Movement Disorders Update Brownlee/Watts

[John Cottingham <johnc@xxxxxxxxx>]

 For the 99% of the Parkinsn list who were unable to attend or see the
recent APDA "Show and Tell", here is a report on similar remarks by Dr.
H. James Brownlee and Dr. Ray L. Watts.

This report was in a recent issue of Southern Medical Journal.


Update on Movement Disorders

"with newer strategies involving early combination therapy using
adjunctive agents with L-dopa, we aim for 10 to 15 years of good
control."


Movement disorders was the subject of a special symposium
presented in conjunction with the 88th Annual Scientific
Assembly of the Southern Medical Association, held in Orlando,
Fla. The topics discussed included the differential diagnosis of
parkinsonism; the epidemiology, pathology, and treatment of
Parkinson's disease (PD); and the diagnosis and treatment of
other movement disorders such as essential tremor and dystonia.

Classification of Movement Disorders

 H. James Brownlee, MD, Chairman and Professor of Family
Medicine at the University of South Florida College of Medicine
in Tampa, Fl, began by pointing out that movement disorders can
be classified as bradykinetic (slowed movement) and
hyperkinetic, with parkinsonism identified as a bradykinetic
movement disorder. The primary type of parkinsonism is
idiopathic PD, while secondary types are infectious,
drug-induced, toxin-induced, vascular, metabolic, degenerative,
and structural, as shown in Fig 1.

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Figure 1



         Classification of Parkinsonism



                   Primary

           (idiopathic, Lewy body)



           Secondary (symptomatic)



Infectious

Drug-induced

Toxin-induced

Vascular

Metabolic

Structural



                 Degenerative



Progressive supranuclear palsy

Multiple-System atrophy

Corticonigral degeneration with neuronal achromasia

Parkinson-dementia complex of Guam

Parkinsonism with amyotrophy

Alzheimer's disease

-------------------------------------------------------------------

Parkinson's Disease: Epidemiology and Pathology

 Dr. Brownlee went on to explain that the incidence of PD is
highest in persons between the ages of 55 and 70, and that it is
uncommon in those younger than 40 years of age. The annual
incidence is 20/100,000, with an estimated 500,000 patients with
PD in the United States.

 The primary pathology associated with the disease is a
selective loss of dopamine-containing neurons, resulting in a
severe loss of dopamine input to the striatum. Other factors are
the presence of microscopic lewy bodies and a reduced amount of
pigmented tissue in the substantia nigra. A genetic
predisposition may also exist, but this has not yet been
confirmed.

Differential Diagnosis of Parkinson's Disease

 Using a videotape showing various patients, Dr. Brownlee
reviewed the primary clinical features of PD--tremor, rigidity,
bradykinesia, and postural reflex impairment-- well as secondary
features such as autonomic dysfunction and speech abnormality
(Fig 2).

-----------------------------------------------------------

Figure 2

Parkinson's Disease: Clinical Features

         Primary Clinical Features

                  Tremor

Resting (subsides with action)

Slower frequency

Starts unilateral, progresses bilateral

Increases with anxiety

                 Rigidity

Cogwheel (superimposed tremor)

Lead-pipe (no superimposed tremor)

        Bradykinesia--slowness of movement

Difficulty arising from chair

Masked facies (looks like depression)

Difficulty swallowing

Micrographia

Reptilian stare

Postural reflex impairment (fall)

           Other Clinical Features

            Autonomic dysfunction

Sexual dysfunction (impotence)

Constipation

Sweating episodes

Orthostatic hypotension

Increased salivation

Urinary incontinence

            Speech abnormality

Low volume

Monotonous voice

-----------------------------------------------------------

 He noted that a characteristic feature is resting tremor, which
differs from an action tremor. The tremor is present at rest and
dampened or abolished by postural manipulation. "You've got to
observe the patients while they're sitting, but also get
involved helping them move, such as getting them on the
examining table. Then you'll be able to better diagnose movement
disorders," said Dr. Brownlee. "You'll also see the tremor end
when they're posturing with their hands or holding onto
something such as a coffee cup."

 As part of his discussion of differential diagnosis, Dr.
Brownlee reviewed the need to differentiate symptoms of PD from
the dyskinetic movements resulting from prolonged treatment with
carbidopa-levodopa (L-dopa). Dyskinesias involve hyperkinetic
movements rather than the bradykinetic movements of PD.

 During a review of the staging scale for PD (Fig 3), Dr.
Brownlee mentioned that the unilateral involvement of stage I
can be confused with partial asymmetric paralysis resulting from
a stroke. Patients with stage II have bilateral disease, with
little arm movement when walking. Patients with stage III show
mild postural imbalance, but they are able to lead an
independent life.

 By stage IV, patients are unable to perform activities of daily
living without help from someone else. Patients with stage V
disease are usually rigid and frozen, and exhibit severe
postural instability, usually being restricted to bed and chair
in a nursing home.

 Referring to patients in stage IV, Dr. Brownlee stated, "If we
as primary care physicians have to get to this point with
patients before we can diagnose then we are playing catch-up
ball. We need to be diagnosing a lot earlier." In the past, when
there were few viable treatments for the disease, an early
diagnosis was less important however, he said that this is no
longer true due to recent advances in the treatment of
neurologic disorders.

-----------------------------------------------------------

Figure 3

         Staging of Parkinson's Disease

Stage I   Unilateral involvement

Stage II  Bilateral involvement, but no postural
          abnormalities

Stage III Bilateral involvement with mild postural
          imbalance; patient leads an independent life

Stage IV  Bilateral involvement with postural instability;
          patient requires substantial help

Stage V   Severe, fully developed disease, patient is
          restricted to bed and chair

----------------------------------------------------------
Hohn and Yahr (1967)


Parkinson's Disease: Symptomatic Therapy, Neuroprotective
Therapy, and Surgical Options

 Symptomatic therapy, in which the treatment agent is
specifically aimed at certain symptoms, was discussed by Ray L.
Watts, MD, Chief of the Movement Disorders Center at Emory
Medical School in Atlanta,Ga. Physicians should avoid designing
a treatment strategy without first questioning their patients
about what symptoms are most troubling to them.

 The degree to which symptoms interfere with function and
employability is the guidepost used for determining when to
introduce L-dopa, the most potent treatment available for PD.
However, the agent does not alter the progressive natural
history of the disease and is associated with a number of
troublesome side effects such as nausea, confusion, and
involuntary movements (dyskinesia).

 Until recently, physicians treating newly diagnosed patients
would immediately start them on L-dopa and proceed to relatively
high doses within a few years. "Five years later the patients
would be showing signs of involuntary movements, and by 6 or 7
years they might be as disabled from the side effects as from
the disease itself," said Dr. Watts. "With newer strategies
involving early combination therapy using adjunctive agents
with L-dopa, we aim for 10 to 15 years of good control."

 In patients with mild, early-onset PD who are in their
fifties or early sixties, symptoms may be alleviated with one of
the older drugs such as amantadine, which increases dopamine
release and its anticholinergic properties (Fig 4). Since this
agent can induce memory or confusional problems, it is used less
commonly in patients in their late sixties or seventies.

 For those needing a higher rate of improvement, small amounts
of L-dopa can be used. Restricting the dose initially is
important because patients will need higher doses as the disease
progresses. "and more is not always better when you get to the
side effects region. So, we use as much as needed, but no more,"
said Dr. Watts.

 "We know that most early patients need about 100 mg of L-dopa
three times a day to get a dramatic improvement in symptoms,"
stated Dr. Watts. But over a few years, signs gradually increase
of the drug wearing off in between doses.

 In the past, higher doses of L-dopa were then given, but this
resulted in periods of involuntary movements that gradually
became unpredictable after about 7 to 8 years. The advent of
slow-release L-dopa administered twice daily has helped maintain
more stable blood and brain levels of L-dopa, and thus has led
to less dyskinesia and on-off fluctuations of PD symptoms.

 Recently, two new adjunctive drug therapies have been added
earlier in the course of therapy selegiline and the dopamine
agonists. Selegiline blocks the major metabolic enzyme monoamine
oxidase type B (MAO-B) in the brain that normally breaks down
dopamine, thus extending dopamine's duration at active brain
sites.

 The addition of selegiline to L-dopa therapy allows physicians
to use 20% to 30% less L-dopa than before. In addition to
blocking MAO-B, Dr. Watts reported that a large clinical study
has shown that selegiline slows the progression of PD by 40% to
50% when used as monotherapy. He added, "1 think the best early
strategy for the treatment of PD, both from a practical and
long-term planning standpoint, is L-dopa combined with
selegiline for the first 3 to 5 years.

 Two dopamine agonists are currently used to treat PD:
bromocriptine and pergolide. Although dopamine agonists act like
synthetic dopamine, they are not as potent. However, their long
half-life in the 10- to 15-hour range helps provide more stable
drug levels in patients with more advanced PD. The biggest shift
in strategy in recent years has been to add dopamine agonists
once patients are on 400 to 600 mg of L-dopa per day rather than
waiting until "on-off" fluctuations become pronounced.

 Most patients in the 5- to 10-year range of disease will
benefit from a combination of L-dopa, selegiline, and a dopamine
agonist, according to Dr. Watts. Many of these individuals will
be able to keep functioning for over a decade, able to work and
remain independent. By keeping the dosage of L-dopa at shout 50%
of what was once thought necessary, physicians are now able to
avoid the involuntary movements such as dyskinesia that are so
debilitating. "The most important message I can leave with you
is their strategic application early in treatment," said Dr.
Watts.


Treatment of Parkinson's Disease: The Future

----------------------------------------------------------

Figure 4

      Treatment for Parkinson's Disease

              Present Treatments

Amantadine

Carbidopa-levodopa (L-dopa)

Combination therapy:

L-dopa and selegiline

L-dopa, selegiline, and a dopamine agonist (bromocriptine,
Pergolide)

               Future Treatments

New dopamine agonists

New MAO-B inhibitors

COMT inhibitors

Neurotropic factors

Sterotaxic surgery (pallidotomy)

Dopamine cell transplantion

----------------------------------------------------------

 Dr. Watts next turned his attention to possible treatment
approaches in the future (Fig 4). In addition to the development
of new dopamine agonists and MAO-B inhibitors, a new class of
compounds looks very promising--the COMT inhibitors, which block
another enzyme that breaks down dopamine and thus greatly
prolong the effectiveness of L-dopa.

 Another potential therapeutic area in the treatment of
neurodegenerative diseases (including Lou Gehrig's disease and
Alzheimer's disease) involves neurotrophic--factors,
particularly brain-derived neurotrophic factor. Research is
currently underway to determine how to move this complex
molecule across the blood-brain barrier so to see if it will
help slow disease progression.

 Another advance in treatment includes stereotaxic surgery
(pallidotomy and thalamotomy) in patients with refractory
tremor. During stereotaxic surgery, a radiofrequency lesion is
created in a part of the brain that has become overactive
because of dopamine deficiencies; the lesion may permanently
stop the related tremor.

 Research in animal models and humans has shown that different
types of dopamine cells, particularly young brain cells, can be
successfully implanted in the brain, where they will make new
connections. For example, human fetal mesencephalic tissue
transplantation into the striatum of patients with idiopathic PD
and MPTP-induced parkinsonism has shown substantial long-term
functional improvement in these patients. These investigational
techniques offer promise for patients with advanced PD.

Diagnosis and Treatment of Other Movement Disorders

 During the second part of the program, Dr. Brownlee explored
other movement disorders such as kinetic/postural (essential),
intention, hysterical, drug-induced, and task-specific tremors.
Unlike parkinsonism, which is a bradykinetic disorder, these
disorders are hyperkinetic disorders.

 Essential tremor, unlike PD, affects all parts of the body,
including the larynx, and is an action tremor that occurs when
the individual is moving or holding on to something. The
rigidity, bradykinesia, and postural reflex impairment of PD is
missing.

 Essential tremor is lessened under the influence of alcohol.
Because this type of tremor does not respond to treatment with
L-dopa, differentiating the condition from PD is important.
First-line treatment includes propranolol or the anticonvulsant
agent primidone in low doses.

 Dr. Watts then presented an overview of dystonia, a syndrome
characterized by involuntary sustained or spasmodic muscle
contractions that frequently cause twisting abnormal postures,
or repetitive movements. The condition can usually be improved
by treatment with injections of botulinum A toxin. He also
reviewed tardive dyskinesia, tic disorder, and myoclonus.

 In closing, Dr. Brownlee pointed out, "In the past, treatments
for movement disorders weren't that good, so the question was,
'Is diagnosis all that important?' Now that we have a variety of
viable treatments, we have more of a mandate as primary care
physicians to correctly diagnose these conditions, since we now
can treat them more effectively."

        The Southern Medical Association acknowledges Allergan and
Sandoz Pharmaceuticals Corporation for unrestricted educational
grants in support of this symposium.


John Cottingham    johnc@xxxxxxxxx OR john.cottingham@xxxxxxxxx