This work by Mark Stacy, M.D. and H. James Brownlee, M.D. is a study of "Novel
Treatments in Parkinson's Disease". I have permission from Dr. Stacy to
reproduce this work here.
 
This work consists of one message. The message, contains the text of
"Recognition and Treatment of Early Parkinson's Disease and Other Tremor
Disorders".  The last part of this message is an uuencoded gif file that
contains a diagram composed by Dr. Stacy to illustrate the text.
 
In order to view the diagram, use the Article/extract function of your news
reader to turn the message in to a file called TOPD.GIF. Once this is
done, you can view the gif with any gif viewer and print it, if you desire.
 
If your newsreader does not support undecoding, a program is available in the
public domain called uudecode.exe which will work also.
 
FOCUS:
 
This work is focused toward bringing the partners of your Parkinson's Quest
more together, getting everyone on the same page, so to speak. If your family
doctor isn't too familiar with your conditions, copy this for them.
 
International members, this is the state of the art from this side of the
Atlantic and Pacific oceans.
 
 
Recognition and Treatment
of Early Parkinson's Disease
and Other Tremor Disorders
By *Mark Stacy. M.D., and #H. James Brownlee, M.D.
 
*Assistant Professor, Division of Neurology, University of Missouri,
 Columbia, MO
 
and
 
#Professor and Chairman, Department of Family Medicine,
 University of South Florida, Tampa, FL
 
Word Count: 2200
 
Abstract:
 
        Proper treatment of tremor in any clinical selling is dependent on
correct diagnosis. Essential or familial tremor (ET) is symptomatic with
movement, and involves the limbs, head and voice. Parkinson's disease (PD)
tremor occurs at rest, involves the jaw and limbs, and is associated with
bradykinesia, rigidity and falling. Beta--blockers or primidone are used to
treat ET, and if no improvement is seen, botulinum toxin injection may be
useful. PD is treated with a number of medications, but levodopa is
considered most effective. However, the treatment of the early patient
may involve levodopa sparing strategies and neuroprotective therapies, and
will differ from the more advanced patient. In the moderate patient,
polypharmacy is often necessary to minimize or avoid drug side effects. An
algorithm addressing these variables is presented in this manuscript.
 
 
Content Sentence:
 
        This paper approaches the diagnosis of tremor disorders (Essential
tremor, Parkinson's disease and others) from a clinical perspective.
Treatment is outlined in respect to algorithms designed to maximize patient
benefit.
 
Abstract:
 
        Proper treatment of tremor in any clinical selling is dependent on
correct diagnosis. Essential or familial tremor (ET) is symptomatic with
movement, and involves the limbs, head and voice. Parkinson's disease (PD)
tremor occurs at rest, involves the jaw and limbs, and is associated with
bradykinesia, rigidity and falling. Beta--blockers or primidone are used to
treat ET, and if no improvement is seen, botulinum toxin injection may be
useful. PD is treated with a number of medications, but levodopa is
considered most effective. However, the treatment of the early patient
may involve levodopa sparing strategies and neuroprotective therapies, and
will differ from the more advanced patient. In the moderate patient,
polypharmacy is often necessary to minimize or avoid drug side effects. An
algorithm addressing these variables is presented in this manuscript.
 
 
Content Sentence:
 
        This paper approaches the diagnosis of tremor disorders (Essential
tremor, Parkinson's disease and others) from a clinical perspective.
Treatment is outlined in respect to algorithms designed to maximize patient
benefit.
 
Introduction:
 
        Recognition and treatment of tremor disorders is an important and
gratifying component to any clinician's practice. In a managed care setting,
the role of the Family Physician in treating these potentially disabling
symptoms will become increasingly prominent. Recently, a group of
investigators met to develop some consensus in the approach to treating
patients with Parkinson's disease (PD), and an algorithm was generated in
an effort to improve treatment of this condition [1].
 
        The most common causes of tremor include Essential or Familial
Tremor, Parkinson's Disease, and those associated with Cerebellar Disorders.
[Figure1] These conditions are characterized by tremor location, frequency,
amplitude, type of movement (e.g. pronation-supination or flexion-extension),
and activity of occurrence (such as at rest or with movement). Other causes
of tremor are drug-induced, dystonic, post-traumatic and exaggerated
physiologic tremors. Common medications reported to produce tremor include:
corticosteroids, Beta-agonists, theophylline, caffeine, thyroid hormone,
valproic acid, lithium, and some tricyclic antidepressants.
 
Essential or Familial Tremor (ET)
 
        ET is an autosomal dominant disorder occurring in approximately 5
percent of the population [2]. The tremor occurs with movement and may
produce difficulty holding the newspaper, writing or eating. ET is usually
characterized by head, voice, trunk and leg tremor, but is not associated
with tremor of the tongue, chin, or face. The arm tremor is most often
symmetric, flexion-extension in nature, and has a frequency of 8 - 10 Hz.
The tremor is also seen when the arms are held in an extended posture or
with finger-to-nose maneuvers, but absent at rest.
 
        Treatment of ET in younger patients with no history of asthma,
smoking, diabetes, bradycardia, hypotension. or congestive heart failure,
is best achieved with propranolol (or other Beta-blocker) 60 - 80 mg per day
[3]. In older patients primidone 25 mg at bedtime is initiated, and titrated
to tremor improvement up to 150 mg a day. All patients should be cautioned
about the risk of depression with these drugs. Primidone incurs the
additional risk of confusion, urinary retention, and memory difficulties
[4] If neither drug produces improvement, combination therapy is sometimes
effective. Benzodiazepines (clonazepam 0.5 - 1.0 mg bid or lorazepam
0.5 - 1.0 mg on a pm basis) are also useful in some patients [5]. In
addition, one alcoholic beverage may reduce tremor for several hours, but
may cause a "rebound" tremor with withdrawal [6]. If a patient is unable to
take medication for tremor, wrist weights during eating may dampen the
tremor amplitude Finally, botulinum toxin type-A (BOTOX), a paralytic
protein injected directly into the muscle may produce satisfactory
improvement of tremor for 3-5 months [7].
 
 
Cerebellar Tremor
 
        Cerebellar or action (intention) tremor, differs in presentation and
neurologic findings from ET or PD. Patients exhibit "cerebellar signs" of
dysanthria, incoordination and walking difficulty. The tremor is higher in
amplitude, and involves more proximal muscles of the limb. On examination a
past-pointing type oscillation is seen with finger-to-nose testing.
Treatment with primidone, Beta-blockers, benzodiazepines, or acetazolamide
is occasionally beneficial. Injection with botulinum toxin is sometimes
helpful.
 
Parkinson's Disease
 
        In contrast to the head and limb tremor of ET, PD tremor occurs at
rest, involves the face, tongue, and limbs, and is often asymmetric. It is
usually 5-7 Hz in frequency, and pronating-supinating in the forearms with
"pill rolling" in the hands. The tremor of PD is associated with
bradykinesia (slow movement), postural instability, and rigidity [8].
Patients may report nightmares, depression, excessive salivation, difficulty
turning over in bed, buttoning buttons or cutting food, and problems with
walking. Other features of PD include autonomic difficulties such as
orthostatic hypotensi0n, constipation, micrographia, hypophonia, urinary
incontinence, and impotence.
 
        Pharmacological intervention in PD is dependent on the severity of
patient symptoms and preferences of the treating physician. However, if a
patient is only bothered by tremor of the non-dominant hand, both the
patient and physician may be comfortable avoiding medications. It is
important to stress an exercise program in all PD patients. Protein intake
interferes with levodopa absorption in only a small percentage of PD
patients, and in these patients diet alteration must be pursued. Educational
materials are readily available from the four PD organizations: the
American Parkinson's Disease Association (APDA), National Parkinson's
Disease Foundation (NPF), Parkinson's Disease Foundation (PDF) or United
Parkinson's Foundation (UPF). In most communities one of these organizations
is easily accessible. Finally, support groups offer an opportunity to learn
of coping strategies beneficial to patients. However, in the early patient
these strategies are usually not necessary, and occasionally, observation of
patients with advanced disease is not helpful to the newly diagnosed PD
patient.
 
COGNITIVE IMPAIRMENT: Treatment of PD can be extremely complicated
[Figure 2], but with a systematic approach, most patients will benefit. In
the patient with dementia, dopaminergic medications are more likely to
produce hallucinations or psychosis, as well as symptoms of toxic delirium
(agitation, confusion, and worsening of PD symptoms) [10-12]. Thus, it is
best avoid amantadine, selegiline, and dopamine agonists, and conservative
use of levodopa is recommended.
 
        Before 1990, the development of hallucinations. agitation and
psychosis were treated by reducing levodopa. The use of anti-psychotic drugs
are contraindicated because of dramatic, often prolonged worsening of
symptoms of parkinsonism. However, in some instances, low doses of low-
potency neuroleptic drugs are appropriate, and molindone (Moban) or
mesoridizine (Serentil) are suggested; if these drugs worsen symptoms of PD,
clozapine may be used although weekly lab monitoring is initially time-
consuming [13].
 
FUNCTIONAL IMPAIRMENT WITH COGNITIVE IMPAIRMENT: Treatment of PD is based on
restoring the dopaminergic (DA) function lost with substantia nigra cell
drop-out in the extrapyramidal pathway. [Figure 3] Because levodopa is the
most effective symptomatic medication in PD, conservative use of this
amino acid maximizes the potential for treatment benefit, while the potential
for delirium or psychosis remains less than with other drugs used
individually or in combination. Levodopa is metabolized to dopamine in the
blood-stream (peripherally) and the brain (centrally). Because "peripheral"
dopamine often causes nausea, vomiting, and orthostatic hypotension, it is
combined with carbidopa, a peripheral dopa-decarboxylase inhibitor. A minimum
of 75 mg per day of carbidopa is suggested to inhibit levodopa metabolism
outside the blood-brain barrier [14].
 
        Individualization of anti-PD therapy requires a thorough
understanding of patient response to each dose of levodopa (e.g. when does
a patient "kick-in," develop dyskinesias, and "turn-off" in relation to each
carbidopa/levodopa) [15]. [Table 1] Patients treated with immediate-release
carbidopa/levodopa often will notice an improvement of symptoms within 30
minutes of dosing, and experience improved mobility for 2 to 4 hours before
requiring a second dose. Patients treated with controlled release
carbidopa/levodopa (Sinemet CR) usually require less frequent dosing
(5 hour intervals), but the "kick-in" time associated with the CR
preparation may be delayed [16]. This is easily overcome by adding one-half
to one immediate-release carbidopa/levodopa 25/100 with the first controlled-
release dose in the morning. The prolonged therapeutic benefit from CR
carbidopa/levodopa is advantageous as patients develop end-of-dose
"wearing-off" in more advanced stages of PD [17]. The CR preparation can be
adjusted by increasing the dose per interval or the interval may be
shortened without changing the dose. Carbidopa/levodopa 10/100 should be
reserved for patients with advanced motor fluctuations not responding well
to the CR preparation. Furthermore, the development of hallucinations on
Sinemet CR, should be treated by dosage reduction, especially in the evening,
and conversion to the immediate release 25/100 or 10/100 preparations.
 
NEUROPROTECTION: The most vigorously debated clinical and pathological
question in Parkinson's disease for the past 30 years has centered on the
pathogenesis of PD and whether levodopa hastens disease progression [18,19].
In the late 1980's investigators reported slowing the rate of patient
decline with selegiline, a monoamine oxidase-B (MAO-B) inhibitor [20]. In
1989 the preliminary analysis of the Deprenyl and Tocopherol Antioxidative
Trial of Parkinson's Disease (DATATOP), a randomized, placebo-controlled
evaluation of 800 patients, concluded that selegiline 10 mg per day
significantly delayed the progression of disability in PD [21]. Although
these findings have met with controversy, the DATATOP investigators and
others now report that selegiline will delay the need for levodopa for
almost nine months, but were unable to determine whether the benefit was
from symptomatic or "neuroprotective" response [22-25]. However, selegiline
has been shown to delay the use of levodopa in the early patient, and when
used with levodopa, may reduce the total levodopa requirements. In
addition, one retrospective autopsy study has reported fewer Lewy bodies
(the pathologic hallmark of PD) in patients treated with selegiline when
compared to those not receiving this drug [26]. Side effects are infrequent
with selegiline, but include insomnia, lightheadedness, nausea, skin rash,
headache, and constipation. The importance of "levodopa sparing" strategies
in PD has not been adequately determined, and often leads to confusion for
both the clinician and patient.
 
        Currently, selegiline is the only MAO-B inhibitor available in this
country, but lazabemide, may be available in the near future [27]. The use
of selegiline as a neuroprotective agent in PD is a decision best decided
jointly by a patient and a physician. It is important to consider the age,
lifestyle, disability and resources of the patient when considering this
therapy.
 
FUNCTIONAL IMPAIRMENT WITHOUT COGNITIVE IMPAIRMENT: An arbitrary age cut-off
of 60 years has been suggested, but duration of symptoms, and relative
activity of the individual patient may be more important. In the mildly
symptomatic or tremor-dominant patient, levodopa-sparing strategies may be
used. [Table 2) This treatment rationale is based on clinical and scientific
data suggesting that both endogenous and exogenous dopamine hastens the
progression of symptoms in this disease. However, the potential long range
benefit of prolonged mobility must be carefully weighed against the
potential loss of function in the short term (e.g. can the patient continue
to work if not treated with levodopa).
 
        The tremor dominant patient may respond dramatically to
anticholinergic medications (e.g. trihexyphenidyl 2-12 mg per day), but most
patients report benefit for only three to four months [1]. These drugs are
believed to restore an "imbalance" between reduced dopamine and uninhibited
cholinergic interneurons in the striatum [Figure 3]. The exact mechanism of
tremor suppression is unknown, but recent data suggests these cells
discharge rhythmically at 2-10 Hz, and anticholinergic drugs may alter the
delay of firing associated with nigrostriatal destruction [28]. Amitriptyline
is another anticholinergic drug useful in PD, especially in patients with
sleep difficulty and excessive salivation. Side effects of the
anticholinergics include dry mouth, urinary retention, constipation, visual
problems, confusion and psychosis [29].
 
        Amantadine (100 mg; 1-4 tablets per day) is a highly effective drug
that can be used in monotherapy, or as an adjunctive medication, particularly
when patients report wearing-off difficulties or problems sleeping [30].
Although its mechanism of action is unknown, it does act on both presynaptic
and postsynaptic dopamine receptors, and has some anticholinergic properties.
Side effects are similar to the anticholinergic drugs, and also include
ankle edema and livedo reticularis [1].
 
        There are only two dopamine agonists currently available in this
country. Pergolide and bromocriptine act at the post-synaptic membrane and
both have been shown to be useful in conjunction with levodopa.
Bromocriptine (at 10 - 20 mg per day) is a potent D2 dopamine agonist, while
pergolide, a Dl and D2 agonist, may be used as a monotherapeutic agent at
I - 4 mg per day [31,32]. Cabergoline is a D2 dopamine agonist currently in
clinical trial in this country, and may soon be available [33]. Side effects
are more common in this class of anti-PD drugs and include: confusion,
hallucinations, orthostatic hypotension, nausea, and depression. Long term
therapy is associated with shortness of breath secondary to pulmonary
fibrosis. Erythromelalgia, headache and back pain are also reported [1].
 
        The remainder of this PD algorithm is an attempt to catalogue
symptoms commonly seen in patients with advancing disease. Although some of
these symptoms are resistant to any treatment, in most cases viable
therapeutic options exist. Recognition of the head and postural tremor of ET
and the chin and resting tremor of PD is necessary to produce symptomatic
benefit in patients with these problems.
 
 
Conclusion:
 
        Treatment of the early patient with either of these conditions is
often quite gratifying, because of the tangible improvement patients achieve
in their daily routines. However, if a patient does not respond adequately
to these initial treatment algorithms, or these treatments become less
effective, referral to a Neurologist or Movement Disorders Center may be
beneficial.
 
References:
 
1.      Pahwa R, KolIer WC. A rational polypharmacy approach to Parkinson's
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2.      Findley LJ. Tremor: Differential diagnosis and pharmacology. In:
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        disorders. Baltimore: Williams and Wilkens, pp. 293-314, 1993.
3.      Koller WC. Dose-response relationship of essential tremor. Arch
        Neurol 1986;43:42-3.
4.      Findley LJ, Cleeves L, Calzett S. Primidone in essential tremor of
        the hands and head. J Neurol Neurosurg Psychiatry 1985;48:911-5.
5.      Heilman KM. Orthostatic tremor. Arch Neurol 1984;41:880-1.
6.      Koller WC, Biary N. Effect of alcohol on tremors. Neurology
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7.      Jankovic J, Schwartz K. Botulinum toxin in the treatment of tremors.
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10.     Mayeux R, Mirabello E, Marder K, et al. An estimate of the incidence
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11.     Biggins CA, Boyd JL, Harrop FA, et al. A controlled, longitudinal
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13.     Friedman JH, Lannon MC. Clozapine in the treatment of psychosis of
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14.     Calne DB. Treatment of Parkinson's disease. N Eng J Med
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15.     Nun JG. Levodopa-induced dyskinesia: review, observations, and
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16.     Markham CH, Diamond SG. Evidence to support early levodopa therapy
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20.     Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the
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22.     The Parkinson study group. Effects of tocopherol deprenyl on the
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23.     Landau WM. Clinical neuromythology IX. Pyramid sale in a bucket shop.
        DATATOP bottoms out. Neurology 199Q;40:1337-9.
24.     Myllyla VV, Sotaniemi KA, Vuorinen JA. Selegiline as initial
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25.     Schulzer M, Mak E, Calne DB. The antiparkinson efficacy of deprenyl
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26.     Rinne JO. Nigral degeneration in Parkinson's disease in relation to
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27.     Lewitt PA, Segel SA, Mistura KL, Schork MA. Symptomatic anti-
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28.     Graybiel AM, Aosaki T, Flaherty AW, Kimura M. The basal ganglia and
        adaptive motor control. Science 1994;265:1826-31.
29.     Fitzgerald PM, Jankovic J. Nondopaminergic therapy in Parkinson's
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30.     Jankovic J, Marsden CD. Therapeutic strategies in Parkinson's
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31.     Nakanishi T, Mizuno Y, Goto I, et al. A nationwide collaborative
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TABLE I
 
Treatment of Parkinson's Disease
 
Immediate-release carbidopa/levodopa
 
Medication:       Indications            Dosage
 
25/100        Early to Advanced         2-10 per day
25/250        Moderate to Advanced      2-10 per day
10/100        Advanced                  As needed       Side effects:
 
                                                        nausea, hypotension
Controlled-release carbidopa/levodopa                   hallucinations
 
Medication:     Indications              Dosage         dyskinesias
CR 25/100       Early to Advanced       1 qd - 2 tid
CR 50/200       most useful with        at 5 hour
                motor fluctuations      intervals
 
TABLE 2
 
ADJUNCTIVE TREATMENT OF PARKINSON'S DISEASE
 
Medication:     Indications             Dosage          Side Effects
 
Amantadine      Night time myoclonus    100 mg          hallucinations, dry
                freezing/dystonia       3-4/d           mouth, 5% insomnia
 
Amitriptyline   Early morning dystonia  20-50 mg at HS  early morning
                (e.g. foot cramping)                    lethargy, dry mouth,
                                                        hallucinations
 
Baclofen        useful for levodopa-    10 - 20 mg with sleepiness
                related dystonia        levodopa dose
 
Bromocriptine   improvement of          2.5-30 mg'd     somnolence,
                PD symptoms                             back pain,
                                                        hallucinations,
               reduction in levodopa                    confusion
 
Lorazepam       anxiety                 1-3 mg'd        sieepiness,confusion
Pergolide       see bromocriptine       1-3 mg'd        see bromocriptine
 
Selegiline      ? protective            5 mg ' 7-12     insomnia
                may improve PD
                symptoms
                may allow 10-30%
                reduction in levodopa
 
Clozapine       hallucinations,         6.25 - 200 mg'd fatal neutropenia
                psychosis                               CBC checked weekly
 
Legends:
 
Figure 1: There are 3 major types of tremor subtypes in clinical practice;
essential tremor (ET), Parkinson's disease (PD) tremor and cerebellar tremor.
In addition, drug-induced tremor has features of both PD and ET. Correct
recognition of these tremors increases the likelihood of therapeutic
response to the options listed in this algorithm.
 
Figure 2: This algorithm is an attempt to organize the extremely complicated
decisions involved in treating the Parkinson's disease (PD) patient. The
Early PD patient may be treated with emphasis on function and relief of
disabling symptoms. Treatment of the advanced patient is concerned with
recognition of later manifestations of the disease and palliation of drug-
related side effects.
 
Figure 3: This diagrammatic representation of the substantia nigra and the
striatum is a highly theoretical model of the sites of action for medications
used in the treatment of Parkinson's disease. LEVEDOPA, metabolized to
dopamine, increases the concentration of this neurotransmitter in the brain,
and is taken up by the nigrostriatal neuron. AMANTADINE enhances the release
of dopamine in the striatum, and has some anticholinergic effects.
TRIHEXYPHENIDYL and AMITRIPTYLINE also act on the acetylcholine interneuron.
SELEGILINE indirectly increases dopamine concentration in the synapse, by
reducing the rate of dopamine metabolism in glial and neuronal cells.
DOPAMINE AGONISTS such as PERGOLIDE or BROMOCRIPTINE improve dopaminergic
tone by acting at the post-synaptic membrane. BACLOFEN alters GABA-ergic
tone in the striatum, pallidum, subthalamic nucleus, thalamus and spinal
cord.
 
Table 1; There are 5 different formulations of carbidopa/levodopa. Of the
traditional preparations 25/100 should be the initial therapy (one-half
tablet daily for one week, then bid for one yveek. then tid for one week,
and then one tablet tid). If subtherapeutic response develops, the 25/250
preparation may be used. The 10/100 should be saved for only the most
advanced patient. Controlled release carbidopa/levodopa may be started at
one tablet every morning for one week, then one tablet bid. If the patient
develops difficulty toward the end of the day. a third tablet can be added.
 
Table 2: These medications may be used as adjunctive or primary therapies in
Parkinson's disease.
 
Biographic Sketch
 
        Dr. Mark Stacy obtained his medical degree at the University of
Missouri, and completed his Neurology training at Hahnemann University in
Philadelphia. After completing a fellowship at Baylor College of Medicine in
Houston, he returned to his alma mater, where he is currently an assistant
professor of Neurology. His wife is also a faculty member in the Department
of Electrical Engineering, and they have two children.
 
        Dr. H. James Brownlee obtained his medical degree at the Health
Sciences Center - Syracuse, and completed his Family Practice Residency
training at the Williamsport Hospital in Williamsport, Pennsylvania. After
completing a faculty development fellowship at the University of Miami, Dr.
Brownlee spent three years as a faculty member at the Carswell AFB Regional
Hospital Family Practice Residency Program. Dr. Brownlee joined the faculty
of the University of South Florida College of Medicine in 1983, completed a
part-time Geriatric Fellowship in 1987, and served as Residency Director at
Bayfront Medical Center until 1994. He was recently named Chairman of the
Department of Family Practice University of South Florida College of
Medicine.
 
 
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end
END -- Cut Here -- cut here
 
John Cottingham                     [log in to unmask]