ADVANCING PARKINSON'S DISEASE
 
DYSAUTONOMIAS
 
CONSTIPATION. Pfeiffer and his colleagues have emphasized the
importance of considering two distinct processes responsible for
normal stool expulsion.[73-75] First, stool moves through the
colon by the sequential contraction of muscles within the
intestinal wall. Intrinsic enteric neurons regulate this
muscular activity. Second, parasympathetic afferent and efferent
fibers mediate the excitatory and inhibitory input to the colon.
 In patients with PD, Lewy bodies have been found within
degenerating colonic neurons (myenteric plexus); the primary
clinical correlate is slowed stool transit time related to
impaired colonic muscle contraction. In a second syndrome,
colonic transit time may or may not be normal, but the primary
abnormality is in defecation. Parkinsonian patients are unable
to straighten the anorectal angle on straining, accentuating its
flap valve action and resulting in an obstruction to the passage
of stool. It has been suggested that this paradoxical
contraction of the pelvic musculature is dystonic in nature and
correlates with the progression of PD. In support of this
argument, apomorphine has been shown to alleviate this
defecatory problem in some patients with PD.[76] Other disorders
associated with constipation in patients with PD include
megacolon and sigmoid volvulus.
 Management (breakout 4). Dietary modification aimed at
increasing bulk and softening the stool should be the first
strategy for constipation, and ultimately the most efficacious,
in patients with PD. They must be encouraged to drink at least
eight glasses of water each day. Low-fiber foods, such as many
breads and cakes need to be reduced, and bananas must be
eliminated from the diet. At least two meals per day should
include high-fiber raw vegetables. Carrots, cauliflower, and
broccoli are good choices. Oat bran as a hot cereal (Quaker Oats
bran) adds significant fiber to the diet, especially when
one-fourth to one-third cup is used in the morning. As a morning
meal, it reduces the amount of protein, adds bulk, and helps
stimulate the gastrocolic reflex.
 Increasing physical activity is also helpful. Although vigorous
exercise is not necessary, just doing a few pushups, situps, or
isometric exercises is not enough. Patients must be encouraged to
walk as much as several miles a day, if possible, or swim regularly.
 If stools remain hard despite the measures outlined above, stool
softeners such as docusate, given with each meal can be useful.
Lactulose, 10 to 20 g per day, may benefit some patients. Patients
are warned that the results with any method of softening stool will
not be immediate and that persistence with dietary and pharmacologic
measures is necessary.
 Since anticholinergic agents decrease bowel motility, stopping such
drugs can be useful for alleviating constipation, but this is often
at the price of increased parkinsonism. The next step is a trial of
cisapride (a cholinomimetic agent) which increases intestinal
motility.[77] Even at the usual dosage of 5 mg bid, it is important
to watch for occasional worsening of Parkinson's signs and symptoms.
Mild laxatives such as milk of magnesia or enemas should be a last
resort and used sparingly-perhaps no more than once a week as
part of an overall bowel regimen-but in some patients enemas may
be necessary. Apomorphine injection may provide enough benefit
to permit successful defecation.
 
URINARY PROBLEMS. The neuro-anatomic substrate for normal
voiding is widespread. The detrusor motor area in the frontal
lobes connects with a similar functional region in the
pontomesencephalic reticular formation. Input from the basal
ganglia to this cortico-mesencephalic loop depresses detrusor
contraction; hypothalamic input increases detrusor contraction.
Peripherally the detrusor is innervated via sacral
parasympathetic neurons, a pathway that is facilitated by
noradrenergic neurons in the locus ceruleus. Seemingly more
important for patients with PD, however, is the loss of
dopaminergic output from the substantia nigra, which appears to
increase detrusor hyperreflexia. Most patients with PD suffer
from detrusor hyperactivity. Relatively few have detrusor
hypoactivity or urethral sphincter dysfunction.
 Common symptoms in PD patients that result from detrusor
hyperactivity include urgency, frequency, and nocturia. Nocturia
is the most common and usually the earliest complaint, only much
later followed by daytime symptoms. In fact, if daytime frequency
or urgency occurs as an initial complaint, causes from mechanical outlet
obstructions, such as prostatic hypertrophy, must be considered.
 Management (breakout 5) Many patients can reduce nighttime
frequency by the simple expedient of reducing liquid intake in
the evening (no liquids after supper). If this nonpharmacologic
intervention is ineffective, peripherally acting
anticholinergics, such as oxybutynin or propantheline, can be
tried. Oxybutynin, 5 to 10 mg, can be administered at bedtime
only or on a tid basis. Propantheline, 7.5 to 15 mg, may also
work well at bedtime or on a tid schedule. If anticholinergics
prove ineffective, hyoscyamine, a parasympatholytic agent, may
work on a qid regimen or at night only (0.15 to 0.30 mg). A
trial of desmopressin, administered at night in escalating doses
(usually 10 to 20 micro g) as an intranasal spray, may work for
otherwise refractory cases.
 Anticholinergic agents, used in the treatment of detrusor
hyperactivity, reduce detrusor contractions, an effect that
may worsen voiding problems in patients with detrusor hypoactivity
or outlet obstruction. Detrusor hyporeflexia, producing incomplete
bladder emptying and urinary frequency, may respond to a reduction
in the dosage of an anticholinergic antiparkinsonian medication
when that is the cause. It is therefore essential that PD patients
with urinary dysfunction have urologic evaluations that include
recording of bladder and sphincter pressure, sphincter
electromyography, and fluoroscopy and that these tests be performed
only by a urologist familiar with their interpretation.
 When cystometric studies reveal a hypoactive detrusor, benefit
may be obtained from alpha adrenergic-blocking agents such as
phenoxybenzamine or prazosin, which decrease tone in the bladder neck.
Unfortunately, these agents can exacerbate or cause orthostatic
hypotension and cardiac arrhythmias and should be used with
caution in patients with PD. Drugs that relax striated
muscle--such as diazepam, baclofen, or dantrolene--can
ocasionally be effective when the external sphincter is
hyperreflexic. Intermittent catheterization is necessary with
myogenic overdystension. Any deterioration in voiding pattern
(even in the absence of dysuria) should raise the concern of
infection, which should be treated promptly.[78]
 
SEXUAL PROBLEMS. Little attention has been paid to the sexual
dysfunction common in patients with PD. Most treatment is aimed
at impotence in men, with virtually nothing being known about
the sexual function of women with PD. In men, the most common
problem is achieving or sustaining an erection.
 Management (breakout 6). Propranolol or other beta-adrenergic blockers,
sometimes used to control postural or action tremor in patients
with PD, are common offenders. Other possible problem drugs
include antihypertensives (alpha-adrenergic blockers such as
clonidine, methyldopa, and guanfacine). Guanethidine, although
less frequently used, is a potential offender, as are thiazide
diuretics, anxiolytics, digoxin, and cimetidine.
 Looking for depression is often rewarding; medical evaluation
is mandatory but rarely helpful. Although depression is a frequent
cause of sexual dysfunction, it is noteworthy that antidepressant drugs
(particularly the serotonin uptake inhibitors fluoxetine,
paroxetine, sertraline) can cause impotence. Tricyclics also
have been implicated as a less frequent cause of impotence.
Depressed patients should be treated with either tricyclic
antidepressants or serotonin uptake inhibitors, despite the
problems described above. Tricyclics (with anticholinergic
properties) have the added advantage of alleviating some of the
parkinsonian symptoms, but the best approach is to use the most
efficacious drug to lift depression in a given patient. Some
patients with anxiety- or stress-associated sexual dysfunction
benefit from low-dose anxiolytics.
 Endocrine function can be ascertained with serum levels of
prolactin testosterone, and luteinizing hormone and studies of
thyroid function. If no medical or psychologic reasons seem to
be causing impotence, one can try yohimbine, 5 mg tid for 1 month.
Further treatment, under consultation with an expert urologist,
can include local injection of phentolamine(an alpha-adrenergic
blocker) and papaverine. This combination provides a short-term
vasodilator effect by acting on smooth muscle. More invasive
approaches, such as implants, are less easily accepted by patients and
treating physicians. Previously untreated patients may find that
starting treatment with levodopa can help sexual dysfunction,
probably by alleviating bradykinesia and increasing desire. In
fact, some patients on high doses of antiparkinsonian agents
become hypersexual, even in the face of inability to perform.
 
ORTHOSTATIC HYPOTENSION. The anatomic site responsible for
orthostatic hypotension (OH) patients with PD are probably
heterogeneous, since no consistency in abnormalities has been
reported. Sympathetic efferent dysfunction in some patients can
be inferred from a failure to increase heart rate with falling
blood pressure and the lack of blood pressure overshoot with
Valsalva. Abnormalities of renin and inadequate increases in
serum norepinephrine on standing may be contributory factors. A
central autonomic defect may be involved, as suggested by an
increased pressor response to norepinephuine patients with PD.
The finding of Lewy bodies in the hypothalamus of these patients
support such an etiology in some. More likely in most patients
however, is a generalized sympathetic degeneration from Lewy
body disease causing cell loss in the sympathetic ganglia.[78]
 Management (breakout 7). OH, although not uncommon in patients
with PD, should be treated only in those who are symptomatic.
Levodopa or dopamine receptor agonists exacerbate OH, the latter
especially during the first weeks of treatment.
 Many patients who have been on antihypertensive drugs begin to
experience OH with progression of PD. They often can tolerate a
reduction in or cessation of their antihypertensive medications.
In those patients who are not taking antihypertensives, the first
step in treating OH should be the addition of salt and fluids to the
diet. Higher salt intake can be achieved by deliberately adding
salt to food at the table (as opposed to adding it in the
cooking process) so that other family members do not get
additional unnecessary salt. Salt tablets, up to 2 g per day,
are another alternative. Compressive stockings and behavior
modification should be used in conjunction with increased salt
and fluid intake. Knee-high stockings are less effective than
thigh-high ones, but the former are preferable because of
increased compliance. Practitioners can teach patients behavior
modification that reduces OH, such as getting up slowly and
sleeping with the head tilted.
 For parkinsonian patients with OH, fludrocortisone (a salt-retaining
steroid) can be started in doses of 0.1 rug per day and titrated
upwards in 0.1 mg increments up to 0.3 mg tid. Patients taking it
should be monitored for possible congestive heart failure and supine
hypertension, however Indomethacin, 25 mg tid is not as
effective as fludrocortisone but is more easily tolerated. It
probably works by inhibiting vasodilating prostaglandins.
Midodrine, 5 to 10 mg qid, is an investigational
alpha-adrenergic agonist that is particularly effective in some
patients. In evaluating patients with "dizziness" OH should be
distinguished from complaints caused by postural instability
visualmotor dysfunction, or multiple sensory deficits.[79]
 
THERMOREGULATION. The neurochemical and anatomic regulation of
temperature is complex and poorly understood. Preoptic and
hypothalamic areas appear to have thermoregulatory function.
Noradrenergic, serotonergic, and cholinergic systems have an
incompletely understood role in thermal homeostatais. Sweating
is mediated by efferent sympathetic cholinergic fibers, which
may be damaged in PD. Lewy bodies and cell loss in the
hypothalamus have been implicated in PD-associated sweating
abnormalities.
 Management (breakout 8). Abnormal sensations of heat or cold,
impaired sweating responses, and hypothermia all can occur in
the untreated patient. Excessive sweating of the head and neck
in response to external heat has been associated with poor heat
dissipation. Some of these phenomena disappear with levodopa
treatment, which suggests a role for central dopaminergic systems
in thermoregulation.[80] Severe drenching sweats occur as an
end-of-dose "off" phenomenon in patients with motor fluctuations,
further supporting a role for dopamine systems in vasomotor tone
and heat regulation. Dopamine agonist therapy may be of benefit to
such patients.
 Although peak-dose chorea can cause sweating, it is rarely if ever
as severe as that seen in the "off' state For patients who experience it,
however, a reduction in the dopaminergic medications may help
but often at the price of more "off" time. These patients are
more likely to respond to beta-adrenergic blockers than are
patients with "off"-period sweating.
 Severe hyperpyrexia after levodopa withdrawal resembles the
neureleptic malignant syndrome and needs to be treated promptly
with reinstitution of dopaminergic agents.
 Other causes of excessive sweating must not be neglected simply
because the patient has PD. Benign sweating can occur with either
a visual, olfactory or gustatory stimulus. Ethanol and aspirin in
high doses also can cause increased intermittent sweats. Therefore,
taking a thorough history usually will clarify these situations
Thyrotoxicosis and postmenopausal states need to be considered and
appropriate endocrine evaluation initiated. Finally, chronic
infections such as tuberculosis must not be forgotten in the
differential diagnosis.
 
PAIN. The mechanisms responsible for pain in PD are unclear and
probably not the same in all patients. It can be mediated via
peripheral somatic or autonomic afferent nerves. Selective
autonomic block, however, does not seem to reduce the pain in
PD, and signs of autonomic disturbance are not usually present.
Since many of these syndromes are associated with dystonia, one
possible site for the origin of PD-associated pain is afferent
nerve fibers within the dystonic muscles. A spinal cord or
cerebral origin for some pains is suggested by the
pseudoradicular pattern seen in some patients. Many pain
syndromes occur in the "off" state only, suggesting a role for
dopamine-containing cells in the diencephalon,[81] which
terminate on receptors in the dorsal horn and intermediolateral
column.[82,83] Sensory symptoms often appear neuritic in
character, including paresthesias, burning dysesthsisa, coldness
or numbness, and deep aching.[84] The legs are more often
involved than the arms; face and neck are rarely involved.[85]
Akathisia sometimes is present. Pain is often, but not always,
worse on the side of worse parkinsonism.[86]
 Management (breakout 9) Pain related to parkinsonism often responds to
adjustment of antiparkinsonian medications. Most often, it is
linked to levodopa "off" states or insufficient levodopa dosage;
thus, optimizing medications (as described later) can be
gratifying. Other causes for radicular pain and neuropathy need
to be evaluated when appropriate. Pain related to arthritis is
not uncommon in elderly patients with PD.[87]
 
DYSPHAGIA. Significant dysphagia in patients with PD is usually;
But not always, related to the severity of disease and occurs in
up to 40% of patients. direct involvement of oropharangeal
muscles is suggested by the observance that many patients suffer
severe dysphagia only when "off," a situation that improves
dramatically as soon as a dose of levodopa becomes effective
Swallowing abnormalities include abnormal lingual control and
inability to pass a bolus of food backward into the pharynx.
Silent aspiration with repetitive reflux of food from the
vallecula and pyriform sinuses into the oral cavity are a
significant problem. Retention of food and pills in the
vallecula are another contributory cause of erratic levodopa
absorption, and therefore, a secondary cause of dysphagia.
Esophageal dysmotility occurs in as many as 70% of patients but
also is present in a significant number of controls.[88,89]
 Management (breakout 10). Soft diets help most types of
dysphagia by making It easier to move food in the mouth and
esophagus. Soft food also decreases aspiration by reducing the
need for separate liquid intake, since liquids often cause more
aspiration than solids. Since dysphagia is usually decreased
dramatically during "on" times, the best strategy is to increase
"on" time with additional dopaminergic medications, if possible.
Increased "off" time, however; is not a realistic goal for many
patients. All patients should eat only during an "on" period.
Feeding gastrostomies or jejunostomies are a last resort and are
rarely necessary in patients with idiopathic PD; but when
needed, these procedures provide the benefit of allowing more
normal intake of food and medication.
 
SEBORRHEA. Excessive secretion of oil by sebaceous glands is
common in PD.
 Management (breakout 11) Coal tar shampoos can be
used not only for dandruff but also for seborrhea over the
eyebrows and forehead. They should not be used more than once or
twice weekly Selenium-based shampoos also work in some patients
when used in a similar manner. Topical hydrocortisone is most
effective on the face but needs to be applied daily.
 
FALLS
 
Falls are a leading cause of morbidity and mortality in the
elderly population and frequently contribute to nursing home
placement.[90,91] The causes of falls in the elderly are usually
multifactorial and can be divided into intrinsic and extrinsic
factors. Intrinsic factors are age- and disease-related elements
in an individual that predispose him to fails. These factors
include gait, balance, and weakness (10 to 25%), dizziness and
vertigo (5 to 20%), orthostatic hypotension (2 to 15%), syncope
(2 to 10%), drop attacks (1 to 10%), and other causes, such as
acute illness, confusion, poor eyesight, and drugs (1 to
10%).[92] Extrinsic factors are environmental elements that may
cause an individual to fall. Environmental factors account for
30 to 50% of falls in elderly individuals.[92]
 Falling is a significant problem in PD (breakout 12).[93-95] Older age,
longer duration of disease, advanced stage of disease increased
disability, rigidity, bradykinesia, inability to rise from
chair, posture and gait impairment, and postural instability are
factors that predispose patients with PD to falls.[95] Mental
status changes, OH, dyskinesias, and age-related physical
changes are other possible factors.[96-100]
 
POSTURAL INSTABILITY. Postural instability often responds poorly
to drug therapy especially with advanced disease. Although
postural instability improves with the administration of
levodopa[94]--or other medications in some patients especially
those with more recent onset disease-most patients with more
advanced disease fail to improve with a change in levodopa
dosage or the addition of dopamine agonists, Gait training and
physical therapy may be beneficial, In patients with severe
postural instability, wheelchairs can be used to prevent
morbidity from falls.
 
SYMPTOMATIC OH. Symptomatic OH can cause falls in patients with
PD, It is critical for the physician to distinguish this cause
from other conditions that also can cause falling. Treatment of
OH is discussed in the "Dysautonomias" section.
 
MOTOR FLUCTUATIONS. Motor fluctuations, including dyskinesias
and episodic freezing, may be additive to postural instability
and contribute to the tendency to fall. (These problems will
also discussed in the "Motor problems" section to follow.)
 
FREEZING AND FESTINATIONS. Freezing  refers to a patient's feet
getting stuck to the ground while walking, with an inability to
initiate lower limb movement for a few seconds to minutes. In
PD, the center of gravity is shifted forward and during
ambulation the flexed trunk precedes the lower limbs, leading
the patient to take increasingly frequent, short steps, often
ending with a fall, This phenomenon is known as "festination."
Pharmacologic treatment of freezing and festination is sometimes
effective but can be very disappointing in more advanced
patients.[101] Occasionally, decreasing or. increasing daily
levodopa dosage or adding a dopamine agonist may help.
 When drugs are of no benefit in freezing and festinations, physical
therapy may he helpful. Behavioral therapy is often beneficial
in freezing. Gait modification by the use of motor and sensory
tricks, such as alteration of the distribution of body weight,
walking sideways, rocking movements of the body, stamping feet,
walking briskly, taking longer steps, consciously lifting one
limb higher and sliding one foot backwards then throwing it
forwards,[102] may work for some patients. Having someone
rhythmically pull or push or passively elevate the patient's
knee also can help,[102] Verbal or auditory stimuli that are
used include marching like a soldier to commands, walking or
dancing to music, sudden clapping of hands and swearing. Visual
stimuli include stepping over objects such as the handle of a
walking stick, another person's foot, or carpet patterns;
watching other people walk; and imagining white lines to step
over.
 
DEMENTIA. The proportion of patients with PD who are also
demented is approximately 15 to 2O%.[103] At times, PD may be
accompanied by Alzheimer's disease, Cognitive impairment is an
independent risk factor for falls in the elderly.[90] Hence,
parkinsonian patients with dementia have an even higher risk of
falls, Patients and their families should be educated about the
increased risk of falls, and occasionally these patients may
benefit with gait training and physical therapy.
 
OTHER NEUROLOGIC DEFICITS. Patients with PD can have associated
neurologic conditions that may increase their risk of falls.
These conditions include myopathy, cervical degenerative
disease, normal pressure hydrocephalus, lower back problems,
multiple sensory deficits (eg, visual, vestibular,
proprioceptive), cerebellar deficits, and other deficits caused
by strokes.[90] If clinical signs and symptoms suggest any other
neurologic condition, a detailed workup should be performed.
Aging,[104] arthritis, physical inactivity and cardiac
disease[105] in the elderly also should be considered as causes
of muscle weakness. It often is overlooked in elderly patients
because examiners are often too "generous" to grade their muscle
strength.[106] Decreased muscle strength in the lower limbs is
associated with falling[107,108] and mortality[109,110] among
the elderly. Physical therapy plays an important role in
strengthening weakened muscles and improving stability and gait.
 
 OTHER MEDICAL CAUSES. Acute illness, such as pneumonia, and the
worsening of chronic conditions, such as congestive heart
failure, can precipitate falls.111 Stable parkinsonian patients
who suddenly begin to have falls or an acute increase in the
frequency of falls should undergo complete medical evaluation.
Medications can contribute to falls by causing volume depletion,
OH, fatigue, impaired mental alertness, or other unknown
mechanisms.[90] The total number of medications used appears to
be directly related to the risk of falls.[111]
 
RECOMMENDATIONS. Every patient with PD who is experiencing falls
should have a home safety evaluation performed by a trained
therapist. The ability to avoid falls decreases with age,
because of changes in posture, body-orienting reflexes, muscle
strength, and decreased height of steppage.[112]
 Extrinsic factors that contribute to the tendency to fall could include
poor lighting, torn carpet, loose rugs, slippery surfaces, small
objects on the floor, inappropriate furniture, and unsafe
stairs.[90] Adaptive equipment, such as walkers, if
inappropriately used, also will increase the risk of falling. As
the chances of falling are proportional to the number of risk
factors,[90,111] everything possible should be done to correct
environmental factors.
 Not all risk factors are correctable and even after optimal
treatment some patients continue to experience falls. Prevention
is the best strategy, but an occasional patient may be safest
using a wheelchair on a permanent basis.
 
MOTOR PROBLEMS
 
During the early stages of PD, the clinical responses to
levodopa therapy are stable and characterized by a
"long-duration" pattern.[113] Patients with early disease
require several days to plateau following a change in their
levodopa dosage. Once plateaued, they experience no clinical
variability, even if doses are late or skipped. If levodopa is
stopped, it may take up to a week to return to the pre-levodopa
baseline. In contrast, with advancement of PD, the levodopa
response shifts to a "short-duration" pattern.[113] Patients
with advanced disease experience clinical motor fluctuations
that reflect ever-changing brain levodopa levels.
 Knowledge of the individual patient's short-duration levodopa response
pattern is often crucial to arriving at the correct treatment
advice The short-duration response typically develops, plateaus,
and abates over several hours after a single dose of levodopa.
The plateau phase of clinical improvement ("on") typically peaks
about 45 to 90 minutes after administration of the standard
formulation of carbidopa-levodopa and 60 to 150 minutes after
the controlled-release CR) formulation. Rare patients with
delayed gastric emptying may have a somewhat more delayed
response. The clinician should focus on the adequacy of the peak
response, the duration of that response, and the time that the
dyskinesias are manifest in the response cycle. This often can
be determined from the history but may require observation in
the office.
 
NO RESPONSE. A few patients with parkinsonism will experience no
beneficial response to carbidopa-levodopa in any dose. Such
patients with parkinsonian symptoms probably do not have PD but
rather striatonigral degeneration or some other similar
condition in which the pathology is beyond the substantia nigra,
involving other portions of the extrapyramidal motor system. An
adequate trial of medication must be employed before concluding
that the patient is a nonresponder.
 Management (breakout 13) Patients who fail to respond to lower
dosages of carbidopa-levodopa can have the dosage gradually raised,
with the standard rather than the CR preparation for the purposes of
this trial. Patients should be instructed to take their doses on
an empty stomach. to make certain the poor response is not
secondary to the inhibitary effects of dietary protein. Once the
dosage has been slowly pushed up to approximately 1,200 mg per
day (eg, 300 mg four times daily) with no response, it would
then be reasonable to conclude that carbidopa-levodopa therapy
is not beneficial. Since the long-duration levodopa response
takes several days to become fully manifest, patients should be
maintained on the higher doses for approximately 1 week to allow
the full effects to occur.
 Certain patients being seen in the office who report no response
to levodopa may be challenged with a somewhat larger dose than they
have been taking. If there is still no response, however, this
strategy should not preclude going ahead with a trial of chronic
administration of higher doses of carbidopa-levodopa, since some
patients manifest a long-duration effect that will not be seen after
one or two doses.
 Obviously, the aforementioned strategies pertain to patients who
simply fail to respond to carbidopa-levodopa rather than those who
cannot tolerate this medication, for whom other strategies may apply.
Patients who fail to respond to very high doses of carbidopa-levodopa
are unlikely to respond to dopamine agonist medications either,
although some clinicians choose to try these nonetheless. Patients
who fail to respond to levodopa and whose primary problem is tremor
or dystonia can he given a trial of anticholinergic therapy {eg,
trihexyphenidyl, benztropine).
 
SUBOPTIMAL PEAK RESPONSE. Patients who experience suboptimal
motor control at the time of peak effect of levodopa can have
their response potentiated in a variety of ways (breakout 14).
 The simplest approach is to raise the individual doses of
levodopa (with carbidopa) by small and gradual increments until
improvement develops. The point of diminishing returns is at
approximately 250 mg of levodopa per dose of the standard
formulation and 400 mg of the CR formulation. Rare patients may
require slightly higher doses for maximum effect.
 Although no compelling evidence points to levodopa toxicity, some
concerns do exist;[114] hence, some clinicians have favored keeping the
levodopa dosage lower and instead adding or increasing one of
the two available adjunctive dopamine agonist drugs,
bromocriptine or pergolide. A minimum total daily dose of 15 mg
of bromoctiptine or 1.5 mg of pergolide (divided) is usually
necessary to achieve a minimally clinically significant effect.
 Selegiline also will potentiate the peak effect of levodopa
therapy[115] by inhibiting MAO-B, one enzymatic route of
dopamine degradation. If tremor is prominent, the addition of an
anticholinergic drug, such as trihexyphenidyl or benztropine,
may be helpful, if tolerated. Amantadine is also mildly
beneficial as an adjunctive drug in this situation.
 Unfortunately occasional patients experience side effects that
limit the dosage of medications that can be administered. These
include hallucinations, psychosis, confusion, nightmares, and
dyskinesias, which can be induced or exacerbated by levodopa,
dopamine agonists, or selegiline. Anticholinergic drugs have
their own side-effect spectrum that includes memory impairment,
hallucinations, psychosis, constipation, urinary hesitancy, and
visual blurring.
 
 
 
John Cottingham         NEW ADDRESS:          [log in to unmask]