3393Parkinson’s Disease CHAPTER 435

Carlsson and colleagues demonstrated that blocking dopamine

uptake with reserpine caused rabbits to become parkinsonian;

this could be reversed with the dopamine precursor, levodopa.

Subsequently, Hornykiewicz demonstrated a dopamine deficiency

in the striatum of PD patients and suggested the potential benefit

of dopamine replacement therapy. Dopamine does not cross the

blood-brain barrier (BBB), so clinical trials were initiated with

levodopa, the precursor of dopamine. Studies over the course of the

next decade confirmed the value of levodopa and revolutionized

the treatment of PD.

Levodopa is routinely administered in combination with a

peripheral decarboxylase inhibitor to prevent its peripheral metabolism to dopamine and the development of nausea, vomiting, and

orthostatic hypotension due to activation of dopamine receptors

in the area postrema (the nausea and vomiting center) that are not

protected by the BBB. In the United States, levodopa is combined

with the decarboxylase inhibitor carbidopa (Sinemet), whereas in

many other countries it is combined with benserazide (Madopar).

Levodopa plus a decarboxylase inhibitor is also available in a

methylated formulation, a controlled-release formulation (Sinemet

CR or Madopar HP) and in combination with a catechol-Omethyltransferase (COMT) inhibitor (Stalevo). A long-acting formulation of levodopa (Rytary) and a levodopa carbidopa intestinal

gel that is administered by continuous intraintestinal infusion via

an implanted jejunal tube are also now available. An inhaled form of

levodopa that is rapidly and reliably absorbed through the pulmonary alveoli has recently been approved as an on-demand therapy

for the treatment of individual “off ” episodes (see below).

Levodopa remains the most effective symptomatic treatment for

PD and the gold standard against which new therapies are compared. No current medical or surgical treatment provides antiparkinsonian benefits superior to what can be achieved with levodopa.

Levodopa benefits the classic motor features of PD, prolongs independence and employability, improves quality of life, and increases

life span. Indeed, levodopa also benefits some “nondopaminergic”

features such as anxiety, depression, and sweating. Almost all PD

patients experience improvement, and failure to respond to an adequate trial of levodopa should cause the diagnosis to be questioned.

There are important limitations of levodopa therapy. Acute

dopaminergic side effects include nausea, vomiting, and orthostatic hypotension. These are usually transient and can generally

be avoided by starting with low doses and gradual titration. If

they persist, they can be treated with additional doses of a peripheral decarboxylase inhibitor (e.g., carbidopa), administering with

food, or adding a peripheral dopamine-blocking agent such as

domperidone (not available in the United States). As the disease

continues to progress, features such as falling, freezing, autonomic

dysfunction, sleep disorders, and dementia may emerge that are

not adequately controlled by levodopa. Indeed, these nondopaminergic features (especially falls and dementia) are the primary

source of disability and the main reason for hospitalization and

nursing home placement for patients with advanced PD in the

levodopa era.

The major concern with levodopa is that chronic levodopa treatment is associated with the development of motor complications

in the large majority of patients. These consist of fluctuations in

motor response (“on” episodes when the drug is working and “off ”

episodes when parkinsonian features return as drug wears off)

and involuntary movements known as dyskinesias, which typically

complicate “on” periods (Fig. 435-6). When patients initially take

levodopa, benefits are long-lasting (many hours) even though the

drug has a relatively short half-life (60–90 min). With continued

treatment, however, the duration of benefit following an individual

dose becomes progressively shorter until it approaches the half-life

of the drug. This loss of benefit is known as the wearing-off effect.

Some patients may also experience a rapid and unpredictable switch

from the “on” to the “off ” state known as the on-off phenomenon.

In advanced cases, because of variability in the bioavailability

of standard oral levodopa, the response to a dose of levodopa

may be variable and unpredictable with a given dose leading to a

full-on response, a partial on-on response, a delay in turning on

(delayed-on), or no response at all (no-on). Peak-dose dyskinesias

can occur at the time of levodopa peak plasma concentration and

maximal clinical benefit. They are usually choreiform but can

manifest as dystonic movements, myoclonus, or other movement

disorders. They are not troublesome when mild but can be disabling

Cortex

Putamen

GPe

STN

GPi

SNr

PPN

VL

SNc

GPi

SNr

PPN

GPe

STN

VL

Putamen

SNc

Cortex

SNc

Cortex

GPi

SNr

PPN

GPe

STN

VL

Putamen

Cortex

DA DA

A B C

Normal PD Dyskinesia

FIGURE 435-5 Basal ganglia organization. Classic model of the organization of the basal ganglia in the normal (A), Parkinson’s disease (PD) (B), and levodopa-induced

dyskinesia (C) state. Inhibitory connections are shown as blue arrows and excitatory connections as red arrows. The striatum is the major input region and receives its

major input from the cortex. The GPi and SNr are the major output regions, and they project to the thalamocortical and brainstem motor regions. The striatum and GPi/SNr

are connected by direct and indirect pathways. This model predicts that parkinsonism results from increased neuronal firing in the STN and GPi and that lesions or DBS of

these targets might provide benefit. This concept led to the rationale for surgical therapies for PD. The model also predicts that dyskinesia results from decreased firing of

the output regions, resulting in excessive cortical activation by the thalamus. This component of the model is not completely correct because lesions of the GPi ameliorate

rather than increase dyskinesia in PD, suggesting that firing frequency is just one of the components that lead to the development of dyskinesia. DBS, deep brain stimulation;

GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; PPN, pedunculopontine nucleus; SNc, substantia nigra, pars compacta; SNr,

substantia nigra, pars reticulata; STN, subthalamic nucleus; VL, ventrolateral thalamus. (Reproduced with permission from JA Obeso et al: Pathophysiology of the basal

ganglia in Parkinson’s disease. Trends Neurosci 23:S8, 2000.)

3394 PART 13 Neurologic Disorders

when severe, and can limit the ability to use higher doses of levodopa to better control PD motor features. In more advanced states,

patients may cycle between “on” periods complicated by disabling

dyskinesias and “off ” periods in which they suffer from severe

parkinsonism and painful dystonic postures. Patients may also

experience “diphasic dyskinesias,” which occur with lower plasma

levodopa levels, and manifest as the levodopa dose begins to take

effect and again as it wears off. These dyskinesias typically consist

of transient, stereotypic, rhythmic movements that predominantly

involve the lower extremities asymmetrically and are frequently

associated with parkinsonism in other body regions. They can be

relieved by increasing the dose of levodopa, although higher doses

may induce more severe peak-dose dyskinesia and disappear as the

concentration declines. Long-term double-blind studies show that

the risk of developing motor complications can be minimized by

using the lowest dose of levodopa that provides satisfactory benefit

and through the use of polypharmacy to avoid the need for raising

the dose of levodopa.

The cause of levodopa-induced motor complications is not precisely known. They are more likely to occur in younger individuals,

with the use of higher doses of levodopa, in women, and in those

with more severe disease. The classic model of the basal ganglia

has been useful for understanding the origin of motor features

in PD but has proved less valuable for understanding levodopainduced dyskinesias (Fig. 435-5). The model predicts that dopamine

replacement might excessively inhibit the pallidal output system,

thereby leading to increased thalamocortical activity, enhanced

stimulation of cortical motor regions, and the development of dyskinesia. However, lesions of the pallidum that dramatically reduce

its output are associated with amelioration rather than induction

of dyskinesia as would be suggested by the classic model. It is now

thought that dyskinesia results from alterations in the GPi/SNr

neuronal firing pattern (pauses, bursts, synchrony, etc.) and not

simply the firing frequency alone. This leads to the transmission of

“misinformation” from pallidum to thalamus/cortex that, along

with firing frequency, contributes to the development of dyskinesia. Surgical lesions or high-frequency stimulation targeted at the

GPi or STN presumably ameliorate dyskinesia by interfering with

(blocking or masking) this abnormal neuronal activity and preventing the transfer of misinformation to motor systems.

A number of studies suggest that motor complications develop

in response to nonphysiologic levodopa replacement. Striatal dopamine levels are normally maintained at a relatively constant level.

In PD, where dopamine neurons and terminals have degenerated,

striatal dopamine levels are dependent on the peripheral availability

of levodopa. Intermittent oral doses of levodopa result in fluctuating plasma levels because of variability in the transit of the drug

from the stomach to the duodenum where it is absorbed and the

short half-life of the drug. This variability is translated to the brain

and results in exposure of striatal dopamine receptors to alternating

high and low concentrations of dopamine. This in turn has been

shown to induce molecular alterations in striatal neurons, neurophysiologic changes in pallidal output neurons, and ultimately the

development of motor complications. It has been hypothesized that

more continuous delivery of levodopa might be more physiologic

and prevent the development of motor complications. Indeed,

double-blind studies have demonstrated that continuous intraintestinal infusion of levodopa/carbidopa or subcutaneous infusion

of apomorphine is associated with significant improvement in “off ”

time and in “on” time without dyskinesia in advanced PD patients

compared with optimized standard oral levodopa. These benefits

are superior to what has been observed in double-blind placebocontrolled studies with other dopaminergic agents. Intestinal infusion of levodopa is approved in the United States (Duopa) and

Europe (Duodopa). The treatment is, however, complicated by

potentially serious adverse events related to the surgical procedure,

problems related to the tubing, and the inconvenience of having

to wear an infusion system. SC apomorphine infusion is approved

in Europe but not yet in the United States (see below). New

approaches are currently being tested in which levodopa is continuously administered by a subcutaneous route, an intraoral infusion

system, or by long-acting oral levodopa formulations in an effort to

avoid the need for a surgical procedure.

Behavioral complications can also be associated with levodopa

treatment. A dopamine dysregulation syndrome has been described

where patients have a craving for levodopa and take frequent and

unnecessary doses of the drug in an addictive manner. (In this

regard, it is noteworthy that cocaine binds to the dopamine uptake

receptor.) PD patients taking high doses of levodopa can also

develop purposeless, stereotyped behaviors such as the assembly

and disassembly or collection and sorting of objects. This is known

as punding, a term taken from the Swedish description of the

meaningless behaviors seen in chronic amphetamine users. Hypersexuality and other impulse-control disorders are occasionally

encountered with levodopa, although these are more commonly

seen with dopamine agonists.

Finally, because levodopa undergoes oxidative metabolism and

has the potential to generate toxic free radicals, there has been

long-standing concern that, independent of the drug’s ability to

provide symptomatic benefits, it might accelerate neuronal degeneration. Alternatively, as levodopa improves long-term outcomes

in comparison to the pre-levodopa era, it has been suggested

that by restoring striatal dopamine, levodopa has the potential

to have a disease-modifying or neuroprotective effect. Neither of

these hypotheses has been established. A recent delayed-start study

showed neither beneficial nor deleterious effects of levodopa on

disease progression. Thus, it is generally recommended that levodopa be used solely based on its potential to provide symptomatic

benefits balanced by the risk of inducing motor complications and

other side effects.

Clinical effect

Dyskinesia

threshold

Response

threshold

246

Time (h)

↑Levodopa

• Long-duration motor response

• Low incidence of dyskinesias

Early PD

Response

threshold

Dyskinesia

threshold

246

Time (h)

↑Levodopa Clinical effect • Short-duration motor response

• “On” time may be associated

 with dyskinesias

Moderate PD

Response

threshold

Dyskinesia

threshold

2 4 6

Time (h)

↑Levodopa Clinical effect • Short-duration motor response

• “On” time consistently associated

 with dyskinesias

Advanced PD

FIGURE 435-6 Changes in motor response associated with chronic levodopa treatment. Levodopa-induced motor complications. Schematic illustration of the gradual

shortening of the duration of a beneficial motor response to levodopa (wearing off) and the appearance of dyskinesias complicating “on” time. PD, Parkinson’s disease.

3395Parkinson’s Disease CHAPTER 435

DOPAMINE AGONISTS

Dopamine agonists are a diverse group of drugs that act directly

on dopamine receptors. Unlike levodopa, they do not require

metabolic conversion to an active product and do not undergo oxidative metabolism. Initial dopamine agonists were ergot derivatives

(e.g., bromocriptine, pergolide, cabergoline) and were associated

with potentially serious ergot-related side effects such as cardiac

valvular damage and pulmonary fibrosis. They have largely been

replaced by a second generation of non-ergot dopamine agonists

(e.g., pramipexole, ropinirole, rotigotine). In general, dopamine

agonists do not have comparable efficacy to levodopa. They were

initially introduced as adjuncts to levodopa to enhance motor function and reduce “off ” time in fluctuating patients. Subsequently, it

was shown that dopamine agonists are less prone than levodopa

to induce dyskinesia, possibly because they are relatively longacting in comparison to levodopa. For this reason, many physicians

initiate therapy with a dopamine agonist particularly in younger

patients who are more prone to develop motor complications,

although supplemental levodopa is eventually required in virtually

all patients. This view has been tempered by the recognition that

dopamine agonists are associated with potentially serious adverse

effects such as unwanted sleep episodes and impulse-control disorders (see below). Both ropinirole and pramipexole are available

as orally administered immediate (tid) and extended-release (qd)

formulations. Rotigotine is administered as a once-daily transdermal patch and may be useful in managing surgical patients who

are not able to be treated with an oral therapy. Apomorphine is the

one dopamine agonist with efficacy thought to be comparable to

levodopa, but it must be administered parenterally as it is rapidly

and extensively metabolized if taken orally. It has a short half-life

and duration of activity (45 min). It can be administered by subcutaneous injection as a rescue agent for the treatment of severe “off ”

episodes but can also be administered by continuous subcutaneous

infusion where it has been demonstrated to reduce both “off ” time

and dyskinesia in advanced patients. This latter approach has been

approved in Europe but not yet in the United States. A sublingual

bilayer formulation of apomorphine has recently been approved as

a rapid and reliable therapy for individual “off ” periods that avoids

the need for a subcutaneous (SC) injection (see below).

Dopamine agonist use is associated with a variety of side effects.

Acute side effects are primarily dopaminergic and include nausea, vomiting, and orthostatic hypotension. These can usually be

avoided or minimized by starting with low doses and using slow

titration over weeks. Side effects associated with chronic use include

hallucinations, cognitive impairment, and leg edema. Sedation with

sudden unintended episodes of falling asleep that can occur in

dangerous situations such as while driving a motor vehicle has been

reported. Patients should be informed about this potential problem

and should not drive when tired. Dopamine agonists can also be

associated with impulse-control disorders, including pathologic

gambling, hypersexuality, and compulsive eating and shopping.

Patients should be advised of these risks and specifically questioned

for their occurrence at follow-up examinations. The precise cause

of these problems, and why they appear to occur more frequently

with dopamine agonists than levodopa, remains to be resolved, but

reward systems associated with dopamine and alterations in the

ventral striatum and orbitofrontal regions have been implicated.

In general, chronic side effects are dose-related and can be avoided

or minimized with lower doses. Injections of apomorphine can be

complicated by skin lesions at sites of administration, which can be

minimized by proper cleaning and alteration of the injection site.

The sublingual bilayer formulation of apomorphine is associated

with a relatively high frequency of oropharyngeal side effects,

which are generally mild and resolve either spontaneously or with

treatment withdrawal.

MAO-B INHIBITORS

Inhibitors of monoamine oxidase type B (MAO-B) block central

dopamine metabolism and increase synaptic concentrations of the

neurotransmitter. Selegiline and rasagiline are relatively selective

suicide inhibitors of the MAO-B isoform of the enzyme. Clinically,

these agents provide antiparkinsonian benefits when used as monotherapy in early disease stages and reduced “off ” time when used as

an adjunct to levodopa in patients with motor fluctuations. MAO-B

inhibitors are generally safe and well tolerated. They may increase

dyskinesia in levodopa-treated patients, but this can usually be

controlled by down-titrating the dose of levodopa. Inhibition of the

MAO-A isoform prevents metabolism of tyramine in the gut, leading to a potentially fatal hypertensive reaction known as a “cheese

effect” because it can be precipitated by foods rich in tyramine such

as some cheeses, aged meats, and red wine. Selegiline and rasagiline

do not functionally inhibit MAO-A and are not associated with a

cheese effect with doses used in clinical practice. There are theoretical risks of a serotonin reaction in patients receiving concomitant

selective serotonin reuptake inhibitor (SSRI) antidepressants, but

these are rarely encountered. Safinamide (Xadago) is a reversible

MAO-B inhibitor that has been approved as an adjunct to levodopa for treating advanced PD patients with motor fluctuations.

The drug also acts to block activated sodium channels and inhibit

glutamate release, and therefore has the potential to provide antidyskinetic as well as anti-parkinsonian effects.

Interest in MAO-B inhibitors has also focused on their potential

to have disease-modifying effects. MPTP toxicity can be prevented

experimentally by coadministration of a MAO-B inhibitor that

blocks its oxidative conversion to the toxic pyridinium ion MPP+

that is taken up by and selectively damages dopamine neurons.

MAO-B inhibitors also have the potential to block the oxidative

metabolism of dopamine and prevent oxidative stress. In addition,

both selegiline and rasagiline incorporate a propargyl ring within

their molecular structure that provides antiapoptotic effects in

laboratory models. The DATATOP study showed that in untreated

PD patients, selegiline significantly delayed the time until the emergence of disability necessitating the introduction of levodopa. However, it could not be definitively determined whether this benefit

was due to a neuroprotective effect that slowed disease progression

or a symptomatic effect that merely masked ongoing neurodegeneration. The ADAGIO study used a two-period delayed-start design

and demonstrated that early treatment with rasagiline 1 mg/d

provided benefits that could not be achieved when treatment with

the same drug was initiated at a later time point, consistent with

the drug having a disease-modifying effect. However, this benefit

was not seen with the 2-mg dose, and it has not received regulatory

approval for this indication.

COMT INHIBITORS

When levodopa is administered with a decarboxylase inhibitor, it

is primarily metabolized in the periphery by the catechol-O-methyl

transferase (COMT) enzyme. Inhibitors of COMT increase the

elimination half-life of levodopa and enhance its brain availability.

Combining levodopa with a COMT inhibitor reduces “off ” time

and prolongs “on” time in fluctuating patients while enhancing

motor scores. Two COMT inhibitors, tolcapone and entacapone,

have been available for more than a decade; tolcapone is administered three times daily while entacapone is administered in combination with each dose of levodopa. More recently opicapone, a

long-acting COMT inhibitor that requires only once-daily administration, has been approved in both Europe and the United States.

A combination tablet of levodopa, carbidopa, and entacapone

(Stalevo) is also available.

Side effects of COMT inhibitors are primarily dopaminergic (nausea, vomiting, increased dyskinesia) and can usually be

controlled by down-titrating the dose of levodopa by 20–30% if

required. Severe diarrhea has been described with tolcapone, and

to a lesser degree with entacapone, and necessitates stopping the

medication in 5–10% of individuals. Rare cases of fatal hepatic

toxicity have been reported with tolcapone. It is still used because

it is the most effective of the COMT inhibitors, but periodic monitoring of liver function is required. Liver problems have not been

3396 PART 13 Neurologic Disorders

TABLE 435-5 Drugs Commonly Used for Treatment of Parkinson’s

Diseasea

AGENT AVAILABLE DOSAGES TYPICAL DOSING

Levodopaa

Carbidopa/levodopa 10/100, 25/100, 25/250 mg 200–1000 mg

levodopa/day

Benserazide/levodopa 25/100, 50/200 mg

 Carbidopa/levodopa

CR

25/100, 50/200 mg

 Benserazide/levodopa

MDS

25/200, 25/250 mg

Parcopa 10/100, 25/100, 25/250 mg

 Rytary (carbidopa/

levodopa)

 Carbidopa/levodopa/

entacapone

23.75/95, 36.25/145, 48.75/195,

61.25/245

12.5/50/200, 18.75/75/200,

25/100/200, 31.25/125/200,

37.5/150/200, 50/200/200 mg

See conversion

tables

Dopamine agonists

Pramipexole 0.125, 0.25, 0.5, 1.0, 1.5 mg 0.25–1.0 mg tid

Pramipexole ER 0.375, 0.75, 1.5. 3.0, 4.5 mg 1–3 mg/d

Ropinirole 0.25, 0.5, 1.0, 3.0 mg 6–24 mg/d

Ropinirole XL 2, 4, 6, 8 mg 6–24 mg/d

Rotigotine patch 2-, 4-, 6-, 8-mg patches 4–24 mg/d

Apomorphine SC 2–8 mg 2–8 mg

COMT inhibitors

Entacapone 200 mg 200 mg with each

levodopa dose

Tolcapone

Opicapone

100, 200 mg

50 mg

100–200 mg tid

50 mg HS

MAO-B inhibitors

Selegiline 5 mg 5 mg bid

Rasagiline

Safinamide

0.5, 1.0 mg

100 mg

1 mg QAM

100 mg QAM

On-demand therapy for

off periods

Inhaled levodopa

 Apomorphine

sublingual strip

5–40 mg Up to 5 doses per day

Up to 5 doses per day

Others

 A2A antagonist—

Istradefylline

 Amantadine—

immediate,

extended-release

20, 40 mg

100–400 mg

20 or 40 mg per day

a

Treatment should be individualized. Generally, drugs should be started in low doses

and titrated to optimal dose.

Note: Drugs should not be withdrawn abruptly but should be gradually lowered or

removed as appropriate.

Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase

type B; QAM, every morning.

encountered with entacapone or opicapone. Discoloration of urine

can be seen with COMT inhibitors due to accumulation of a metabolite, but it is of no clinical concern.

It has been proposed that initiating levodopa in combination

with a COMT inhibitor to enhance its elimination half-life could

provide more continuous levodopa delivery and reduce the risk of

motor complications. While this result has been demonstrated in a

preclinical MPTP model of PD, and continuous infusion reduces

both “off ” time and dyskinesia in advanced PD patients, no benefit

of initiating levodopa with a COMT inhibitor compared to levodopa alone was detected in early PD patients in the STRIDE-PD

study. This may have been because the combination was not administered at frequent enough intervals to provide continuous levodopa

availability. For now, the main value of COMT inhibitors continues

to be in patients who experience motor fluctuations.

OTHER MEDICAL THERAPIES

Adenosine A2A receptor antagonists are a class of drugs that

inhibit A2A receptors, which form heterodimers with D2 dopamine

receptors on medium spiny striatal D2-bearing neurons of the

indirect pathway. Blockade of A2A receptors decreases the excessive

activation of the indirect pathway in PD and theoretically restores

balance in the basal ganglia-thalamocortical circuit, providing a

dopaminergic effect without the need to increase levodopa doses.

These agents are generally used in combination with low doses

of levodopa and provide modest anti-parkinsonian effects with a

reduced risk of motor complications. Three A2A antagonists have

been studied in PD but development in two has been discontinued;

preladenant because it failed in phase 3 studies and tozadenant

because of agranulocytosis in a few patients. Istradefylline is the

only agent which is currently approved for use. Clinical trials in

advanced PD patients showed improvement in “off ” time comparable to other available agents but not in dyskinesia. The drug is

generally well tolerated with adverse events similar to dopaminergic

agents. Interestingly, caffeine is a potent A2A antagonist, and large

epidemiologic studies suggest that drinking coffee is associated

with a reduced frequency of PD. This has raised the question as to

whether this class of agent might be neuroprotective, but this has

not been established in clinical trials.

Amantadine was originally introduced as an antiviral agent but

the drug was appreciated to also have antiparkinsonian effects,

likely due to N-methyl-d-aspartate (NMDA) receptor antagonism.

While some physicians use amantadine in patients with early

disease for its mild symptomatic effects, it is most widely used as

an antidyskinesia agent in patients with advanced PD. Indeed, it

is the only oral agent that has been demonstrated in controlled

studies to reduce dyskinesia without worsening parkinsonian features (indeed, motor benefits have been reported). Cognitive

impairment is a major concern particularly with high doses. Other

side effects include livedo reticularis and weight gain. Amantadine should always be discontinued gradually because patients

can experience withdrawal-like symptoms. An extended-release

formulation of amantadine has recently been approved in the

United States.

Central-acting anticholinergic drugs such as trihexyphenidyl

and benztropine were used historically for the treatment of PD,

but they lost favor with the introduction of levodopa. Their major

clinical effect is on tremor, although it is not certain that this benefit

is superior to what can be obtained with agents such as levodopa

and dopamine agonists. Still, they can be helpful in individual

patients with severe tremor. Their use is limited particularly in the

elderly, due to their propensity to induce a variety of side effects

including urinary dysfunction, glaucoma, and particularly cognitive impairment.

The anticonvulsant zonisamide has also been shown to have

antiparkinsonian effects and is approved for use in Japan. Its

mechanism of action is unknown. Several classes of drugs are

currently being investigated in an attempt to enhance antiparkinsonian effects, reduce “off ” time, and treat or prevent dyskinesia.

These include nicotinic agonists, glutamate antagonists, and 5-HT1A

agonists.

A list of the major drugs and available dosage strengths currently

available to treat PD is provided in Table 435-5.

ON-DEMAND THERAPIES FOR “OFF” PERIODS

Despite all available therapies, many patients continue to experience “off ” periods. “Off ” periods represent a return of parkinsonian

features following the benefit of a levodopa dose administration

and can be disabling for patients, causing them to be at risk for

falling and choking. As noted above, taking an additional levodopa

tablet does not reliably treat individual “off ” episodes, and some

patients may continue in the “off ” state for hours despite more frequent levodopa use. This inability to reliably and rapidly treat “off ”

episodes causes many patients to become depressed, withdrawn,

3397Parkinson’s Disease CHAPTER 435

and unwilling to participate in social activities. Three therapies

have now been approved as specific on-demand treatments for

“off ” periods: inhaled levodopa, subcutaneous injections of apomorphine, and sublingual apomorphine. Each of these avoids the

variable bioavailability seen with levodopa and provides relatively

predictable return to the “on” state.

NEUROPROTECTION

Despite the many therapeutic agents available for the treatment of

PD, patients continue to progress and to develop intolerable disability. A neuroprotective or disease-modifying therapy that slows

or stops disease progression remains the major unmet therapeutic

need. Some trials have shown positive results (e.g., selegiline,

rasagiline, pramipexole, ropinirole) consistent with a diseasemodifying effect. However, it has not been possible to determine

with certainty if the positive results were due to neuroprotection

with slowing of disease progression or confounding symptomatic

or pharmacologic effects that mask disease progression. Based on

genetic and laboratory findings described above, several novel targets for a putative neuroprotective therapy have been discovered and

multiple candidate therapies are currently being investigated. The

most exciting targets among these etiopathogenic factors include

agents that interfere with SNCA accumulation, LRRK2 inhibitors,

GBA and GCase enhancers and anti-inflammatory agents that

inhibit activation of microglia and cytokine production. Many of

these agents have already shown promise in relevant animal models

of PD and are currently in clinical trials in PD patients.

SURGICAL TREATMENT

Surgical treatments for PD have been used for more than a century.

Lesions were initially placed in the motor cortex and improved

tremor but were associated with motor deficits, and this approach

was abandoned. Subsequently, it was appreciated that lesions

placed into the ventral intermediate (VIM) nucleus of the thalamus reduced contralateral tremor without inducing hemiparesis,

but these lesions did not meaningfully help other more disabling

features of PD. In the 1990s, it was shown that lesions placed in the

posteroventral portion of the GPi (motor territory) improved rigidity and bradykinesia as well as tremor. Importantly, pallidotomy

was also associated with marked improvement in contralateral dyskinesia. This procedure gained favor with greater understanding of

the pathophysiology of PD (see above). However, this procedure is

not optimal, because bilateral lesions are associated with side effects

such as dysphagia, dysarthria, and impaired cognition. Lesions

of the STN are also associated with antiparkinsonian benefit and

reduced levodopa requirement, but there is a concern about the risk

of hemiballismus, and this procedure is not commonly performed.

Most surgical procedures for PD performed today use deep brain

stimulation (DBS). Here, an electrode is placed into the target area

and connected to a stimulator inserted subcutaneously over the

chest wall. DBS simulates the effects of a lesion without needing to

make a brain lesion. The precise mechanism whereby DBS works

is not fully resolved but may act by disrupting the abnormal neurophysiologic signals associated with PD and motor complications.

The stimulation variables can be adjusted with respect to electrode

configuration, voltage, frequency, and pulse duration in order to

maximize benefit and minimize adverse side effects. The procedure

does not require making a lesion in the brain and is thus suitable

for performing bilateral procedures with relative safety. In cases

with intolerable side effects, stimulation can be stopped and the

system removed.

DBS for PD primarily targets the STN or the GPi. It provides

dramatic results, particularly with respect to tremor and reducing

both “off ” time and dyskinesias but does not provide superior

clinical benefits to levodopa. The procedure is thus primarily indicated for patients who suffer disability resulting from levodopa-induced motor complications that cannot be satisfactorily controlled

with drug manipulation or those with severe tremor. Side effects

can result from the surgical procedure (hemorrhage, infarction,

infection), DBS system (infection, lead break, lead displacement,

skin ulceration), or the stimulation itself (ocular and speech abnormalities, muscle twitches, paresthesias, depression, and rarely suicide). Recent studies indicate that benefits following DBS of the

STN and GPi are comparable, but that GPi stimulation may be

associated with a reduced frequency of depression. Although not

all PD patients are candidates, the procedure can be profoundly

beneficial for many. Long-term studies demonstrate continued benefits with respect to the classic motor features of PD, but DBS does

not prevent the development of nondopaminergic features, which

continue to evolve and are a source of disability. Studies continue

to evaluate the optimal way to use DBS (low- vs high-frequency

stimulation, closed-loop systems, etc.). Trials of DBS in early PD

patients show benefits that may be superior to best medical therapy,

but this must be weighed against the cost of the procedure and the

risk of side effects in patients who might otherwise be well controlled with medical therapies for many years. Additionally, the PD

landscape is changing with the availability of on-demand therapies

for treating “off ” periods and the likelihood that future therapies

may provide continuous levodopa availability with reduced risk of

motor complications. Controlled studies comparing DBS to other

therapies aimed at improving motor function without causing dyskinesia, such as Duodopa and apomorphine infusions, remain to be

performed. The utility of DBS may also be reduced in future years

if new medical therapies are developed that provide the benefits of

levodopa without motor complications. New targets for DBS are

also being actively explored, as well as “smart” closed-loop devices

that sense the patient’s need for stimulation, to provide greater benefits against gait dysfunction, depression, and cognitive impairment

(Chap. 487).

MRI-guided ultrasound is also now being used as a means of

damaging critical target regions such as the GPi or STN in PD

patients with motor complications in a noninvasive manner that

avoids the needs for a surgical procedure. Preliminary results suggest good target localization and safety.

OTHER EXPERIMENTAL THERAPIES FOR PD

There has been considerable scientific and public interest in a

number of novel interventions that are being investigated as possible treatments for PD. These include cell-based therapies (such

as transplantation of fetal nigral dopamine cells or dopamine

neurons derived from stem cells), gene therapies, trophic factors,

and therapies directed against gene-specific targets. Transplant

strategies are based on the concept of implanting dopaminergic

cells into the striatum to replace degenerating SNc dopamine neurons. Fetal nigral mesencephalic cells have been demonstrated to

survive implantation, re-innervate the striatum in an organotypic

manner, and restore motor function in PD models. However, two

double-blind studies failed to show significant benefit of fetal nigral

transplantation in comparison to a sham operation with respect to

their primary endpoints. Additionally, grafting of fetal nigral cells

is associated with a previously unrecognized form of dyskinesia

(graft-induced dyskinesia) that persists after lowering or even stopping levodopa. This has been postulated to be related to suboptimal

release of dopamine from grafted cells leading to a sustained form

of diphasic dyskinesia. In addition, there is evidence that after many

years, transplanted healthy embryonic dopamine neurons from

unrelated donors develop PD pathology and become dysfunctional,

suggesting transfer of α-synuclein from affected to unaffected neurons in a prion-like manner (see discussion above). Perhaps most

importantly, it is not clear how replacing dopamine cells alone will

improve nondopaminergic features such as falling and dementia,

which are the major sources of disability for patients with advanced

disease. While stem cells, and specifically induced pluripotent stem

cells (iPSCs) derived from the recipient, may overcome problems

related to immunity, type and number of cells, and physiologic

integration, many of these same concerns still apply. To date, stem

cells have not yet been properly tested in PD patients and bear the

additional concern of tumors and other unanticipated side effects.

3398 PART 13 Neurologic Disorders

While there remains a need for scientifically based studies attempting to evaluate the potential role of cell-based therapies in PD, there

is no scientific basis to warrant routine treatment of PD patients

with stem cells as is being marketed in some countries.

Trophic factors are a series of proteins that enhance neuronal

growth and restore function to damaged neurons. Several different

trophic factors have been demonstrated to have beneficial effects

on dopamine neurons in laboratory studies. Glial-derived neurotrophic factor (GDNF) and neurturin have attracted particular

attention as possible therapies for PD. However, double-blind trials

of intraventricular and intraputaminal infusions of GDNF failed to

show benefits compared to placebo in PD patients, possibly because

of inadequate delivery of the trophic molecule to the target region.

Gene therapy offers the potential of providing long-term expression of a therapeutic protein with a single procedure. Gene therapy

involves placing the nucleic acid of a therapeutic protein into a viral

vector that can then be taken up and incorporated into the genome

of host cells and then synthesized and released on a continual basis.

The AAV2 virus has been most often used as the vector because it

does not promote an inflammatory response, is not incorporated

into the host genome, does not induce insertional mutagenesis, and

is associated with long-lasting transgene expression. Clinical trials

of AAV2 delivery of the trophic factor neurturin showed promising

results in open-label trials but failed in double-blind trials, even

when injected into both the putamen and the SNc. Nonetheless,

long-term postmortem studies have demonstrated transgene survival with biological effects as long as 10 years after treatment. Still,

the degree of putaminal coverage was very small and it is likely

that much higher gene doses will be required if this type of therapy

is to provide positive results. Gene delivery is also being explored

as a means of delivering aromatic amino acid decarboxylase with

or without tyrosine hydroxylase to the striatum to facilitate the

conversion of orally administered levodopa to dopamine. Animal

studies suggest that this approach can provide antiparkinsonian

benefits with reduced motor complications, and clinical trials in PD

patients are underway. Gene therapy is also being studied as a way

to enhance GBA and the gene product GCase in an attempt to promote clearance of toxic alpha synuclein. Importantly, no clinically

significant adverse events have been encountered in gene therapy

studies to date, but there remains a risk of unanticipated side effects.

Further, it is not clear how current approaches, even if successful,

will address the nondopaminergic features of the illness.

MANAGEMENT OF THE NONMOTOR AND

NONDOPAMINERGIC FEATURES OF PD

Although PD treatment has primarily focused on the dopaminergic features of the illness, management of the nondopaminergic

features should not be ignored. Some nonmotor features, although

they likely reflect nondopaminergic pathology, nonetheless benefit

from dopaminergic drugs. For example, problems such as anxiety,

panic attacks, depression, pain, sweating, sensory problems, freezing, and constipation all tend to be worse during “off ” periods and

have been reported to improve with better dopaminergic control.

Approximately 50% of PD patients suffer depression during the

course of the disease, and depression is frequently underdiagnosed

and undertreated. Antidepressants should not be withheld, particularly for patients with major depression, although dopaminergic

agents such as pramipexole may prove helpful for both depression

and PD motor features. Anxiety is also a common problem, and if

not adequately managed with better antiparkinsonian control, can

be treated with short-acting benzodiazepines.

Psychosis can be a problem for some PD patients and is often

a harbinger of developing dementia. In contrast to AD, hallucinations are typically visual, formed, and nonthreatening. Importantly,

they can limit the use of dopaminergic agents necessary to obtain

satisfactory motor control. They can be associated with the use of

dopaminergic drugs, and the first approach is typically to withdraw

agents that are less effective than levodopa such as anticholinergics,

amantadine, and dopamine agonists followed by lowering the dose

of levodopa if possible. Psychosis in PD often responds to low doses

of atypical neuroleptics and may permit higher doses of levodopa

to be tolerated. Clozapine is an effective drug, but it can be associated with agranulocytosis, and regular monitoring is required.

Quetiapine avoids these problems, but it has not been established to

be effective in placebo-controlled trials. Pimavanserin (Nuplazid)

differs from other atypical neuroleptics in that it is also an inverse

agonist of the serotonin 5-HT2A receptor. It has been shown to be

effective in double-blind trials with a relatively good safety profile,

and was recently approved for use in the United States.

Dementia in PD (PDD) is common, ultimately affecting as

many as 80% of patients. Its frequency increases with aging and, in

contrast to AD, primarily affects executive functions and attention,

with relative sparing of language, memory, and calculation domains.

When dementia precedes, develops coincident with, or occurs

within 1 year after onset of motor dysfunction, it is by convention

referred to as dementia with Lewy bodies (DLB; Chap. 434). These

patients are particularly prone to experience hallucinations and

diurnal fluctuations. Pathologically, DLB is characterized by Lewy

bodies distributed throughout the cerebral cortex (especially the

hippocampus and amygdala) and is more likely to be associated

with AD pathology. It is likely that DLB and PD with dementia

represent a spectrum of PD rather than separate disease entities. It

is notable that variants of the GBA gene are a significant risk factor

for both PD and DLB. Mild cognitive impairment (MCI) frequently

precedes the onset of dementia and is a more reliable index of

impending dementia than in the general population. Indeed, many

PD patients demonstrate abnormalities in cognitive testing even

at the earliest stages of the disease despite having no overt clinical

dysfunction. Drugs used to treat PD can worsen cognitive function

and should be stopped or reduced to try to provide a compromise

between antiparkinsonian benefit and preserved cognitive function.

Drugs are usually discontinued in the following sequence: anticholinergics, amantadine, dopamine agonists, COMT inhibitors, and

MAO-B inhibitors. Eventually, patients with cognitive impairment

should be managed with the lowest dose of standard levodopa that

provides meaningful antiparkinsonian effects and does not worsen

mental function. Anticholinesterase agents such as memantine and

cholinesterase inhibitors such as rivastigmine improve measures

of cognitive function and can improve attention in PD, but do not

improve cognition or quality of life in any meaningful way. More

effective therapies that treat or prevent dementia are a critical

unmet need in the therapy of PD.

Autonomic disturbances are common and frequently require

attention. Orthostatic hypotension can be problematic and contribute to falling. Initial treatment should include adding salt to the

diet and elevating the head of the bed to prevent overnight sodium

natriuresis. Low doses of fludrocortisone (Florinef) or midodrine

provide control for most cases. The norepinephrine precursor

3-0-methylDOPA (Droxidopa) has been shown to provide mild

and transient benefits for patients with orthostatic hypotension and

was recently approved by the U.S. Food and Drug Administration.

Vasopressin and erythropoietin can be used in more severe or

refractory cases. If orthostatic hypotension is prominent in early

parkinsonian cases, a diagnosis of MSA should be considered

(Chap. 440). Sexual dysfunction may be helped with sildenafil or

tadalafil. Urinary problems, especially in males, should be treated

in consultation with a urologist to exclude prostate problems. Anticholinergic agents, such as oxybutynin (Ditropan), may be helpful.

Constipation can be a very important problem for PD patients.

Mild laxatives or enemas can be useful, but physicians should first

ensure that patients are drinking adequate amounts of fluid and

consuming a diet rich in bulk with green leafy vegetables and bran.

Agents that promote gastrointestinal (GI) motility can also be helpful. Several recent studies are evaluating the effect on constipation

of agents that interfere with inflammation and alpha synuclein

misfolding in the GI tract.