) is an antioxidant involved in the mitochondrial electron
transport chain and has been shown to be reduced in patients with PD.
analysis in untreated PD patients treated with CoQ10
significance but met the threshold for futility. Two subsequent phase III trials of early
PD patients failed to show symptomatic or neuroprotective benefits.
evaluation of 600 patients with early PD, subjects were randomized to receive either
1,200 or 2,400 mg of CoQ10 daily in addition to 1,200 IU of α-tocopherol. The study
was terminated prematurely due to failure to meet prespecified futility endpoints and
trend in adverse outcomes compared to placebo.
127 Due to the lack of data supporting
CoQ10, K.B. should be counseled to avoid its use.
, creatine is thought to play a role in mitochondrial energy
production and has been shown to protect from MPTP-induced dopamine depletion
occurs because dopaminergic neurons are lost in PD. Minocycline has been shown to
be protective in MPTP animal models of PD.
The use of both creatine and minocycline in PD was examined in a futility-design
study, in which patients with early PD not requiring therapy were randomly assigned
to receive creatine 10 g/day, minocycline 200 mg/day, or placebo.
months, the mean change in the total UPDRS could not be rejected as futile and met
criteria for further clinical testing. A long-term follow-up of this trial found that by
18 months, patients requiring symptomatic treatment did not differ but significantly
more patients on minocycline discontinued therapy prematurely (23% vs. 9% of
creatine and 6% of placebo patients). Given the unresolved issues surrounding the
induction of antibiotic resistance with long-term use of an agent such as minocycline
and concerns for tolerability, it is generally not recommended. A long-term,
randomized, double-blind, placebo-controlled trial of creatine 10 g/day versus
placebo in early treated PD was terminated early for futility based upon an interim
analysis. The trial concluded that treatment with creatine for at least 5 years does not
129 Given the lack of data supporting these agents, they should
With developments in PD research and biopharmaceutical technology, new treatment
targets and modalities are constantly being investigated. Such targets include
transcription factors, proteins, and their mutations. Novel pharmaceutical and
biologic technologies under development include small-molecule drug delivery, such
as with glial-cell-derived neurotrophic factor, stem cell therapies, and nerve cell
Nonmotor Symptoms of Parkinson’s Disease
Although PD is mostly recognized for its cardinal features of motor dysfunction,
nonmotor symptoms are an important part of the disease throughout all stages and are
a key determinant of quality of life.
130 More than 98% of patients with PD have at
least one nonmotor symptom; the average per patient is nearly eight, with the number
and impact increasing with disease duration and severity.
symptoms include autonomic dysfunction (e.g., gastrointestinal disorders, orthostatic
hypotension, sexual dysfunction, urinary incontinence, sialorrhea, seborrhea, and
constipation), sleep disorders (e.g., RLS, PLMS, excessive daytime somnolence,
insomnia, REM sleep behavior disorder), fatigue, and psychiatric disorders (e.g.,
dementia, depression, and anxiety).
In one longitudinal study of patients with PD,
the most common nonmotor symptoms were psychiatric symptoms (68%, most
commonly anxiety), fatigue (58%), leg pain (38%), insomnia (37%), urinary
symptoms (35%), drooling (31%), and difficulty concentrating (31%).
screening for these nonmotor symptoms should occur. L.M. has a history of
depression treated with citalopram that could be attributable to PD, and his therapy
should be periodically evaluated. The forgetfulness and decreased memory described
by L.M. could be early signs of cognitive decline and warrant close observation. The
management of several commonly encountered nonmotor symptoms is reviewed
QUESTION 1: J.D. is a 74-year-old man with advanced PD, Hoehn and Yahr
stage 4. During the last year,
that J.D. is experiencing be treated?
The prevalence of dementia in patients with PD is high; 48% to 80% of patients
may develop dementia during the disease course, at a rate approximately 6 times
greater than healthy individuals.
132 One longitudinal study of 136 incident cases of
PD followed for 20 years found that nearly 100% eventually exhibited dementia.
The prevalence of cognitive decline and dementia among patients with PD ranges
from 10% to 30% and may be associated with a more rapid progression of diseaserelated disability.
6 Successful management of cognitive impairment in patients with
PD first requires that all potentially reversible causes and underlying contributing
factors be addressed. These include treating infections, dehydration, and metabolic
abnormalities, as well as eliminating unnecessary medications (particularly
anticholinergics, sedatives, and anxiolytics) that can exacerbate dementia or
Experience with cholinesterase inhibitors for treating cognitive impairment in PD
indicates marginal improvements with their use.
134–136 Two randomized, controlled
trials of donepezil have failed to show consistent benefit, whereas galantamine has
only been evaluated in a single open-label trial.
provide clinically meaningful (moderate or marked improvement on the Alzheimer’s
Disease Cooperative Study–Clinician’s Global Impression of Change) benefit to
significantly more patients than placebo in a large, randomized, placebo-controlled
trial and has demonstrated sustained cognitive benefit for up to 48 weeks.
a result, rivastigmine was FDA-approved for the management of mild-to-moderate
dementia in PD and is therefore the drug of choice. Compared with placebo, the
cholinesterase inhibitors often result in statistically significant changes on cognitive
scales; though, their impact on function and disposition is unclear.
A cholinesterase inhibitor such as rivastigmine may be considered for patients
such as J.D., although he must be monitored closely for signs of deterioration of
motor function such as worsening of tremor.
137 Cholinesterase inhibitors are
associated with other adverse events that may be overlooked and attributed to the PD
itself, including sialorrhea, excessive lacrimation, incontinence, nausea, vomiting,
and orthostasis. Perhaps more important than any medication therapy, adequate social
support for J.D. should be ensured. Because he becomes further dependent on family
members for assistance with ADLs, the increased needs of the caregiver(s) should
also be considered. In the case of J.D., attending
adult day care several times weekly, if available, would provide a structured,
supervised environment for interaction with others, as well as providing a rest
period for his caregiver. Dementia is a leading cause of nursing home placement for
CASE 59-3, QUESTION 2: How should anxiety and depression be treated in J.D.?
Despite being one of the strongest predictors of quality of life in PD patients,
depression is often poorly recognized and inadequately treated.
because depression and PD share overlapping features that often confound the
identification of depression. Withdrawal, lack of motivation, flattened affect,
decreased physical activity, and bradyphrenia are examples of overlapping
Treatment of depression in PD should first focus on providing adequate treatment
of the symptoms of PD by attempting to restore mobility and independence,
particularly in patients whose depression can be attributed to lengthy off periods.
trials and case reports have shown that depression in patients with PD can be
successfully treated with antidepressant drugs, including tricyclic agents such as
amitriptyline, desipramine, nortriptyline, bupropion, and selective serotonin reuptake
inhibitors (SSRIs) such as citalopram and paroxetine.
high-quality trials, it is difficult to know whether expected benefits reflect class
responses or are unique to the individual agents studied. Importantly, the potential for
adverse effects should always be considered. For example, some SSRIs, such as
fluoxetine, can be activating. Although this may be beneficial in patients who are
apathetic or withdrawn, it may worsen symptoms in patients with PD who are
agitated. Selective serotonin reuptake inhibitors have additionally been noted to
worsen PD tremor in approximately 5% of patients.
141 With tricyclic antidepressants,
care must be taken to observe for anticholinergic side effects that may worsen PD
symptoms, such as impaired cognition, delayed gastric emptying (which may reduce
levodopa effectiveness by increasing levodopa degradation in the gut), urinary
problems, orthostatic hypotension, and increased risk of falls. Additionally,
consideration should be taken for drug interactions and the risk for serotonin
syndrome with concomitant MAO-B inhibitors. Electroconvulsive therapy may be
considered in refractory cases, but may adversely affect cognition.
Based on his symptoms, it is reasonable to start J.D. on an antidepressant. Clinical
experience suggests a good initial choice for balancing efficacy and safety is an
SSRI, such as citalopram. As with other patients with depression, the choice of agent
should be individualized based on other pragmatic factors such as cost, potential for
adverse effects, and personal or family history of response to prior agents.
Regardless of which agent or class of antidepressant is selected, therapy should be
started at the lowest dose and gradually titrated to effect. He should be monitored
closely for side effects, particularly anticholinergic symptoms with tricyclic
antidepressants, and for any adverse effects on mobility. He should be observed
carefully for changes in parkinsonian symptoms, including development of
extrapyramidal symptoms, as well as any signs of psychomotor agitation. Short-term
use of benzodiazepines, such as lorazepam or alprazolam, may also provide relief of
anxiety symptoms, but must be used cautiously due to adverse effects on cognition
142 Generally, anxiety symptoms should improve with treatment of
In PD, the incidence of psychotic symptoms increases with age, cognitive
impairment, and disease duration.
143 Other risk factors include higher age at PD
onset, high doses of dopaminergic drugs, and REM sleep behavior disorder.
Symptoms are often more pronounced at night (the “sundowning” effect), and
hallucinations are typically visual. As with the management of cognitive impairment,
it is important to eliminate or minimize any potential causative factors, particularly
anticholinergic medications that could be contributing to the hallucinations or
delirium. In some patients, reducing the dose of levodopa improves mental function
and also provides satisfactory control of motor features. If it is not possible to
achieve a balance between preserving motor control and decreasing neuropsychiatric
symptoms through reduction in levodopa dosage, antipsychotics may be considered.
Older antipsychotic medications, such as haloperidol, perphenazine, and
chlorpromazine, block striatal dopamine D2
parkinsonian symptoms. Therefore, these agents are not recommended. Newer
atypical antipsychotics are more selective for limbic and cortical D3
receptors; they have minimal activity at D2
receptors and may control symptoms
without worsening parkinsonism. Of these agents, clozapine has the best evidence of
efficacy in patients with PD without adversely affecting motor function and should be
137 However, its use is complicated by the need for frequent
monitoring of white blood cell counts because of the risk of agranulocytosis. Other
newer agents, particularly quetiapine, appear promising and have controlled
psychosis without worsening parkinsonism.
137 Risperidone and olanzapine have
also been studied, but both worsened parkinsonism and were inferior to clozapine in
145 Aripiprazole, also a newer atypical antipsychotic, has been
associated with worsening motor function in patients with PD, whereas experience
with ziprasidone has yielded mixed results.
Patients with PD frequently experience dysautonomia, including orthostasis, erectile
dysfunction, constipation, nocturia, sensory disturbances, dysphagia, seborrhea, and
thermoregulatory imbalances. Management of these symptoms is generally
supportive, and appropriate medical interventions similar to those used in other
geriatric patients can be used to treat these symptoms whenever encountered. In some
cases, fludrocortisone or midodrine can be considered if orthostatic hypotension is
severe, although these drugs have not been well studied in PD patients specifically.
Other possibly effective treatments for symptoms of autonomic dysfunction include
sildenafil for erectile dysfunction and polyethylene glycol for constipation.
A new atypical antipsychotic, pimavanserin, was FDA-approved in April 2016
based on results from one randomized, placebo-controlled trial. This agent’s
mechanism of action is unique, acting through serotonin receptors, and as such it
avoids interaction with dopamine receptors responsible for the worsening of PD
symptoms with other antipsychotics. It is not without its own risks, including
cardiovascular and paradoxical worsening of psychosis.
Patients with PD and their caregivers should be counseled on the prevention of falls
because they can result in serious morbidity and mortality. Falls generally result from
one of several factors, including postural instability, freezing and festination,
levodopa-induced dyskinesia, symptomatic orthostatic hypotension, coexisting
neurologic or other medical disorders, and environmental factors. Prevention
remains the best strategy and includes environmental precautions, such as proper
lighting, use of handrails, removing tripping hazards, and incorporating physical and
therapy. Reversible causes of postural or gait instability should be addressed
whenever suspected. Patients with PD are advised to take a vitamin D supplement to
reduce their risk of fracture with future falls.
Sleep disorders may occur at any time during the disease course and may even
precede motor symptom development.
In excessive daytime drowsiness, a common
sleep disorder in PD, treatment with modafinil may be considered.
disorders such as insomnia, sleep fragmentation owing to PD symptoms, RLS, and
REM sleep disorder (characterized by vivid dreams that are often acted out,
especially if frightening) are common and a source of decreased quality of life. When
sleep dysfunction can be directly attributed to PD symptoms, such as akinesia,
tremor, dyskinesia, or nightmares, dosage adjustment of dopaminergic medications is
indicated. Proper sleep hygiene should be encouraged. Insomnia symptoms unrelated
to PD symptoms are treated similar to non-PD patients and can be managed
RESTLESS LEGS SYNDROME AND PERIODIC
RLS, also known as Willis–Ekbom disease, is a disabling sensorimotor disorder
estimated to affect approximately 2% of the adult population.
patients with mild symptoms will not require treatment, RLS can be associated with
adverse health outcomes, including sleep-onset insomnia, missed or late work,
anxiety, depression, marital discord, and even suicide in severe cases.
Four essential criteria have been established by the International Restless Legs
Syndrome Study Group to diagnose RLS (Table 59-6).
149 The pathognomonic trait of
RLS is an almost irresistible urge to move the legs (akathisia), often associated with
uncomfortable paresthesias or dysesthesias felt deep inside the limbs. Patients
describe the sensation as “creepy-crawly” or “like soda water in the veins.”
symptoms may occur unilaterally or bilaterally, affecting the ankle, knee, or entire
lower limb. With progressive disease, symptoms can begin earlier in the day, and
progressive involvement of the arms or trunk may occur. Temporary or partial relief
of symptoms can be achieved with movement. If patients attempt to ignore the urge to
move the legs, akathisia will progressively intensify until either they move their legs
or the legs jerk involuntarily.
150 Symptoms usually manifest in a circadian pattern
with onset or worsening during nighttime hours (usually between 6 PM and 4 AM, with
peak symptoms between midnight and 4 AM). The circadian pattern persists even in
patients with inverted sleep–wake cycles. As a result of their symptoms, patients
with RLS become “nightwalkers,” spending significant time walking, stretching, or
bending the legs in an effort to relieve symptoms.
Clinical Features of Restless Legs Syndrome (RLS)
Urge to move legs, associated with paresthesias or dysesthesias
Relief of symptoms with movement
Onset or exacerbation of symptoms at rest
Onset or worsening of symptoms during nighttime
Accompanying sleep disturbance (sleep-onset insomnia)
Positive response to dopaminergic therapy
Positive family history of RLS
Otherwise normal physical examination
The symptoms described by J.J. are an example of a classic presentation of RLS.
The prevalence of RLS increases with age and appears to be slightly more common
151 She describes “creepy-crawly” sensations that are relieved partially
with walking, a core feature of RLS. Her symptoms are worse during the evening
hours. J.J. reports that her mother suffered from similar symptoms. The observation
of a familial tendency suggests a genetic component, and several chromosomal loci
have been linked to the disease.
152 A strong family history of RLS appears to
correlate with an early age of onset (<45 years), whereas presentation at a later age
is associated with more neuropathy and accelerated disease progression.
Most cases of RLS are considered primary or idiopathic; therefore, the diagnosis
does not require elaborate laboratory tests or diagnostic procedures. Several
RLS, including medications with antidopaminergic properties, such as
metoclopramide and prochlorperazine. Nicotine, caffeine, and alcohol can aggravate
RLS through their own ability to interfere with quality of sleep. Additionally, SSRIs,
tricyclic antidepressants, and commonly used over-the-counter antihistamines, such
as diphenhydramine, can trigger or worsen RLS symptoms.
leg cramps, and other conditions such as arthritis, which can cause positional
discomfort with extended periods of sitting in one position, can mimic RLS. These
conditions are easily distinguished from RLS because they are usually localized to
certain joints or muscles, do not have a circadian pattern, and are not associated with
an uncontrollable urge to move.
With an otherwise unremarkable physical examination and medical history,
specific laboratory tests that should be performed in J.J. are limited to serum ferritin
and percent transferrin saturation (total iron-binding capacity) to rule out iron
deficiency anemia. Several studies have documented a relationship between low
ferritin concentrations and increased symptom severity.
153 J.J. is postmenopausal, so
a pregnancy test is not necessary. Polysomnography is not usually indicated unless
there is clinical suspicion for sleep apnea or if sleep remains disrupted despite
RLS. When clinical suspicion from the physical examination or medical history
suggests a possible peripheral nerve or radiculopathy cause, a routine neurologic
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