MODERATE-ADVANCED
PARKINSON’S DISEASE:
A GUIDE FOR PATIENTS AND CAREGIVERS
A.
Understanding Parkinson’s
Disease (PD) And Its Care
B. Treatment and Functional Issues
A.
Understanding Parkinson’s Disease (PD)
And Its Care
1.
Generalities
PD is a disorder of some parts of the brain
that control movement. One major area of involvement
is the substantia nigra, in the rear part of
the brain (midbrain). It is there that, for
reasons we are still trying to discover, nerve
cells in PD stop functioning normally and some
cells die prematurely. Because of the usual
slow worsening of PD, there are still enough
working nerve cells to be able to respond to
medications and surgical treatment for a long
while.
We’d all like to prevent continued loss
of nigral and other nerve cells in PD with “neuroprotective”
medication treatment, and several groups in
Michigan are involved in a long-term NIH study
of such potentially useful drugs. However, results
of such studies will take several years to be
known, and our concern here is to address the
practical, symptomatic treatment of PD for patients
whose illness has interfered with work- and/or
home-related activities most of the time. This
covers the spectrum of disability we’d
call moderate-advanced.
2.
What This Guide Is and Isn’t
This is a general review of current concepts
and practices regarding PD evaluation and treatment.
Inevitably, statements made will reflect personal
opinions and approaches, not buttressed here
by citations from the medical literature. The
statements must not be taken as reflecting what
is happening to any particular person medically,
or what’s best for a particular person’s
treatment, now or in the future. The offering
of this guide is not “practicing medicine”
via informational exchange by website. The practice
of medicine occurs when an individual consults
a physician to obtain a diagnosis and treatment
plan specifically for him or her. That’s
not what this guide can or should do, and it
is no substitute for an individual consultation
or an ongoing medical relationship between a
doctor and a patient.
Medication doses or dose ranges are best dealt
with at the individual doctor-patient level,
addressing the need presented by particular
clinical situations. The effects of treatment
can vary enormously, and much telephone and
clinic time is spent sorting out risks, benefits,
side effect possibilities, alternate treatments,
etc. This is the art of medicine. The desire
to help people drives the passion.
3.
Getting the Best Medical Care for Your PD
The best model for care of any chronic medical
disorder is to have a trusting, working relationship
between patients, caregivers, doctors, nurses
and other health professionals. Practically,
this means having patients benefit from the
expertise of the medical team and having the
medical team benefit from the experience of
patients as they try to create an effective
treatment plan together. It means having as
frequent contact between these individuals as
is really needed to optimize care. This may
be by phone calls, clinic visits and, in some
instances, by e-mail or letters. It will vary,
depending on the needs of patients and the needed
availability of the medical team. The following
points, through many years of experience, are
most important:
> Get the right diagnosis and treatment.
There are various forms of parkinsonism, aside
from PD itself, which may evident early on,
or only with the passage of time (e.g., multiple
system atrophy [MSA], progressive supranuclear
palsy [PSP], vascular parkinsonism [due to strokes]),
and others. Such other illnesses may require
various studies to diagnose or different treatments
to be most helpful. A neurologist with expertise
in movement disorders is best poised to make
a definitive diagnosis and recommend treatment
in this field, especially when the answers are
not straightforward. Seek out such an opinion
if your general doctor or neurologist cannot
either make a diagnosis or, after a reasonable
period of time and trials of treatment, can’t
help enough. However, don’t assume that
having a medication side effect means either
that the doctor doesn’t know what you
have, or doesn’t know how to treat it.
> Get enough time with the doctor or nurse
to review details of how you’re coping
with daily activities in light of the anti-PD
medication and other drug(s), doses and their
timing, that you’re taking. For those
who are getting deep brain stimulation (DBS)
as well, careful review of the electrical settings
is also critical.
> Patients and caregivers often misunderstand
verbal treatment directions, especially those
that are complex. Be sure that you have understandable,
written instructions.
> Important reasons for drug treatment “failure”
may be that too little was either prescribed
or taken. The latter may be because the timing
of doses was impractical or ineffective, or
that side effects may have developed and not
brought to the attention of the medical team.
> You need to learn about PD to be a full
partner in your care. Good doctors welcome that.
There are several well-written books and pamphlets
on the subject; ask the Michigan Parkinson Foundation
staff about them. The internet can be helpful,
but remember that it’s a worldwide, uncensored
bulletin board, not a “truth machine”,
so that what you get can span the gap between
potentially misleading or unsubstantiated claims
to truly high quality reviews of our current
understanding of PD and its treatment. Among
the latter are offerings on the websites of
the Parkinson’s Disease Foundation, National
Parkinson Foundation and the American Parkinson’s
Disease Association.
>· Remember, it’s your life
and you should live it to the fullest possible
extent. PD is not your life, but some hurdle
to cope with courageously, getting the help
you need from loving family, friends, your religious
community, health professionals and others.
People want to see you do well. Speaking personally,
nothing is more gratifying than to see patients
make small gains or great strides as they live
a meaningful life.
4.
Goal of Symptomatic Treatment of PD
What is the goal of treatment
in PD? It is the individualized crafting of
a plan of care that allows each patient to get
and maintain the best function that he/she can
with few or no side effects of therapy. Because
each plan is individualized, the ultimate functional
outcome will vary, depending on the severity
of the illness, as well as patients’ ability
to benefit from, and to tolerate, adequate doses
of medications, DBS (if appropriate), as well
as physical, occupational and speech therapy.
We need to be realistic about what is achievable,
and this may have to be revised as time goes
on. Generally, we offer as few drugs, and as
little of them, as patients need to be as functional
as possible. Whenever possible, new drugs are
introduced at low doses, and at a suitable,
individualized pace, in order not to give more
than is needed, as well as to limit potential
side effects.
Not every symptom can, or needs to be, treated.
Some symptoms are relatively minor, particularly
when considering whether an otherwise effective
treatment plan would have to be overhauled,
complicating daily life unduly for unclear potential
benefits. This is an important part of the cooperative
realism that patient and doctor must discuss.
B.
Treatment and Functional Issues
1.
Medications for PD
a.
Anticholinergics
These drugs include Artane® (trihexyphenidyl)
and Cogentin® (benztropine). They are
useful for treatment of tremor of a hand or
foot at rest, i.e., when supported, not when
raised up or during action. They give little
or no benefit for bradykinesia (slow movement),
muscular rigidity (stiffness), or gait imbalance.
Neither drug should be used in those with dementia
(loss of memory, other cognitive function),
or in those with glaucoma, prostate enlargement,
visual blurring, rapid heartbeat, or excessive
constipation.
If a patient develops mental confusion, with
or without visual hallucinations (seeing visions),
while on them, they may need to be discontinued.
b.
Amantadine
The drug is used either as a mild agent to help
tremor, bradykinesia and rigidity, or to decrease
choreic (jerky) limb dyskinesias (involuntary
movements) due to excessive dopaminergic (dopamine-promoting)
medications.
Amantadine is usually well-tolerated, though
it can cause foot or leg edema (swelling) and
a leg rash that looks like a red roadmap, called
livedo reticularis. Among demented individuals,
it alone can be responsible for mental confusion,
and/or hallucinations.
c.
Dopamine Agonists versus Sinemet® as
Initial Treatment
Recent data suggest that dopamine agonists (dopamine-mimicking
drugs), may be used before Sinemet® (levodopa-carbidopa)
to get adequate motor benefit, and that such
benefit can persist in many patients for years.
Moreover, unlike with Sinemet®, drug-induced
motor fluctuations (“wearing-off”
or “on-off” impairment of mobility
between doses) are less likely with the agonists.
For this reason, if a patient’s condition
permits it, an agonist may be a better initial
choice than Sinemet®. However, more severely
disabled patients may need Sinemet® from
the start. Most patients with advanced PD will
need both an agonist and Sinemet® (see
below).
There are data that suggest that there may be
a neuroprotective action of Requip® and
Mirapex®, but this is an area of controversy.
Further research is needed.
d.
Dopamine Agonists
These drugs act on nerve cells in the brain
that respond to dopamine, the major signaling
chemical (neurotransmitter) that is low in PD.
By stimulating the dopamine receptor (signal
receiver), dopamine agonists act as though they
were dopamine, and they activate the nerve cells
they stimulate. In so doing, they improve motor
function. However, they are not as powerful
as Sinemet®.
The agonists were developed over many years,
with Parlodel® and Permax® introduced
earlier, and Requip® and Mirapex®
becoming available more recently. All are potentially
effective drugs, depending on whether a particular
patient can tolerate enough medication to improve
mobility adequately. The agonists have not often
been tested directly against one another in
clinical trials, but have either been tested
against placebo (no effective drug) alone, or
as additions to a Sinemet® regimen. One
has a general impression of rough equality of
efficacy among the agonists, if adequate doses
of drug can be given, but it is possible that
some patients may benefit from one or another
to a greater extent. Only individual trials
of medications with patients can establish that,
however, and if a particular agonist is effective
enough, it is unwise to try another. If sufficient
side effects appear, though, a trial of a different
agonist may be warranted. Any of the agonists
may produce side effects, often having a similar
dopamine-mediated motor and mental character
(see 6, below).
e.
Sinemet® (levodopa-carbidopa)
This drug is accepted as the gold standard for
symptomatic PD treatment, i.e., the most powerful
one against which clinical effectiveness can
be measured. Its introduction by the late Dr.
George Cotzias and colleagues in 1967 was a
watershed event in neurology, and one which
brought great hope and functional benefit to
patients with PD everywhere.
It used to be that nearly every patient with
PD was begun on Sinemet® as soon as the
diagnosis was made. However, many movement disorders
neurologists today reserve that treatment for
patients whose mobility, dexterity and tremor
we judge will not be sufficiently responsive
to either an anticholinergic, amantadine or
an agonist, either by mental comparison of our
experience with that of other patients, or after
a trial of these other drugs sequentially. This
is because many patients may benefit adequately
from either an anticholinergic, amantadine or
an agonist for several years, without the risk
of motor fluctuations (“wearing off”
or “on-off” effects, between Sinemet®
doses) that levodopa treatment typically produces
after several years of treatment.
In practice, as PD advances, most patients will
need Sinemet® at some dose to function
well. It will often be gratifying to them and
to caregivers to see significant improvement,
allowing more activities and independence to
occur.
f.
Dopamine-mediated Side Effects
Following patients on Sinemet® or agonists
involves balancing the doses needed for adequate
mobility against the possibility of inducing
dopamine-mediated side effects. Such effects
may include:
>· Drowsiness. This can be a dose-limiting
side effect, i.e., one which prevents giving
as much medication as would be needed to fully
treat motor issues in PD. For that reason, it’s
best to review whether drowsiness is related
to giving higher doses of Sinemet® or an
agonist, or whether drowsiness is related to
too little social interaction. If it is the
latter, efforts to get the patient to be more
active are very worthwhile.
> Nausea and vomiting. Taking the drug in
mid-meals or with small snacks is the simplest
solution. If this isn’t successful, a
trial of domperidone (available in Canada),
about an hour before taking the drug, may eliminate
the problem.
>· Lightheadedness (near-fainting)
on standing. Decreasing the drug dose and taking
one’s time when standing, and holding
onto solid support, are often helpful. If not,
try another drug that is tolerated.
> Rapid heartbeat. This uncommon side effect
should be evaluated by an internist or cardiologist,
and may require either reducing or discontinuing
an anti-PD drug.
> Dyskinesias (involuntary bodily movements).
These come in two basic varieties: 1) those
jerky (choreic) excessive movements that occur
after dopaminergic drug(s) (most often Sinemet®),
and which almost always mean that too much medication
has been taken; and 2) those dystonic (twisting,
tightening) movements that occur before the
next (most often Sinemet®) dose is due.
Jerky, choreic dyskinesias can be controlled
either by reducing Sinemet® prior to
such episodes, watching for the re-emergence
of PD slowing and related disability, and considering
adding an agonist to maintain mobility, or by
adding amantadine to the existing Sinemet®
regimen. It is a fine clinical judgment about
which of the anti-PD medications a patient is
taking is/are responsible for the side effects
seen, requiring frequent phone and/or clinic
contact to regulate.
Dystonic dyskinesias can often be controlled
by increasing the dopaminergic medication a
patient is taking before the dystonic episode
occurs.
> Confusional (disorientation), hallucinatory
(unreal visions) or delusional (unreal beliefs).
Control of these symptoms will, most often,
require reducing the number, types and doses
of anti-PD medications (e.g., anticholinergics,
Eldepryl® (selegilene), others). During
this time, adequate medication needs to be taken
to maintain mobility, while considering the
use of anti-psychotic agents [e.g., first, Seroquel®
(quetiapine), then Clozaril® (clozapine)],
depending on the severity and frequency of hallucinations
and delusions. In some cases, working on these
issues closely with a knowledgeable psychiatrist
can be of great value.
g.
Wearing-Off Effects
During the early stages of PD, patients don’t
notice a difference in motor function between
medication (usually Sinemet®) doses.
However, in moderate-advanced PD, an increasing
number of patients will. They may become slower,
stiffer and less coordinated, more tremulous,
and have more gait imbalance before the next
dose is due. If such disabilities are marked,
they may not be able to get out of a chair,
get dressed, bathe, or do other activities of
daily living without help. Falling may be more
likely at such times. This is distressing and
potentially dangerous and needs to be dealt
with.
Several choices are available. Though it is
possible to increase each Sinemet® immediate
release dose (i.e., 10/100, 25/100, 25/250)
and/or to decrease the interval between doses,
that is not what is preferred. This is because
we wish to decrease the likelihood of Sinemet®-related
side effects (see above), and to reduce later
motor fluctuations. It is possible to add controlled-release
Sinemet® (i.e., 25/100CR, 50/200) to
the existing immediate-release Sinemet®
regimen, but, again, it is desirable to limit
total daily levodopa, if possible. This may
not be possible in individual cases, however,
and the giving of both immediate- and controlled-release
Sinemet® is certainly a viable and valuable
option for many patients.
With these issues in mind, it’s often
best to consider the use of a COMT inhibitor
(Comtan® [entacapone], Tasmar®
[tolcapone]), or an agonist. COMT inhibitors
extend the duration of levodopa (but not agonist)
action by preventing breakdown of brain dopamine.
Comtan® is easy to use as individual
200 mg tablets, given at the same time as Sinemet®
doses, matching the times of the day when wearing-off
occurs. The recent incorporation of Comtan®
into one pill with Sinemet® (Stalevo®)
is suitable for those patients with wearing-off
of all Sinemet® doses, but doesn’t
allow dose-by-dose individuation that using
Comtan® alone permits.
Tasmar® is a highly effective COMT inhibitor,
but came under special FDA guidelines when several
patients died as a result of unmonitored liver
injury. For this reason, Tasmar® may
be used only when other medications have been
found to be ineffective or not tolerated. If
used, blood studies of liver enzymes (SGPT)
must be done every two weeks, and even values
just above normal must be taken as grounds for
discontinuing the drug. There is no such issue
with Comtan®.
The agonists are often helpful in treating wearing-off
effects because their duration of action is
relatively long (4-6 hours, depending on the
drug).
2.
Functional Issues in PD
a.
Freezing and Falling
Freezing is the sudden loss of the ability to
walk forward. It may occur during a wearing-off
episode (more commonly) or not, and may or may
not be associated with a greater likelihood
of falling. At such times, patients may recover
if they either focus mental attention on walking,
try marching in place or to either side, or
get verbal or physical support to walk from
someone else.
Falling is to be feared and avoided, if possible.
Hips, arms, pelvises, necks, etc. can be broken
and may not be repairable to restore adequate
function. Heads can be injured, producing blood
clots in or over the brain, requiring surgery.
Staying mobile, however, is essential. Whenever
possible, patients should walk, within their
own limitations. Others who can do more, physically,
should.
Certainly, safe mobility must be maintained,
whether that is achievable with some combination
of medical, physical, occupational or surgical
treatment. If these treatment modes alone cannot
fully succeed, some form of physical support
[i.e., cane, walker, scooter, or holding onto
someone or some immovable object(s)] has to
be used.
b.
Speech and Swallowing
These issues are dealt with in detail elsewhere,
but several general points are worth making.
Communication with others is so important that
it may be best to consult with a speech pathologist
working with your doctor to optimize your individual
function if you cannot be understood. Similarly,
swallowing function needs to be evaluated in
those patients who are choking on liquids or
solids.
c.
Occupational Therapy
This important area of expertise is offered
to patients who need special help to do activities
of daily living, including standing, balancing,
gait training, bathing and other bathroom activities,
feeding, and others. Occupational therapists
work well with others in the medical team to
optimize function, offering individualized treatment
programs.
d.
Constipation
This is very common, especially among those
with moderate-advanced PD. It is because of
an illness-related abnormality in the nerves
supplying the bowel. It can be made worse by
the use of anticholinergic drugs, and these
may need to be discontinued if constipation
poses a serious problem.
Patients often benefit from a high fiber diet,
increased liquid intake, exercise, and the use
of over-the-counter stool softeners. Frequent
laxatives or enemas should be avoided, if possible,
but these measures need to be discussed with
a treating physician.
e.
Urinary Difficulties
Patients will often notice an increased urgency
to urinate, as well as an increased urinary
frequency. In men, this may exaggerate ongoing
symptoms of prostate enlargement, and such issues
need to be clarified with urological consultation.
Generally, it is useful to limit fluid intake
after supper, and the use of either Ditropan®
(oxybutynin) or Detrol® (tolterodine)
may be considered.
f.
Sexual Function
Impotence (impaired erection) in men may occur
in PD, as it does in nearly all cases of multiple
system atrophy (MSA). One needs to consider
the potential role of medications (e.g., beta-blockers,
anti-anxiety drugs, anti-depressants, others),
and of depression itself, when impotence occurs.
Both men and women may experience a decrease
in libido, independent of depression.
g.
Depression
Depression is common among those with advancing
PD, affecting as many as 30-50% over the course
of the illness. There is often a loss of pleasure
in usual activities, decreased desire to socialize,
a loss of interest in sexual activity, insomnia,
weight loss or gain, increased irritability,
and, sometimes, a lesser ability to concentrate
and perform other usual mental functions. Think
about the possible presence of depression when
these symptoms appear and go on for weeks or
months. They rob people of the joy in life they
otherwise might have and appear to make the
motor portion of PD worse.
It is a common clinical experience that, unless
depression is adequately treated with medication
at least, and often also with some form of counseling,
full responses of PD patients to their medications
will not occur. So, not only should depression
be treated on humanitarian grounds, but also
to help the PD itself. Many experienced non-psychiatrists
manage depression well, but some instances are
best co-managed with a psychiatrist.
h.
Sleep Disturbances
Some PD patients will have vivid dreams and/or
insomnia because of one or more of their anti-PD
medications. Such sleep disruptions may not
only awaken the patient and his/her partner,
but can also make it impossible to get all the
rest that’s needed to recuperate enough
to do the next day’s activities well or
at all. In such circumstances, consider with
your doctor reducing or eliminating late evening
anti-PD medication dose(s).
We need to realize that some patients will require
nighttime doses of anti-PD medication(s) to
get out of bed to go to the bathroom, or simply
to turn comfortably in bed to rest well. Obviously,
this is another individual clinical decision
to make, and one that may need revision over
time.
Several years ago, it was reported that some
patients may have “sleep attacks”
(unheralded, sudden, irresistible sleep episodes)
when taking agonist drugs. This remains an area
of controversy since it isn’t clear that
such “attacks” haven’t occurred
because of another ongoing sleep disorder (e.g.,
due to excessive daytime sleepiness, depression,
other medication effects, etc.). However, although
there may be variable explanations for “attacks”,
the potential occurrence of dangerous sleep
episodes (e.g., when driving a vehicle) makes
it important to be aware of such a possibility.
In my view, a physician should not hesitate
to prescribe an otherwise potentially beneficial
agonist or other anti-PD drug, and both doctor
and patient should be vigilant about this uncommon,
possible issue. As with many other therapeutic
issues in PD, this needs thorough, individualized
attention in a medical setting.
i.
Dementia
Dementia (loss of acquired cognitive function,
including memory) can occur in about 30% of
PD patients over the course of the illness.
It is not inevitable.
When dementia occurs, it is important to try
to identify the cause, as some 5-10% are potentially
reversible, partly or fully. The list of potentially
reversible causes includes hypothyroidism (low
thyroid), vitamin B12 or folate deficiency,
syphilis, subdural hematoma (blood clot over
the brain), communicating hydrocephalus (impaired
circulation of spinal fluid), and others. Studies
to identify these disorders include blood tests
(for thyroid [TSH and perhaps others], B12,
folate, RPR or VDRL [syphilis], MRI or CT scan
of the brain) and, perhaps, a spinal fluid examination
for those whose dementia is rapidly advancing
or otherwise atypical. Correcting the abnormalities,
medically or surgically, will follow.
The same diagnostic studies, and perhaps others,
may be needed to establish the cause of other
forms of dementia. Some causes cannot be reversed,
including:
> stroke(s) affecting areas of brain that
cause, not PD itself, but both vascular parkinsonism
(i.e., signs that mimic the motor effects of
PD), often other neurological signs of disability,
as well as dementia. Strokes are often seen
in brain MRI or CT scans. The consultant neurologist
will often want studies done to try to learn
why the stroke(s) occurred, in an effort to
prevent further damage. Such studies often include
MRI of the brain, carotid Doppler ultrasound,
echocardiographic ultrasound and EKG. Patients
are often placed on aspirin or other medications.
> Alzheimer’s disease is seen more
commonly among PD patients with dementia than
among non-PD dements. We believe that the two
illnesses have shared genetic and/or environmental
risk factors, though these have yet to be discovered.
There is no specific test (e.g., MRI, PET or
SPECT scan, blood or spinal fluid test) that
can make the diagnosis during life, and a determination
is made by excluding other possibilities. Though
AD is irreversible, some mildly-moderately affected
patients may benefit cognitively and socially
by anticholinesterase medications, such as Aricept®
(donepezil), Exelon® (rivastigmine),
Reminyl® (galantamine), or other agents.
> Dementia with Lewy Bodies is a disorder
of some PD dements that causes hallucinations
when patients are not taking anti-PD drugs,
causes variability in cognitive function even
within parts of a day, and is progressive. It
may appear relatively early in the course of
PD, when motor disability is minor. Some patients
may temporarily worsen if placed on anti-psychotic
medications. Some may benefit from Reminyl®
or other anticholinesterase medications.
Whatever
the cause of dementia, its management should
include having the patient live in a caring,
safe, clean and comfortable environment. If
possible, living at home is most desirable and
least disruptive. Ideally, family, friends or
paid help may share the burden of care. If this
is not possible, moving a patient, with or without
his/her spouse, to an assisted care facility
should be considered. If this is unrealistic,
a patient may be placed in a nursing home that
family members determine provides good care.
Often, an experienced social worker will be
immensely helpful in reviewing realistic care
options and in helping to implement them; most
often, these professionals are associated with
larger healthcare organizations. Moreover, the
Michigan Parkinson Foundation (1.800.852.9781)
and the Alzheimer’s Diesease and Related Disorders
Association (1.800.337.3827) are invaluable
resources for caregivers of PD patients who
face these difficult challenges.
3.
Surgery for PD
The advent of functional surgery for PD, especially
deep brain stimulation (DBS) of the subthalamic
nucleus, has been a major advance in treatment
for the right patients in the right medical
setting. The subject is covered at length elsewhere,
but several points are worth emphasizing:
> Appropriate patients should be selected.
1) Current evidence suggests that only those
who have typical PD will have successful results,
not those with atypical forms of parkinsonism.
2) Functional motor improvement is likely only
among those who have clear responses to dopaminergic
medication. 3) Patients without dementia must
be selected because dementia may worsen if present
pre-operatively. 4) Patients selected must be
willing and able to work with members of the
medical team to help regulate both electrical
and medication doses in order to optimize their
function. They must be full partners in their
care. 5) Patients who are selected for surgery
need to be in adequate general health. That
is, they should not have significant cardiac
disease, crippling arthritis, cancer, or other
severe conditions pre-operatively.
> The timing of surgery is important. DBS
is something that is offered to patients who
have not been able to either fully benefit from,
or to tolerate, anti-PD medications, after adequate
trials of drugs, including combinations of medications
at various doses.
> The surgical team must have sufficient
skill and experience to be able to offer patients
and caregivers adequate likelihood of success
without undue risk.
Jay
M. Gorell, MD, FAAN
President and Former Chairman, MPF
Professor in Neurology, Wayne State University School of Medicine
William T. Gossett Chair in Neurology
Head, Division of Movement Disorders
Department of Neurology
Henry Ford Health System
Former
Chairman, Board of Directors
Michigan Parkinson Foundation
