlled, the maximum dose
is reached, or adverse effects emerge#

$he most common adverse effects of dopamine agonists are nausea, orthostatic hypotension,
hallucinations, somnolence, and impulse control disorders# .ausea can usually !e reduced !y
having the patient take the medication after meals# Domperidone, a peripheral dopamine
agonist availa!le outside the 8nited 7tates, is very helpful in relieving refractory nausea#

Patients on dopamine agonists should !e routinely asked a!out sleepiness, sudden onset of
sleep, and impulse control disorders such as pathologic gam!ling, shopping, internet use, and
sexual activity# $hese adverse effects typically resolve "ith reduction in dose or
discontinuation of the medication# Patients should !e "arned not to drive if they are
experiencing undue sleepiness# $hey should also !e "arned a!out the possi!ility of impulse
control disorders and the need to let their physician kno" if such an effect occurs#

"nticholinergic agents

?nticholinergic agents can !e used for patients "ho have disa!ility due to tremor that is not
adeAuately controlled "ith dopaminergic medication, !ut these are not first)line drugs,
!ecause of their limited efficacy and the possi!ility of neuropsychiatric side effects#
?nticholinergic medications provide good tremor relief in approximately *% of patients !ut
do not meaningfully improve !radykinesia or rigidity# =ecause tremor may respond to one
anticholinergic medication !ut not another, a second anticholinergic agent usually can !e tried
if the first is not successful# $hese medications should !e introduced at a lo" dose and
escalated slo"ly to minimiCe adverse effects, "hich include memory difficulty, confusion, and
hallucinations# ?dverse cognitive effects are relatively common, especially in elderly persons#

@ne of the most commonly used anticholinergic is trihexyphenidyl# $he initial dose of
trihexyphenidyl should !e lo" and gradually increased# (t is recommended to !egin therapy
"ith a single 1)mg dose# Dosage can !e titrated !y 1 mg each "eek or so, until a total of /)6
mg is given daily or until satisfactory control is achieved# 7ome patients may reAuire higher
doses# =enCtropine (+ogentin) is also commonly used, "ith an initial dose of #*)1 mg daily at
!edtime# Dose can !e titrated at "eekly intervals in increments of #* mg to a maximum of 6
mgDday#

"mantadine

?mantadine is an antiviral agent that has antiparkinsonian activity# (ts mechanism of action is
not fully understood, !ut amantadine appears to potentiate +.7 dopaminergic responses# (t
may release dopamine and norepinephrine from storage sites and inhi!it the reuptake of
dopamine and norepinephrine# ?mantadine may offer additional !enefit in patients
experiencing maximal or "aning effects from levodopa#

?mantadine is commonly introduced at a dose of 1 mg per day and slo"ly increased to an

initial maintenance dose of 1 mg % or 1 times daily# $he most concerning potential side
effects of amantadine are confusion and hallucinations# +ommon side effects include nausea,
headache, diCCiness, and insomnia# 'ess freAuently reported side effects include anxiety and
irrita!ility, ataxia, livedo reticularis, peripheral edema, and orthostatic hypotension#

(n a small, dou!le)!lind crossover study, amantadine "as found to ameliorate pathologic

gam!ling associated "ith Parkinson disease#
,*1-
Ho"ever, in a large cross)sectional study,
amantadine "as associated "ith a higher prevalence of impulse control disorders, including
gam!ling#
,*%-
$hus, further research is needed to understand the role of amantadine as a
treatment or cause of impulse control disorders in patients "ith Parkinson disease#
Motor fluctuations
Patients initially experience sta!le, sustained !enefit through the day in response to levodopa#
Ho"ever, after several months to years, many patients notice that the !enefit from immediate)release
((6) levodopaDcar!idopa "ears off after /)* hours# @ver time, this shortened duration of response
!ecomes more fleeting, and clinical status fluctuates more and more closely in concert "ith peripheral
levodopa concentration# 8ltimately, !enefit lasts only a!out % hours# $he time "hen medication is
providing !enefit for !radykinesia, rigidity, and tremor is called RonR time, and the time "hen
medication is not providing !enefit is called RoffR time#
$reating motor fluctuations in the a!sence of peak)dose dyskinesia is relatively easy# 7everal different
strategies, either alone or in com!ination, can !e used to provide more sustained dopaminergic
therapy# Possi!le strategies include the follo"ing9
?dding a dopamine agonist, catechol)* )methyltransferase (+@<$) inhi!itor, or monoamine
oxidase (<?@))= inhi!itor
Dosing levodopa more freAuently
(ncreasing the levodopa dose
7"itching from immediate)release ((6) to sustained)release (+6) levodopaDcar!idopa or
levodopaDcar!idopaDentacapone
8nless limited !y the emergence of peak)dose symptoms such as dyskinesia or hallucinations,
dopaminergic therapy should !e increased until off time is eliminated# @nce)daily formulations of the
dopamine agonists ropinirole and pramipexole are no" availa!le# $hese medications appear to
provide efficacy and safety similar to the (6 formulations that are administered 1 times daily#
,*1-
Dyskinesia
=y several months to years after the introduction of levodopa, many patients develop peak)dose
dyskinesia consisting of choreiform, "hich is t"istingDturning movements that occur "hen levodopa)
derived dopamine levels are peaking# ?t this point, increasing dopamine stimulation is likely to "orsen
peak)dose dyskinesias, and decreasing dopamine stimulation may "orsen Parkinson disease motor
signs and increase off time# $he therapeutic "indo" lies a!ove the threshold reAuired to improve
symptoms (on threshold) and !elo" the threshold for peak)dose dyskinesia (dyskinesia threshold)#
$he therapeutic "indo" narro"s over time !ecause of a progressive decrease in the threshold for
peak)dose dyskinesia#
?lthough many patients prefer mild dyskinesia to off time, the clinician should recogniCe that
dyskinesias can !e sufficiently severe to !e trou!lesome to the patient, either !y interfering "ith
activities or !ecause of discomfort# ?sking patients ho" they feel during !oth off time and time "ith
dyskinesia is important in titrating medication optimally# Having patients fill out a diary may !e helpful>
the diary should !e divided into half)hour time periods on "hich the patient denotes "hether they are
off> on "ithout dyskinesia> on "ith non)trou!lesome dyskinesia> or on "ith trou!lesome dyskinesia
(see the follo"ing image)# $he goal of medical management is to minimiCe off time and time on "ith
trou!lesome dyskinesia# 7tated another "ay, the goal is to maximiCe on time "ithout trou!lesome
dyskinesia#
Parkinson disease diary# $he patient or caregiver should place 1 check mark in
each half)hour time slot to indicate the patient5s predominant response during most of that period# $he goal of
therapeutic management is to minimiCe off time and on time "ith trou!lesome dyskinesia# +opyright 6o!ert Hauser,
1::6# 8sed "ith permission#
Treatment of motor fluctuations with dyskinesia
$he treatment of patients "ith !oth motor fluctuations and trou!lesome peak)dose dyskinesia can !e
difficult# $he goal of treatment in this situation is to provide as much good functional time through the
day as possi!le# $his is accomplished !y maximiCing on time "ithout trou!lesome dyskinesia# ?n
attempt is made to reduce !oth off time and time "ith trou!lesome or disa!ling dyskinesia#
8nfortunately, a decrease in dopaminergic therapy may increase off time, and an increase in
dopaminergic therapy may "orsen peak)dose dyskinesia#
Gor patients on the levodopaDcar!idopa +6 formulation, s"itching to levodopaDcar!idopa (6 often
provides a more consistent and predicta!le dosing cycle and allo"s finer titration# (n general, smaller
levodopa doses are administered more freAuently# ? dose should !e sought that is sufficient to
provide !enefit "ithout causing trou!lesome dyskinesia# $he time to "earing)off then determines the
appropriate interdose interval# $he extreme of this strategy is using liAuid levodopa, a solution "ith
"hich the dose can !e titrated finely and administered every hour#
+@<$ inhi!itors inhi!it the peripheral meta!olism of levodopa to 1)* )methyldopa (1)@<D), there!y
prolonging the levodopa half)life and making more levodopa availa!le for transport across the !lood)
!rain !arrier over a longer period# =ecause of the potential risk of hepatotoxicity "ith tolcapone
($asmar), liver function test monitoring is reAuired, and this medication should !e used only in patients
"ho are experiencing motor fluctuations on levodopa that cannot !e adeAuately controlled "ith other
medications# (f dyskinesia emerges, the levodopa dose should !e reduced# (n patients "ho already
have dyskinesia, the levodopa dose often is reduced !y 1)*% at the time tolcapone is introduced#
Entacapone (+omtan) is a +@<$ inhi!itor that does not cause hepatotoxicity> liver function tests are
not reAuired "ith this medication# 'evodopaDcar!idopaDentacapone (7talevo) is currently availa!le as
a drug com!ination for Parkinson disease#
7imilarly, dopamine agonists can !e added to levodopa to try to smooth the response# (f the patient
has !oth fluctuations and dyskinesias on levodopa, adding a dopamine agonist is likely to decrease
the disease severity and could delay dyskinesias and motor fluctuations> then, an attempt can !e
made to lo"er the levodopa dose#
(mportantly, the one availa!le drug that can reduce dyskinesis is amantadine# $his should !e
considered for patients "ho have clinically relevant dyskinesia and "ho appear likely to !e a!le to
tolerate this medication# 6esults from the 1)month, parallel)group, "ashout ?<?.DK7J (?<?.tadine
for DK7Jinesia) study sho"ed that amantadine treatment maintained its antidyskinetic effect over
several years in patients "ith Parkinson disease and levodopa)induced dyskinesia#
,*/, **-
$he principal side effects of amantadine are hallucinations and confusion, so the drug is usually not
appropriate for patients "ith preexisting cognitive dysfunction#
Gor patients "ho have motor fluctuations and dyskinesia that cannot !e adeAuately managed "ith
medication manipulation, surgery is considered#
Tremor
'evodopaDcar!idopa, dopamine agonists, and anticholinergics each provide good !enefit for tremor in
approximately *)6% of patients# (f a patient is experiencing trou!lesome tremor and if symptoms
are not controlled adeAuately "ith one medication, another should !e tried# (f the tremor is not
controlled adeAuately "ith medication, surgical therapy may !e considered at any time during the
disease#
.europrotective therapies are defined as those that slo" underlying loss of neurons# +urrently, no
proven neuroprotective therapies exist for Parkinson disease# (f a neuroprotective therapy "ere
availa!le for Parkinson disease, it "ould !e administered from the time of diagnosis on"ard# ?t the
current time, the greatest interest in possi!le neuroprotection resides "ith the monoamine oxidase
(<?@))= inhi!itors, selegiline, and rasagiline# @ther agents of interest include creatine and isradipine#
+linical trials have not provided support for neuroprotective effects for vitamin E or coenCyme 41#
Selegiline
7elegiline (Eldepryl, Melapar) is an irreversi!le inhi!itor of <?@)=# (n humans, !rain dopamine is
meta!oliCed !y <?@)=, and the !lockade of this enCyme "ill reduce the meta!olism of dopamine#
7elegiline "as sho"n conclusively to delay the need for levodopa therapy in early Parkinson disease,
in the D?$?$@P (Deprenyl ?nd $ocopherol ?ntioxidative $herapy @f Parkinsonism) study#
,*6, *;-
$he
Parkinson 7tudy 0roup evaluated the a!ility of selegiline and tocopherol to delay progression of
clinical disa!ility in early Parkinson disease !y randomiCing 2 patients to receive selegiline (1
mgDday) or place!o and tocopherol (% (8Dday) or place!o# Patients "ho received selegiline, "ith
place!o or "ith tocopherol, experienced a significant delay in the need for levodopa therapy# Patients
"ho received place!o reAuired levodopa at a pro&ected median of 1* months from enrollment,
"hereas those "ho received selegiline reAuired levodopa at
apro&ectedmedianof%/monthsafterenrollment#$ocopherolhadnoeffectonprogression of disa!ility#
,*6, *;-
=ecause selegiline "as o!served to provide a small !ut statistically significant symptomatic (early)
!enefit, it is not possi!le to determine "hether a neuroprotective effect contri!uted to the delay in
need for levodopa in the D?$?$@P study#
,*6, *;-
(n another study, patients "ith early Parkinson disease "ho received selegiline over a ;)year period
experienced less clinical progression and reAuired less levodopa than patients receiving place!o#
,*2-
(n
this study, patients "ith early Parkinson disease "ere randomiCed to selegiline or place!o, and
levodopa "as added as needed# ?fter * years, patients "ho "ere treated "ith place!o had 8nified
Parkinson Disease 6ating 7cale (8PD67) scores that "ere 1*% higher ("orse) than those treated
"ith selegiline, even as they "ere receiving 1:% higher doses of levodopa#
,*2-
$his is a striking finding,
considering that as monotherapy in early disease, selegiline provides only modest symptomatic
improvement#
7elegiline is the medication that first garnered "ide interest as a possi!le neuroprotective agent for
Parkinson disease# 'a!oratory investigations continue to provide evidence that selegiline affords a
neuroprotective effect for dopamine neurons independent of <?@)= inhi!ition# 7elegiline "as
reported to protect dopamine cells in mice from <P$P (1)methyl)/)phenyl)1,%,1,6)tetrahydropyridine)
toxicity, even "hen the agent "as administered after a delay sufficient to allo" the oxidation of <P$P
to <PPL (1)methyl)/)phenylpyridinium),
,*:-
an effect that cannot !e attri!uted to <?@)= inhi!ition#
(n cell)culture systems, selegiline5s neuroprotective effect is mediated !y ne" protein synthesis#
7elegiline induces transcriptional events that result in increased synthesis of antioxidant and
antiapoptotic proteins# Evidence indicates that one of selegiline5s meta!olites, desmethylselegiline, is
the active agent for neuroprotection# (t is possi!le that selegiline5s amphetamine meta!olites may
interfere "ith its neuroprotective actions#
%asagiline
6asagiline (?Cilect) is also an <?@)= inhi!itor that exhi!its neuroprotective effects in cell culture and
animal models# Possi!le disease)modifying effects of rasagiline "ere studied in % large, delayed)start
studies# (n such studies, su!&ects are randomiCed to treatment "ith active study medication or to
place!o follo"ed !y active study medication# $his creates % phases "ithin the study# (n phase (, one
group is on place!o, and the other is on active study medication> in phase ((, !oth groups are
receiving active study medication# (f phase (( is long enough to allo" full "ash)in of symptomatic
effects, any differences !et"een the groups at the end of the study should !e due to enduring !enefits
(ie, disease modification) that accrue only to the group that received active study medication during
phase (#
7tated another "ay, in a delayed)start design, half of the su!&ects in the study take the trial drug from
day 1 and the other half take place!o# Ho"ever, half"ay through the study, the place!o group is
s"itched from place!o to the trial drug# (f the drug is truly !eneficial in slo"ing progression of the
disease, those that started the trial on place!o should never catch up, in terms of disease
progression, to those "ho "ere given the trial drug from the !eginning of the study#
ADA&#* and T+%P* studies
(n @cto!er %11, the 87 Good and Drug ?dministrationOs (GD?Os) Peripheral and +entral .ervous
7ystem Drugs ?dvisory +ommittee voted against approval of an indication for disease)modifying
effects for rasagiline# $he advisory committee determined that the % delayed)start rasagiline studies
did not provide compelling evidence that rasagiline slo"s progression of Parkinson disease# $hese
trials "ere the ?D?0(@ (?ttenuation of Disease progression "ith ?Cilect 0iven @nce)daily)
,6, 61-
and
$E<P@ (6asagiline in Early <onotherapy for Parkinson5s Disease @utpatients)
,6%, 61-
studies, "hich are
discussed !elo"#
(n the $E<P@ study, patients "ere randomiCed to treatment "ith rasagiline 1 mgDday for 1% months>
rasagiline % mgDday for 1% months> or place!o for 6 months, follo"ed !y rasagiline % mgDday for 6
months#
,6%-
6asagiline administered at a dosage of 1 or % mgDday for the first 6 months resulted in
improved 8nified Parkinson Disease 6ating 7cale (8PD67) scores relative to place!o> there "as also
a higher proportion of patients "ith treatment responses in the active treatment groups than in the
place!o group#
,6%-
(n addition, !oth of the rasagiline groups sho"ed significant differences, compared
"ith the place!o group, in the motor and activities of daily living (?D') su!scales of the 8PD67 and in
the Parkinson Disease 4uality of 'ife (PD48?'(G) scale#
,6%-
@ver the 1% months of the $E<P@ study, patients "ho "ere initially treated "ith place!o had a
greater progression in clinical symptomatology as assessed !y 8PD67 scores than did patients "ho
"ere treated "ith rasagiline for the full 1% months# $his finding suggested that there "as an effect
over and a!ove a simple symptomatic effect and potentially consistent "ith a disease)modifying
effect#
,6/-
Bhen the $E<P@ investigators looked at the long)term (6#*)year follo")up period) outcome
of early rasagiline therapy relative to late therapy in early Parkinson disease, patients in the early
rasagiline treatment groupV"ho received the drug from the !eginning of the $E<P@ studyVhad
significantly less "orsening of their total 8PD67 scores than patients in the delayed)start group, even
as investigators added other antiparkinson medications as needed#
,61-
(n the large and rigorous delayed)start study called ?D?0(@, patients "ith early Parkinson disease
"ere randomiCed to rasagiline 1 mgDday for 12 months> rasagiline % mgDday for 12 months> place!o
for : months, follo"ed !y rasagiline 1 mgDday for : months> or place!o for : months, follo"ed !y
rasagiline % mgDday for : months# 6esults demonstrated that rasagiline at 1 or % mgDday "as
associated "ith a slo"er rate of "orsening in the active drug groups, relative to the place!o groups#
,61-
@ver 12 months, rasagiline 1 mgDday started early resulted in less "orsening in mean total 8PD67
score than "hen it "as started late# Ho"ever, for the groups that received rasagiline % mgDday, there
"as no difference at 12 months !et"een the early)start and delayed)start groups#
,61-
=ased on their findings, the ?D?0(@ investigators concluded that early treatment "ith rasagiline at a
dose of 1 mgDday provided !enefits that "ere consistent "ith a possi!le disease)modifying effect, !ut
early treatment "ith rasagiline at a dose of % mgDday did not#
,61-
$hey speculated that the effect of the
%)mg dose on symptoms may have masked any disease)modifying effects in patients "ith mild
Parkinson disease> they also noted that it "as possi!le that results "ith 1 mgDday "ere false positive,
rather than the results "ith % mgDday !eing false negative#
,61-
$hus, there remains interest as to "hether selegiline and rasagiline improve long)term outcome for
Parkinson disease patients, !ut this is not definitively proven, and the mechanism is unclear#
&evodopa
+linical trial data suggest that levodopa therapy in early Parkinson disease can potentially slo"
progression or has a prolonged effect on the symptoms of the disease#
,6*-
Ho"ever, neuroimaging
studies also indicate that loss of nigrostriatal dopamine nerve terminals may !e accelerated or the
dopamine terminals may !e modified "ith use of levodopa#
,6*-
(n a study !y Parkkinen et al that
evaluated "hether chronic levodopa use accelerates pathologic cere!ral processes in parkinsonism,
the investigators did not find such a progression !ased on nigral neuronal count and 'e"y !ody
pathology#
,66-
.onetheless, the lo"est dose that is necessary to maintain good function should !e used
to avoid motor complications#
,%1-
?dditional research is needed to determine "hether levodopa
accelerates, slo"s, or has no effect on disease progression#
Dopamine agonists
Dopamine agonists have !een used to provide symptomatic relief in early Parkinson disease# #n
,i,o experiments have demonstrated that the ergot and nonergot dopamine agonists protect cultured
cells from death due to oxidative damage# +linical data in patients "ith early Parkinson disease
provide neuroimaging results that suggest a possi!le neuroprotective effect#
,6*, 6;-
Farious studies have
!een conducted "ith ropinirole and pramipexole> ho"ever, definitive neuroprotection cannot !e
confirmed on the !asis of these studies#
,62
Deep !rain stimulation (D=7) has !ecome the surgical procedure of choice for Parkinson disease for
the follo"ing reasons9
(t does not involve destruction of !rain tissue
(t is reversi!le
(t can !e ad&usted as the disease progresses or adverse events occur
=ilateral procedures can !e performed "ithout a significant increase in adverse events
Deep !rain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of
Parkinson disease largely !ecause long)term complications of levodopa therapy result in significant
disa!ility over time# ? !etter understanding of !asal ganglia physiology and circuitry and
improvements in surgical techniAues, neuroimaging, and electrophysiologic recording have allo"ed
surgical procedures to !e performed more accurately and "ith lo"er mor!idity#
7urgery for movement disorders previously involved predominantly destructive lesioning of
a!normally hyperactive deep !rain nuclei> ho"ever, the o!servation that high)freAuency
electrostimulation in the ventral lateral nucleus (F') of the thalamus eliminates tremors in patients
undergoing thalamotomy led to investigation of long)term D=7 as a reversi!le alternative to lesioning
procedures#
+ontinued refinement of the kno"ledge of !asal ganglia circuitry and Parkinson disease
pathophysiology has narro"ed the focus of movement disorder surgery to 1 key gray)matter
structures9 the thalamus, the glo!us pallidus, and the su!thalamic nucleus (7$.)# +urrently, the 7$.
is the most commonly targeted site for Parkinson disease# (7ee the follo"ing image#)
7agittal section, 1% mm lateral of the midline, demonstrating the su!thalamic
nucleus (7$.) (lavender)# $he 7$. is one of the preferred surgical targets for deep !rain stimulation to treat symptoms
of advanced Parkinson disease#
D=7 surgery includes su!thalamic nucleus (7$.) stimulation, glo!us pallidus interna (0Pi)
stimulation, and thalamic deep !rain stimulation (see the follo"ing images)# $he 8J .ational
+olla!orating +entre for +hronic +onditions notes the follo"ing indications for 7$. and 0Pi in
patients "ith Parkinson disease
,%1-
9
$he presence of motor complications refractory to medical therapy
$he a!sence of significant comor!idities in a !iologically fit individual
$he a!sence of significant mental health pro!lems (eg, depression, dementia)
6esponse to levodopa
? key to patient selection is that appropriate patients still experience a good response to levodopa, !ut
that response cannot !e adeAuately maintained through the day or is complicated !y excessive
dyskinesia#
$he deep !rain stimulating lead is eAuipped "ith / electrode contacts, each of
"hich may !e used, alone or in com!ination, for therapeutic stimulation#
(mplantation of the deep !rain stimulation (D=7) lead# (nsertion of an electrode during deep
!rain stimulation for Parkinson disease#
$halamic D=7 has !een used in patients "ith predominantly severe and disa!ling tremor#
,%1-
Ho"ever,
this surgery is no" rarely used in patients "ith Parkinson disease, !ecause it has !een sho"n that
other symptoms continue to progress, causing significant disa!ility that is not controlled !y thalamic
D=7#
6ecent landmark studies have demonstrated the effectiveness of 7$. and 0Pi D=7 for appropriate
Parkinson disease patients#
,;-
(n a randomiCed, controlled trial of %** patients enrolled in the Feterans
?ffairs (F?) +ooperative 7tudies Program (+7P) trial for patients "ith advanced Parkinson disease,
!ilateral D=7 (7$. and 0Pi) "as more effective than !est medical therapy in improving on time
"ithout trou!lesome dyskinesia, motor function, and Auality of life at 6 months> ho"ever, D=7 "as
associated "ith an increased risk of serious adverse events#
,;1-
(n the same study, "hen the %)year
outcomes of 1/; patients "ho received 7$. D=7 and 1*% patients "ho received 0Pi D=7 "ere
compared, motor function and adverse events "ere not significantly different !et"een the % sites#
,;%-
Ho"ever, those "ho received 7$. D=7 had a greater reduction in dopaminergic medications, and
individuals "ho received 0Pi D=7 had significantly less depression#
,;%-
(nvestigators from the E?6'K7$(< 7tudy 0roup reported that relative to medical therapy alone, 7$.
D=7 in con&unction "ith medical therapy offers !enefits earlier in the course of PD, !efore the
appearance of severe disa!ling motor complications#
,;1, ;/-
<oreover, su!thalamic stimulation plus
medical therapy "as superior to medical therapy alone on several key measures of Auality of life and
motor function# Ho"ever, */#2% of the patients in the D=7 group suffered serious adverse events,
compared to //#1% of those in the medical)therapy group
,;1, ;/-
> 1;#;% of patients suffered serious
adverse events related to surgical implantation or the neurostimulation device#
? study !y Goltynie assessed ;: consecutive patients "ho under"ent !ilateral su!thalamic nucleus
D=7 at the .ational Hospital for .eurology and .eurosurgery using an <6()guided surgical techniAue
"ithout microelectrode recording#
,;*-
?t a median follo")up period of 1%)1/ months, a mean
improvement of %;#; points (standard deviation, 11#2) "as noted in the off)medication motor part of
the 8nified Parkinson Disease 6ating 7cale (8PD67 (((), eAuivalent to a mean improvement of *%%#
7ignificant improvements in dyskinesia duration, disa!ility, and pain "ere noted# $his suggests that in
"ell)selected patients "ith Parkinson disease, image)guided 7$. D=7 "ithout microelectrode
recording can lead to su!stantial improvements in motor disa!ility and improvements in Auality of life,
"ith very lo" mor!idity#
? randomiCed trial !y <oreau et al assessed the effectiveness of the drug methylphenidate in
improving gait disorders and freeCing of gait in patients "ith advanced Parkinson disease "ithout
dementia "ho also received su!thalamic nucleus stimulation (7$.)# Eighty)one patients from 11
movement disorders departments in Grance "ere randomly assigned to methylphenidate or place!o
for : days# +ompared "ith patients in the place!o group, patients in the methylphenidate group used
fe"er steps at : days# $hese results suggest methylphenidate may improve gait hypokinesia and
freeCing although further study is needed to determine long)term risks#
,;6-
$here is evidence that long)term motor improvement from 7$. D=7 is sustained overall# Ho"ever,
axial signs progressively decline over time and contri!ute to a "aning of the initial !enefit of this
procedure#
,;;-
?lthough not specifically approved !y the Good and Drug ?dministration (GD?) for pain, 7$. D=7
may !e effective in improving specific types of pain related to Parkinson disease,
,;2, ;:-
such as
musculoskeletal pain
,;2, 2-
and dystonic pain# Ho"ever, there is a risk of postoperative deterioration of
somatic pain exacer!ated !y Parkinson disease and radicularDperipheral neuropathic pain due to
lum!ar spine diseases# Patients "ith central pain have had a poor response to 7$. D=7#
,;2-
7$. D=7 may result in either a favora!le or an unfavora!le outcome in patients "ith Parkinson
disease and impulse control and related disorders#
,21-
?lthough there may !e resolution or
improvement of impulse control disorders follo"ing 7$. D=7, the procedure may also induce,
exacer!ate, reveal, or have no effect on these conditions#
,21-
(7ee Deep =rain 7timulation forParkinson Disease for a more extensive discussion of deep !rain
stimulation in this setting, including mechanisms of action, advantages and disadvantages, and
stages of the procedure#)
'esion surgeries involve the destruction of targeted areas of the !rain to control the symptoms of
Parkinson disease# 'esion surgeries for Parkinson disease have largely !een replaced !y deep !rain
stimulation (D=7)# During neuroa!lation, a specific deep !rain target is destroyed !y
thermocoagulation# ? radiofreAuency generator is used most commonly to heat the lesioning electrode
tip to the prescri!ed temperature in a controlled fashion#
Thalamotomy and pallidotomy
$halamotomy involves destruction of a part of the thalamus, generally the ventralis intermedius (F(<),
to relieve tremor# $he F(< nucleus is considered the !est target for tremor suppression, "ith excellent
short) and long)term tremor suppression in 2):% of patients "ith Parkinson disease# $halamotomy
has little effect on !radykinesia, rigidity, motor fluctuations, or dyskinesia# Bhen rigidity and akinesia
are prominent, other targets, including the glo!us pallidus interna (0Pi) and su!thalamic nucleus
(7$.), are preferred#
7venillson and 'eksell descri!ed ventral posterior pallidotomy in the 1:6s
,2%-
> ho"ever, their report
"as largely overlooked# $he original pallidotomy target "as in the medial and anterodorsal part of the
nucleus# $his so)called medial pallidotomy effectively relieved rigidity !ut inconsistently improved
tremor# 'eksell su!seAuently moved the target to the posteroventral and lateral 0Pi, resulting in
sustained improvement in as many as :6% of patients# (n 1::%, 'aitinen et al reported reduced
tremor, rigidity, akinesia, and levodopa)induced dyskinesia in 12 patients treated "ith pallidotomy,
prompting a reappraisal of the procedure performed "ith more modern techniAues#
,21-
Pallidotomy involves destruction of a part of the 0Pi# Pallidotomy studies have demonstrated
significant improvements in each of the cardinal symptoms of Parkinson disease (tremor, rigidity,
!radykinesia), as "ell as a significant reduction in dyskinesia#
$he most serious and freAuent (1#6%) adverse effect of pallidotomy is a scotoma in the contralateral
lo"er)central visual field# $his complication occurs "hen the 0Pi lesion extends into the optic tract,
"hich lies immediately !elo" the 0Pi# $he risk of visual)field deficit is reduced greatly !y accurate
delineation of the ventral 0Pi !order !y microelectrode recording# 'ess freAuent complications (U *%)
include in&ury to the internal capsule, facial paresis, and intracere!ral hemorrhage (1)%%)#
?!normalities of speech, s"allo"ing, and cognition may also !e o!served#
=ilateral pallidotomy is not recommended !ecause complications are relatively common and include
speech difficulties, dysphagia, and cognitive impairment#
Subthalamotomy
Hyperactivity of the excitatory 7$. pro&ections to the 0Pi is a crucial physiologic feature of Parkinson
disease# 7u!thalamotomy involves destruction of a part of the 7$.# ?lthough lesioning the 7$.
usually has !een avoided !ecause of the concern a!out producing hemi!allismus, results o!tained !y
experimental lesions of the 7$. in animals and humans suggest that su!thalamotomy may !e
performed safely and may reverse parkinsonism dramatically# 7u!thalamotomy studies have sho"n
significant improvements in the cardinal features of Parkinson disease, as "ell as the reduction of
motor fluctuations and dyskinesia#
0ood surgical outcomes !egin "ith careful patient selection and end "ith attentive, detail)oriented
postoperative care# $he authors !elieve that this level of care is !est provided !y a multidisciplinary
team that includes a movement disorder neurologist, a neurosurgeon "ho is "ell)versed in
stereotactic techniAue, a neurophysiologist, a psychiatrist, and a neuropsychologist# ?dditional
support from neuroradiology and reha!ilitation medicine is essential#
Girst, a neurologist "ith expertise in movement disorders evaluates the patient# Patient selection is
particularly important for successful su!thalamic nucleus (7$.) deep !rain stimulation (D=7),
!ecause a num!er of factors determine positive surgical outcome#
,2/, 2*-
$hese can !e summariCed as
follo"s9
? diagnosis of Parkinson disease
Positive response to levodopa
?!sence of atypical parkinsonian features
?dvanced disease, virtually unmanagea!le "ith dopaminergic medications
6elatively young age> ho"ever, advanced age (W;* years) is not an a!solute contraindication
to surgery (if a patient other"ise meets the selection criteria for a procedure and the Auality of life is
predicted to improve su!stantially, surgery should !e offered)
.o significant cognitive impairment
?!sence of active psychiatric disease
0ood social support and access to programming
Potential surgical candidates are then evaluated !y the neurosurgeon, "ho determines "hether the
patient is indeed a surgical candidate and decides "hich procedure(s) "ould !enefit the patient most#
+lose colla!oration !et"een the neurologist and the neurosurgeon aids the decision)making process,
minimiCing patient confusion and stress# (f the neurologist and neurosurgeon agree that the patient is
a good surgical candidate, further "orkup includes the follo"ing9
=rain magnetic resonance imaging (<6() to rule out comor!id conditions and to assess the
degree of !rain atrophy> significant atrophy may increase the risk of perioperative hemorrhage
Detailed neuropsychological testing to rule out cognitive impairment, "hich can !e "orsened
!y the surgical procedure
? psychiatrist "ith expertise in psychiatric complications of movement disorders may !e consulted to
rule out active psychiatric disease and screen for relevant past psychiatric history that may pose a
contraindication to surgery (eg, ma&or depression, suicidality)#
? fluorodopa positron emission tomography (PE$) scan may !e performed in the unusual
circumstance of diagnostic uncertainty# ? medical evaluation is performed to determine the patient5s
general fitness for surgery#
7urgery is reserved for patients "ith disa!ling motor fluctuations and dyskinesia or disa!ling tremor
that cannot !e adeAuately controlled "ith medications# Jey points to consider are as follo"s9

?!lative surgery such as thalamotomy, pallidotomy, and su!thalamotomy have largely !een
replaced !y D=7

$halamic D=7 is offered to the minority of patients "ith Parkinson disease "ho have
predominant and disa!ling tremor (more commonly, this procedure is performed on patients "ith
disa!ling essential tremor)

=ilateral 7$. D=7 (or glo!us pallidus interna ,0Pi- D=7) is offered to patients "ith advanced
Parkinson disease "ith disa!ling motor fluctuations andDor dyskinesia or disa!ling tremor that
cannot !e adeAuately controlled !y medications> outcomes have !een sho"n to !e similar after 7$.
and 0Pi D=7

=efore surgery, the patient should !e informed that these procedures do not cure Parkinson
disease and that progression is expected

;eural transplantation is a potential treatment for Parkinson disease, 'eause the most
signifiant neuronal degeneration is site and t&pe speifi (ie, dopaminergi)2 the
target area is (ell defined (ie, striatum)2 posts&napti reeptors are relativel& intat2
and the neurons provide toni stimulation of the reeptors and appear to serve a
modulator& funtion!

-ransplantation of autologous adrenal medullar& ells and fetal porine ells has not
'een found to 'e effetive in dou'le-'lind studies and has 'een a'andoned! Although
open-la'el studies of fetal dopaminergi ell transplantation &ielded promising results,
# randomi5ed, dou'le-'lind, sham-surger&<ontrolled studies found no net 'enefit! 4n
addition, some patients reeiving these transplants developed a potentiall& disa'ling
form of d&skinesia that persisted even after (ithdra(al of levodopa! =eatures suh as
gait d&sfuntion, free5ing, falling, and dementia are likel& due to nondopaminergi
patholog& and hene are unlikel& to respond to dopaminergi grafts!
"0)%

3e(& 'od&<like inlusions have 'een found in grafted nigral neurons in long-term
transplant reipients2 these inlusions stained positivel& for alpha-s&nulein and
u'i9uitin and had redued immunostaining for dopamine transporter, suggesting that
Parkinson disease ma& affet grafted ells!
"/)%

Human retinal pigment epithelial ells produe levodopa, and retinal pigment
epithelial ells in gelatin miroarriers have 'een implanted into the putamen in
preliminar& studies! A phase 44 dou'le-'lind, randomi5ed, multienter, sham-surger&<
ontrolled stud& of this tehni9ue has 'een ompleted!
"07, 00%
Parkinson disease patients
reeived no 'enefit from this proedure ompared to sham surger&! 4n addition, in one
ase stud&, postmortem examination in a patient (ho died ) months after surgial
implantation of #.,,$$$ retinal pigment epithelial ells found onl& //0 surviving
ells!
"0>%

Previous
7everal studies have demonstrated the safety of gene therapy as a treatment for Parkinson disease,
and larger studies have !een initiated to examine the efficacy of this procedure# $hree investigational
strategies that use gene transfer for targeted protein expression are as follo"s
,:-
9
(mproving dopamine availa!ility to the striatum using more continuous delivery,
6educing 7$. activity "ith local induction of gamma)amino!utryic acid (0?=?) expression
ProtectionDrestoration of nigrostriatal neuronal function "ith trophic factor expression
? dou!le)!lind, phase ((, randomiCed, controlled trial of gene delivery of the trophic factor neurturin via
an adeno)associated type)% vector (??F%) in Parkinson patients aged 1);* years suggested mild
efficacy# Gurther studies are ongoing#
,:1-
Previous
.ext 7ection9 <anagement of Psychiatric
<anagement of Psychiatric +omor!idities
Dementia
?lthough no specific therapy exists for dementia, the ?merican ?cademy of .eurology evaluated the
evidence regarding the use of cholinesterase inhi!itors in Parkinson disease dementia#
,:%-
=ased on
their revie", they suggested that rivastigmine (Exelon) and donepeCil (?ricept) are pro!a!ly effective
in treating Parkinson disease dementia# ?nticholinergic drugs used for the treatment of motor
symptoms of Parkinson disease may exacer!ate memory impairment# Bhen possi!le, avoid these
medications#
Depression
Depression is one of the most common nonmotor symptoms of Parkinson disease, occurring in
approximately 1*% of patients#
,:1, :/-
$his condition is more common in patients "ith Parkinson disease
than in the general elderly population and in those "ith chronic conditions such as osteoarthritis#
Depression in Parkinson disease has a profound impact on Auality of life and is associated "ith
reduced function, cognitive impairment, and increased caregiver stress#
? systematic revie" of prevalence studies of depression in Parkinson disease found that 1;% of
patients present "ith ma&or depression, %%% "ith minor depression, and 11% "ith
dysthymia
,:*-
<oreover, multiple studies have found that a history of depression is a risk factor for the
su!seAuent development of Parkinson disease#
,:6-
(maging, cere!rospinal fluid, and autopsy studies indicate that depression in Parkinson disease is
associated "ith dysfunction of !asal ganglia dopaminergic circuits that pro&ect to the frontal lo!es, as
"ell as noradrenergic lim!ic and !rainstem structures#
,:/-
Bhether serotonin (*)H$) dysfunction plays a
role in depression in PD is unclear#
7elective serotonin reuptake inhi!itors (776(s) are the most commonly used medications to treat
depression in Parkinson disease in clinical practice# Ho"ever, several randomiCed controlled trials,
systematic revie"s, and meta)analyses have suggested that 776(s may !e no more effective than
place!o in this situation#
,/*, :/, :;-
Positive results in randomiCed clinical trials have !een demonstrated for nortriptyline (a tricyclic
antidepressant ,$+?- "ith serotoninergic and adrenergic activity), desipramine (a predominantly
noradrenergic reuptake inhi!itor $+?), venlafaxine (a serotonin)noradrenaline uptake inhi!itor),
citalopram (an 776(), and paroxetine (an 776()#
,:/-
Gor example, in Parkinson disease patients that
"ere diagnosed "ith depressive disorder or operationally)defined su!syndromal depression,
venlafaxine extended release or paroxetine significantly reduced scores on the Hamilton 6ating 7cale
for Depression compared to place!o# =oth venlafaxine and paroxetine "ere "ell tolerated and did not
"orsen motor function#
,:2-
$here is a suggestion that noradrenergic or dual action (noradrenergicDserotoninergic)
antidepressants may !e more effective for treating depression in Parkinson disease than 776(s#
Ho"ever, "hether this is an artifact of clinical)trials methodology is not yet clear, and more research is
necessary#
?ntiparkinsonian medications can also exert an antidepressant effect# (n a large, randomiCed trial,
pramipexole (mean daily dose, %#12 mg) significantly reduced depression scores relative to place!o#
,::-
$he monoamine oxidase (<?@))= inhi!itor selegiline "as also demonstrated to provide an
antidepressant effect in patients "ith early Parkinson disease "ho "ere not clinically depressed#
,1-
Preliminary studies suggest that repetitive transcranial magnetic stimulation (r$<7) may !e effective
for depression in Parkinson disease, !ut more research is reAuired# Electroconvulsive therapy (E+$)
can !e considered for refractory moderate to severe depression#
Psychotic symptoms )hallucinations or delusions*
?ntiparkinsonian drugs can trigger psychosis in patients "ith Parkinson disease# (n Parkinson disease
patients "ith psychosis, antiparkinsonian medications other than levodopa should !e "ithdra"n in an
effort to resolve psychosis "hile maintaining motor control "ith levodopa# (n individuals "ith only mild
hallucinations that are "ell tolerated, active antipsychotic treatment may not !e necessary#
8se of typical antipsychotics can exacer!ate motor symptoms of Parkinson disease and should !e
avoided#
,%1-
4uetiapine is the atypical neuroleptic agent most commonly used !y movement)disorder experts,
!ecause it rarely exacer!ates motor symptoms and !lood monitoring is not reAuired# Ho"ever, its
efficacy has not !een confirmed in clinical trials# 4uetiapine is used in Parkinson disease at doses
much lo"er than those used in schiCophrenia# (t is usually introduced at a dose of %* mg at !edtime
and can !e increased to * mg or more at !edtime as necessary#
+loCapine can also !e used, !ut !lood monitoring is reAuired due to its potential for agranulocytosis
and other severe side effects#
,%1, 11-
Gor this reason, cloCapine is usually reserved for patients "ho are
not adeAuately controlled "ith Auetiapine# @ther atypical neuroleptics generally have more potential to
"orsen Parkinson disease motor symptoms than Auetiapine and cloCapine#
"nxiety
$he %1 ?merican ?cademy of .eurology (??.) practice parameter on the treatment of nonmotor
symptoms in Parkinson disease found insufficient evidence to support or refute the treatment of
anxiety in Parkinson disease "ith levodopa#
,/6-
Ho"ever, 776(s and venlafaxine (Effexor, Effexor X6)
may !e !eneficial# =uspirone is "ell tolerated !ut has not !een studied in this population#
=enCodiaCepines can !e considered, !ut adverse effects such as cognitive impairment, somnolence,
and !alance pro!lems may !e concerning# =ehavior modification techniAues can play an important
role in the treatment of anxiety#
,1%-
+mpulse behaviors
+ognitive)!ehavioral therapy (+=$) can help control impulse !ehaviors in PD# (n a study of /*
patients "ith idiopathic PD and associated impulse control !ehaviors that had not responded to
standard treatment, +=$ significantly improved symptom severity, neuropsychiatric distur!ances, and
depression and anxiety levels# @f the /* patients, 1; "ere randomly assigned to a 6)month "ait list
for +=$ along "ith standard medical care and %2 "ere randomiCed to +=$ starting immediately#
?mong the %2 patients in the treatment group, *2% completed all 1% sessions of +=$ and 22%
completed at least 6# $hree)Auarters of those receiving the treatment had improved symptom severity
compared "ith only a!out a third of those "ho did not receive the therapy#
,11, 1/-
Sleep disturbances
=enCodiaCepines can !e helpful in the treatment of rapid eye movement (6E<) sleep !ehavior
disorder (6=D), and o!structive sleep apnea (@7?) can !e treated "ith positive air"ay pressure "ith
either continuous pressure or !ilevel pressure# 7leep hygiene techniAues include avoiding
stimulantsDfluids near !edtime, avoiding heavy late)night meals, and follo"ing a regular sleep
schedule#
,1%, 1*-
(t is advised that patients "ith Parkinson disease and sudden)onset sleep avoid driving
and take precautions against potential occupational haCards#
,%1-
$he %1 ??. practice parameter found insufficient evidence to support or refute !eneficial effects
from the treatment of 6=D in Parkinson disease# @ther sleep disorders may !enefit from treatment#
'evodopaDcar!idopa should !e considered to treat periodic lim! movements of sleep# <odafinil may
improve patientsO su!&ective perceptions of excessive daytime somnolence (ED7), and
methylphenidate may !e considered in patients "ith fatigue#
,/6-
Exercise therapy in patients "ith Parkinson disease using a variety of physiotherapy interventions
may play a role in improving gait, !alance and flexi!ility, aero!ic capacity, initiation of movement, and
functional independence# 7tudies generally have suggested improvement in functional outcomes, !ut
the o!served !enefits "ere small in magnitude and "ere not sustained follo"ing discontinuation of the
exercise#
,6:-
? systematic revie" of 11 randomiCed trials involving 1*12 patients evaluated various physiotherapy
interventions, including general physiotherapy, exercise, treadmill training, cueing, dance and martial
arts# $here "ere significant improvements for "alking speed, "alking endurance and step length,
mo!ility (the $imed 8p N 0o test), and !alance# 8nified ParkinsonOs Disease 6ating 7cale (8PD67)
scores "ere also improved "ith physiotherapy# $here "as no !enefit o!served for falls or patient)
rated Auality of life, and there "as no evidence that one type of physiotherapy "as superior to others#
,16-
$here has !een a resurgence of interest in the potential !enefit of exercise in Parkinson disease,
including a possi!le neuroprotective effect#
,1;-
Figorous exercise in mid)life is associated "ith a
reduced risk of su!seAuent Parkinson disease# (n animal models, vigorous exercise provides a
protective effect against a variety of toxins that cause parkinsonism# (n addition, in healthy people,
serum !rain)derived neurotrophic factor (=D.G) increases after exercise, in proportion to the intensity
of the activity# (n Parkinson disease, =D.G levels in the su!stantia nigra are reduced, and in animal
models of Parkinson disease, =D.G provides a neuroprotective effect# $his is an area of active
research#
-he lar&ngeal manifestations of Parkinson disease often lead to dereased partiipation in the
ativities of dail& living 'eause of an ina'ilit& to ommuniate effetivel&! 1uring the ourse
of the disease, *,-0>+ of patients report speeh pro'lems, and more than #$+ find speeh
pro'lems to 'e the most de'ilitating part of the disease!
Mediations and surger& annot effetivel& treat the lar&ngeal manifestations of Parkinson
disease! =or this reason, speeh therap& pla&s a ke& role in the disease?s voal treatment
regimen! Speeh therap& is effetive in treating the lar&ngeal manifestations of Parkinson
disease, 'ut despite the signifiant num'er of patients (ith voal s&mptoms, onl& an
estimated #-*+ of patients (ith Parkinson disease undergo speeh therap&!
-he 3ee Silverman @oie -reatment (3S@-) is a program designed to inrease voal intensit&
in patients (ith Parkinson disease! -he treatment fouses on a simple set of tasks that are
pratied intensivel&, * sessions per (eek during a *-(eek period, resulting in maximi5ation
of phonator& and respirator& funtions! -he goal of 3S@- is to improve voal performane
for )-.* months (ithout interval intervention! 3S@- fouses on maximi5ing voal effort
(Athink loud, think shoutA) and maximi5ing sensor& pereption of voal effort and loudness
'& therapists! -herapists (ho 9uantif& results give onstant feed'ak to patients during
sessions and enourage patients to self-monitor and internall& ali'rate their loudness! After
3S@-, patients (ith Parkinson disease speak at a normal volume and (ith a health& voie
9ualit& despite the need to Athink loud, think shout!A
4n studies (ith a .-&ear follo(-up, patients (ho reeived 3S@- maintained or improved
voal intensit& ompared (ith pretreatment levels! Blottal inompetene and s(allo(ing
a'ilit& 'oth improved after 3S@-, (ithout an& signifiant hange in supraglottal
h&perfuntion! Preliminar& positron emission tomograph& (PE-) sans after 3S@- training in
patients (ith Parkinson disease sho( redued ativit& in the glo'us pallidus, an effet similar
to pallidotom&! 3S@- ma& also stimulate oordination of motor output 'e&ond the phonator&
s&stem in the form of inreased orofaial expression!
Cther therapies have 'een suggested for the treatment of the voal s&mptoms in Parkinson
disease, 'ut most data so far support 3S@- as the most promising therap& for Parkinson
disease lar&ngeal s&mptoms! Alternative methods of delivering therap& that do not involve /)
fae-to-fae sessions (ith a therapist are urrentl& 'eing studied! -hese methods inorporate
(e'am deliver& of 3S@- (e3CD1) and soft(are programs that patients an perform at
home! -hese tehnologiall& enhaned methods, (hen used to replae half of the fae-to-fae
sessions, have doumented outomes that are e9uivalent to lassi 3S@-! -he hope is that
suh alternatives (ill 'e implemented to allo( a less transportation-intensive therap& ourse
for the patient and to allo( follo(-up revie( of the 3S@- tehni9ues as needed!
A s&stemati revie( of linial trials of speeh and language therap& in Parkinson disease
identified # randomi5ed ontrolled trials that inluded )/ patients! -he authors onluded that
although improvements (ere noted, the& (ere not a'le to onlusivel& onfirm or refute the
'enefit of speeh and language therap& in Parkinson disease due to the small num'er of
patients in these trials, methodologi limitations, and possi'le pu'liation 'ias!
"/$0%
Previous
Proper nutritional support is essential for patients (ith Parkinson disease, inluding ade9uate
dietar& fi'er to prevent the ommon pro'lem of onstipation! Patients reentl& diagnosed
(ith Parkinson disease are often onfused regarding dietar& protein, 'eause the& reeive
onfliting information!
3evodopa is a'sor'ed via a large neutral amino aid ative arrier s&stem and therefore
ompetes (ith dietar& proteins for a'sorption2 this effet is generall& relativel& small and is
not liniall& important for most patients, espeiall& those (ith earl& or moderate disease!
Ho(ever, as the disease progresses and patients 'eome more and more sensitive to
maintaining relativel& narro( therapeuti serum onentrations of levodopa, this effet an
'eome liniall& relevant! -hese patients usuall& have signifiant motor flutuations! Some
report that (hen the& are AonA and the& eat a meal inluding protein, the& turn Aoff!A Cthers
find that if the& eat a protein meal, their next levodopa dose does not kik in! -hese patients
ma& 'enefit from a lo( protein or a protein redistri'uted diet!
4n a lo(-protein diet, the total dail& protein intake is spread more or less e9uall& over the da&!
4n a protein-redistri'uted diet, individuals onl& onsume food ver& lo( in protein during the
da& and then eat a high-protein meal in the evening! Dnfortunatel&, these diets are diffiult to
follo(2 dietar& onsultation ma& 'e 'enefiial for patients in (hom suh diets are onsidered!
=or patients (ith earl& and moderate Parkinson disease, the onsiderations are 9uite different!
As (ith patients (ith more advaned Parkinson disease, patients (ith earl& and moderate
Parkinson disease (ill get the most omplete and onsistent a'sorption of levodopa '& taking
their levodopa doses a half hour or more 'efore meals or / hour or more after meals!
Ho(ever, most patients (ith earl& or moderate disease (ill not notie a differene in linial
'enefit, (hether the& take their levodopa (ith meals or apart from meals!
Even if there is some redution in linial 'enefit (hen levodopa is taken (ith meals, this an
'e mitigated '& inreasing the levodopa dose, if neessar&! 4n patients (ith earl& disease, the
primar& onern regarding levodopa is t&piall& nausea, (hih is less likel& to our if the&
take their levodopa dose at the ompletion of meals! -herefore, in earl& Parkinson disease, it
is ommon to instrut patients to take their levodopa after meals to redue the likelihood of
nausea as the dose is titrated to linial effet!
Some studies have sho(n mild motor 'enefit (ith Mucuna pruriens (o(hage, velvet 'ean),
(hih ontain levodopa, and Vicia faba ('road or fava 'ean) ma& have short-term 'enefits!
")>%
Ho(ever, additional studies are needed!
@itamin E and oen5&me E/$ have not 'een sho(n to have a neuroprotetive effet in
Parkinson disease,
",), /$>%
and the& are not urrentl& reommended as dietar& supplements for
this ondition!
Previous
Patients "ith Parkinson disease must have regular follo")up care to ensure adeAuate treatment of
motor and !ehavioral a!normalities# @nce patients are sta!le on a medication regimen, provide
follo")up care at least every 1)6 months, and periodically ad&ust medication dosages as necessary#
Patients also need to !e monitored for adverse events, including somnolence, sudden)onset sleep,
impulse control disorders, and psychosis# (n addition, patients should !e evaluated and treated for
emergence of clinically relevant nonmotor symptoms, including dementia, psychosis, sleep disorders,
and mood disorders
Patients "ith Parkinson disease must have regular follo")up care to ensure adeAuate treatment of
motor and !ehavioral a!normalities# @nce patients are sta!le on a medication regimen, provide
follo")up care at least every 1)6 months, and periodically ad&ust medication dosages as necessary#
Patients also need to !e monitored for adverse events, including somnolence, sudden)onset sleep,
impulse control disorders, and psychosis# (n addition, patients should !e evaluated and treated for
emergence of clinically relevant nonmotor symptoms, including dementia, psychosis, sleep disorders,
and mood disorders
,uture treatments for Parkinson disease are covered in ,uture Treatments for Parkinson-s
Disease: Surfing the PD Pipeline. This article provides a discussion of new therapies in
clinical development that may alleviate motor features or slow disease progression/
including "0a antagonists/ levodopa formulations/ other antiparkinsonian medications/
antidyskinesia medications/ and gene therapy.
1
'lass Summary
1opamine agonists are effetive as monotherap& in earl& P1 and as ad8unts to levodopaFP14
(peripheral dear'ox&lase inhi'itor) in moderate to advaned disease! 1opamine agonists
diretl& stimulate posts&napti dopamine reeptors to provide antiparkinsonian 'enefit! All
availa'le dopamine agonists stimulate 1. reeptors, an ation that is thought to 'e liniall&
'enefiial! -he role of other dopamine reeptors is urrentl& unlear!
1opamine agonists are effetive to treat motor features of earl& P1, and the& ause less
development of motor flutuations and d&skinesia than levodopa! =or patients (ith motor
flutuations on levodopaFP14, the addition of a dopamine agonist redues off time, improves
motor funtion, and allo(s lo(er levodopa doses!
@ie( full drug information
'arbidopa2levodopa )Sinemet/ Sinemet '%/ Parcopa*

Car'idopaFlevodopa is approved for the treatment of s&mptoms of idiopathi P1,
postenephaliti parkinsonism, and s&mptomati parkinsonism that ma& follo( in8ur& to the
nervous s&stem '& ar'on monoxide andFor manganese intoxiation! 3evodopa, om'ined
(ith a peripheral dear'ox&lase inhi'itor (P14) suh as ar'idopa, is the riterion standard of
s&mptomati treatment for P12 it provides the greatest antiparkinsonian effia& in moderate
to advaned disease (ith the fe(est aute adverse effets! Ghen administered alone,
levodopa auses a high inidene of nausea and vomiting due to the formation of dopamine
in the peripheral irulation! Car'idopa inhi'its the dear'ox&lation of levodopa to dopamine
in the peripheral irulation there'& reduing nausea and allo(ing for greater levodopa
distri'ution into the C;S! Car'idopa does not ross the 'lood-'rain 'arrier!
@ie( full drug information
"pomorphine )"pokyn*

Apomorphine is a nonergoline dopamine agonist indiated for the aute, intermittent
treatment of h&pomo'ilit& AoffA episodes (Aend-of-dose (earing offA and unpredita'le
AonFoffA episodes) assoiated (ith advaned P1! 4t is administered '& a su'utaneous
in8etion! Although the exat mehanism '& (hih apomorphine exerts its therapeuti effets
in P1 is unkno(n, it is thought to our via ativation of posts&napti 1. reeptors in the
striatum!
@ie( full drug information
Pramipexole )Mirapex/ Mirapex E%*

Pramipexole is approved as monotherap& in earl& disease and as ad8untive therap& to
levodopaFP14 in more advaned stages! -he mehanism of ation of pramipexole as a
treatment for Parkinson disease is unkno(n, although it is 'elieved to 'e related to its a'ilit&
to stimulate 1. dopamine reeptors in the striatum! 4t is availa'le as an immediate-release
and an extended-release ta'let!
@ie( full drug information
%opinirole )%e3uip and %e3uip 4&*

Hopinirole is approved as monotherap& in earl& disease and as ad8untive therap& to
levodopaFP14 in more advaned disease! Hopinirole is a nonergot dopamine agonist that has
high relative in vitro speifiit& and full intrinsi ativit& at the 1. su'famil& of dopamine
reeptors2 it 'inds (ith higher affinit& to 1# than to 1. or 1* reeptor su't&pes! -he
mehanism of ation of ropinirole is stimulation of dopamine 1. reeptors in striatum! 4t is
availa'le as an immediate-release and an extended-release ta'let!
@ie( full drug information
"mantadine

Amantadine is approved for the treatment of idiopathi P1, postenephaliti parkinsonism,
and s&mptomati parkinsonism, (hih ma& follo( in8ur& to the nervous s&stem '& ar'on
monoxide intoxiation! 4t is also indiated in those elderl& patients 'elieved to develop
parkinsonism in assoiation (ith ere'ral arterioslerosis! -he usual dosage is /$$ mg given
t(ie a da& (hen used alone!
@ie( full drug information
%otigotine )(eupro*

1opamine agonist stimulating 1#, 1., and 1/ reeptors! 4mprovement in Parkinson-related
s&mptoms thought to 'e its a'ilit& to stimulate 1. reeptors (ithin the audate putamen in
the 'rain! 4ndiated for the treatment of the signs and s&mptoms of idiopathi Parkinson
disease (P1)! 1osage ranges differ for earl&-stage P1 and advaned-stage P1! Availa'le as
transdermal path that provides ontinuous deliver& for .* h
Previous
'lass Summary
?nticholinergics are commonly used as symptomatic treatment of PD, !oth as monotherapy and as
part of com!ination therapy# ?nticholinergic agents provide !enefit for tremor in approximately *% of
patients !ut do not su!stantially improve !radykinesia or rigidity# (f one anticholinergic does not "ork,
try another#
Fie" full drug information
Trihexyphenidyl

$rihexyphenidyl is indicated as an ad&unct in the treatment of all forms of parkinsonism
(postencephalitic, arteriosclerotic, and idiopathic)# (t is often useful as ad&uvant therapy "hen treating
these forms of parkinsonism "ith levodopa#
(t is a synthetic tertiary amine anticholinergic agent# (t has a direct antispasmodic action on smooth
muscle and has "eak mydriatic, antisecretory, and positive chronotropic activities# (n addition to
suppressing central cholinergic activity, trihexyphenidyl may also inhi!it reuptake and storage of
dopamine at central dopamine receptors, there!y prolonging the action of dopamine# (t is commonly
used in com!ination "ith other antiparkinsonian agents# 0enerally, anticholinergic agents can help
control tremor !ut are less effective for treating !radykinesia or rigidity#
Fie" full drug information
$en5tropine mesylate )'ogentin*

=enCtropine mesylate is approved for use as an ad&unct in the therapy of all forms of PD# (t partially
!locks striatal cholinergic receptors, and !y !locking muscarinic cholinergic receptors in the +.7,
!enCtropine reduces the excessive cholinergic activity present in parkinsonism and related states# (t
can also !lock dopamine reuptake and storage in +.7 cells# (n general, anticholinergic agents can
help control tremor !ut are less effective for treating !radykinesia or rigidity#
'lass Summary
<?@)= inhi!itors inhi!it the activity of <?@)= oxidases that are responsi!le for inactivating dopamine#
Fie" full drug information
Selegiline )Eldepryl*

7elegiline is approved as ad&unctive therapy to levodopaDcar!idopa in patients "ho exhi!it
deterioration in response to that therapy# Gor patients "ho are experiencing motor fluctuations on
levodopaDcar!idopa, the addition of selegiline reduces off time, improves motor function, and allo"s
levodopa dose reductions# (f a patient experiences an increase in trou!lesome dyskinesia, reduce the
levodopa dose# 7elegiline !locks the !reakdo"n of dopamine and extends the duration of action of
each dose of levodopa#
Fie" full drug information
%asagiline )"5ilect*

6asagiline is indicated for the treatment of the signs and symptoms of idiopathic PD as initial
monotherapy and as ad&unctive therapy to levodopa# 6asagiline is an irreversi!le <?@)= inhi!itor that
!locks dopamine degradation# 6asagiline at a dosage of 1 mg once daily is given as monotherapy#
Bhen it is given as ad&unctive therapy, an initial dose of #* mg once daily is administered# Dosage
ad&ustments are reAuired if clinical response is not seen#
'lass Summary
Pathologic changes in dementia associated "ith PD involve cholinergic neuronal path"ays that
pro&ect from the !asal fore!rain to the cere!ral cortex and hippocampus# $hese path"ays may !e
involved in memory, attention, learning, and other cognitive processes# ?cetylcholinesterase inhi!itors
may exert their therapeutic effect !y enhancing cholinergic function through inhi!ition of
acetylcholinesterase#
Fie" full drug information
Donepe5il )"ricept*

DonepeCil is a reversi!le inhi!itor of ?+h and exerts its !eneficial effects !y enhancing cholinergic
function# (t is indicated for the treatment for dementia of the ?lCheimer type#
Fie" full drug information
%ivastigmine )Exelon*

6ivastigmine is indicated for the treatment of mild to moderate dementia associated "ith PD# (n
addition, it is also approved for the treatment of mild to moderate dementia of the ?lCheimer type#
6ivastigmine is a selective, competitive, and reversi!le acetylcholinesterase (?+h) inhi!itor# (t may
reversi!ly inhi!it cholinesterase, "hich may, in turn, increase concentrations of ?+h availa!le for
synaptic transmission in +.7 and there!y enhance cholinergic function# $he effect may lessen as the
disease process advances and fe"er cholinergic neurons remain functionally intact#
Fie" full drug information
!alantamine )%a5adyne/ %a5adyne E%*

0alantamine is a competitive and reversi!le inhi!itor of ?+h# (t is approved for the treatment of mild to
moderate dementia of the ?lCheimer type#