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Parkinson's disease
(paralysis agitans or PD) is a neurodegenerative disease of
the substantia nigra, an area in the basal ganglia of the
brain. The disease was first recognised and its symptoms
documented in 1817 in An Essay on the Shaking Palsy by the
British physician Dr James Parkinson; the associated
biochemical changes in the brain of patients were identified
in the 1960s. Some gene defects associated with the disease
were identified only recently; others remain unknown.
The disease involves a progressive disorder of the
extrapyramidal system, which controls and adjusts
communication between neurons in the brain and muscles in
the human body. It also commonly involves depression and
disturbances of sensory systems.
Parkinson's disease is
widespread, with a prevalence estimated between 100 and 250
cases per 100,000 in North America; globally prevalence
estimates range from a low of 15 per 100,000 in China to a
high of 657 per 100,000 in Argentina. Because prevalence
rates can be affected by socio-economically driven
differences in survival, incidence is a more sensitive
indicator: rates have ranged from 1.5 per 100,000 in China
to a high of 14.8 per 100,000 in Finland. [BC Medical
Journal Volume 43, Number 3, April 2001, 133-137
Epidemiology of Parkinson’s disease Benjamin C.L. Lai, MD,
MSc, and Joseph K.C. Tsui, MD, FRCP(UK), FRCPC]
About 2% of the population
develops the disease some time during life, though the mean
age at onset is 58-60. Symptoms usually begin in the upper
extremities, and are usually unilateral (one-sided) or
asymmetrical at onset.
Parkinson's is perceived by
some to be a recent phenomenon. In researching both
religious and secular texts, descriptions of many of today's
diseases such as Alzheimers can be found in the literature
by description of their clinical symptoms. The two notable
exceptions from ancient texts are AIDs and PD. The first
literature that characterizes the symptoms of PD shows up in
the early 19th century. This leads some to believe that the
disease may result in part due to a combination of
environmental toxins due to the onset of the industrial era.
Symptoms
Parkinson disease affects
movement (motor symptoms). Typical other symptoms include
disorders of mood, behavior, thinking, and sensation
(non-motor symptoms). Individual patients' symptoms may be
quite dissimilar; progression is also distinctly individual,
presumably because the pattern of brain cell pathology is
individual.
Motor symptoms
The
cardinal symptoms are:
tremor: 4-7Hz tremor,
maximal when the limb is at rest and decreased with
voluntary movement. It is typically unilateral at onset.
This is the most apparent and well-known symptom. However,
an estimated 30% of patients have little perceptible tremor;
these are classified as akinetic-rigid.
rigidity: stiffness; increased muscle tone. In combination
with a resting tremor, this produces a ratchety, "cogwheel"
rigidity when the limb is passively moved.
bradykinesia/akinesia: respectively, slowness or absence of
movement. Rapid, repetitive movements produce a dysrhythmic
and decremental loss of amplitude.
postural instability: failure of postural reflexes, which
leads to impaired balance and falls.
(The
mnemonic TRAP (Tremor; Rigidity;
Akinesia/bradykinesia; Postural instability)
can be used to remember these symptoms.)
Other motor symptoms
include:
-
Gait
and Posture Disturbances:
- Shuffling: gait is
characterized by short steps, with feet barely leaving
the ground, producing an audible shuffling noise. Small
obstacles tend to trip the patient
- Decreased arm swing: a
form of bradykinesia
- Turning "en bloc":
rather than the usual twisting of the neck and trunk and
pivoting on the toes, PD patients keep their neck and
trunk rigid, requiring multiple small steps to
accomplish a turn.
- Stooped, forward-flexed
posture. In severe forms, the head and upper shoulders
may be bent at a
right angle relative to the trunk (camptocormia).
- Festination: a
combination of stooped posture, imbalance, and short
steps. It leads to a gait that gets progressively faster
and faster, often ending in a fall.
- Gait freezing:
"Freezing" is another word for akinesia, the inability
to move. Gait freezing is characterized by inability to
move the feet, especially in tight, cluttered spaces or
when initiating gait.
-
Dystonia:
abnormal, sustained, painful twisting muscle
contractions, usually affecting the foot and ankle in PD
patients. This causes toe flexion and foot inversion,
interfering with gait. Foot dystonia can be a presenting
symptom of PD, especially in younger patients.
- Speech and Swallowing
Disturbances
- Hypophonia: soft
speech. Speech quality tends to be soft, hoarse, and
monotonous.
- Festinating speech:
excessively rapid, soft, poorly-intelligible speech.
-
Drooling:
most likely caused by a weak, infrequent swallow and
stooped posture.
- (Non-motor causes of
speech/language disturbance in both expressive and
receptive language: these include decreased verbal
fluency and cognitive disturbance especially related to
comprehension of emotional content of speech and of
facial expression
-
Dysphagia:
impaired ability to swallow. Can lead to
aspiration,
pneumonia, and death.
- Other motor symptoms:
-
fatigue
(up to 50% of cases);
- masked facies (a
mask-like face also known as hypomimia), with infrequent
blinking;
- difficulty rolling in
bed or rising from a seated position;
-
micrographia
(small, cramped handwriting);
- impaired fine motor
dexterity and coordination;
- impaired gross motor
coordination;
- "Poverty of movement:
overall loss of accessory movements, such as decreased
arm swing when walking, as well as spontaneous movement.
Non-Motor Symptoms
Mood disturbances:
depression: occurs in 40-70%
of cases; 20% of depression cases are major depressive
disorder; severity and persistence of depression is
positively associated with executive dysfunction and
dementia;
anxiety or panic attacks
Note: 70% of individuals with parkinson's disease diagnosed
with pre-existing depression go on to develop anxiety; 90%
of Parkinson's disease patients with pre-existing anxiety
subsequently develop depression);
apathy or abulia: abulia translates from Greek as the
absence or negative of will; apathy is an absence of feeling
or desire.
Cognitive
disturbances:
slowed reaction time; both voluntary and involuntary motor
responses are significantly slowed.
executive dysfunction, characterized by difficulties in:
differential allocation of attention, impulse control, set
shifting, prioritizing, evaluating the salience of ambient
data, interpeting social cues, and subjective time
awareness. This complex is present to some degree in most
Parkinson's patients; it may progress to:
dementia: a later development in approximately 20-40% of all
patients, typically starting with slowing of thought and
progressing to difficulties with abstract thought, memory,
and behavioral regulation.
memory loss; procedural memory is more impaired than
declarative memory. Prompting elicits improved recall.
- Excessive daytime
somnolence;
- Initial, intermediate,
and terminal insomnia;
- Disturbances in REM
sleep: disturbingly vivid dreams, and REM Sleep Disorder,
characterized by acting out of dream content;
Sensation
disturbances:
slowed reaction time; both
voluntary and involuntary motor responses are significantly
slowed.
executive dysfunction, characterized by difficulties in:
differential allocation of attention, impulse control, set
shifting, prioritizing, evaluating the salience of ambient
data, interpeting social cues, and subjective time
awareness. This complex is present to some degree in most
Parkinson's patients; it may progress to:
dementia: a later development in approximately 20-40% of all
patients, typically starting with slowing of thought and
progressing to difficulties with abstract thought, memory,
and behavioral regulation.
memory loss; procedural memory is more impaired than
declarative memory. Prompting elicits improved recall.
Autonomic
disturbances:
oily skin
and seborrheic dermatitis;
urinary incontinence, typically in later disease progression
constipation and gastricdysmotility: severe enough to
endanger comfort and even health
altered sexual function: characterized by profound
impairment of sexual arousal, behavior, orgasm, and drive is
found in mid and late parkinson disease. Current data
addresses male sexual function almost exclusively.
Other notes
Symptoms usually only begin
to appear after about 80% of the dopaminergic
(dopamine-secreting) neurons located in the basal ganglia
are lost. More recent data based on PET scans suggests that
symptoms may occur when 50-60% of dopaminergic neurons are
lost. The level of dopamine will continue to fall slowly
over time, with an attendant worsening of symptoms.
It is an incapacitating disease, disturbing important human
functions and ultimately substantially reducing quality of
life. As in many neurologic diseases, psychological
complications are often extremely serious and require the
patient's family members and relatives to pay keen attention
to the emotional fragility that usually follows the
emergence of the disease; indeed, the depression which often
results is seen by many as one of the worst aspects of the
disease.
Fairly effective medication
for the movement difficulties of Parkinson disease have been
available for some time, but the neuropsychiatric aspects of
the disease, especially depression and anxiety, are more
recently characterized, less well understood, and often less
adequately treated. As patients become more disabled, they
become more dependent on care from others to perform all
manner of tasks, from eating and bathing to monitoring and
taking medication. Helping individuals with chronic
disability and psychiatric comorbidity to maintain
purposeful engagement with life takes a physical and
emotional toll on caregivers, who may consequently
experience illness and depression themselves.
Cases of PD are reported at
all ages, though it is quite rare in people younger than 30
and the average age at which symptoms begin is 58-60; the
risk of developing it substantially increases with age. It
occurs in all parts of the world, but appears to be more
common in people of European ancestry than in those of
African ancestry. Those of East Asian ancestry have an
intermediate risk. It is more common in rural than urban
areas and men are affected slightly more often than women.
Diagnosis
Differential diagnosis
The
differential diagnosis for a patient presenting with
Parkinsonian symptoms is:
Idiopathic Parkinson's
disease
Essential tremor (ET): tremor is typically associated with
posture-holding and voluntary movement, and absent at rest.
A head tremor suggests ET; a lip or chin tremor is more
typical of PD.
Parkinson plus syndromes (see below)
Secondary parkinsonism due to drugs, toxins, stroke, head
trauma, or hydrocephalus
Parkinson's tremors differ
from essential tremors in that the latter are posture or
action tremors, have bilateral tremors involving the hands,
head and voice, and are alcohol responsive. In contrast,
Parkinson's tremors are rest tremors, and usually start
unilaterally.
Imaging
SPECT with ([123I]FP-CIT) or
PET with 18F-fluorodopa are the two imaging modalities used
to assess dopamine transporter density and the integrity of
nigrostriatal pathways in the central nervous system.
Currently (2005) FP-CIT is widely used in Europe for the
diagnostic workup of Clinically Uncertain Parkinsonian
Syndromes; although it is not available in the United
States.
Related diseases
Parkinson-Plus diseases
There are other disorders
that are called
Parkinson-Plus diseases. These include:
-
Multiple System Atrophy
(MSA)
-
Shy-Drager Syndrome
(SDS)
- Striatonigral
degeneration (SND)
- Olivopontocerebellar
Atrophy (OPCA)
- Progressive
Supranuclear Palsy (PSP)
- Corticobasal
Degeneration (CBD)
Some people include Dementia
with Lewy Bodies (DLB) as one of the 'Parkinson-Plus'
syndromes. Although Idiopathic Parkinson Disease patients
also have Lewy bodies in their brain tissue, the distibution
is denser and more widespread in DLB. Even so, the
relationship between Parkinson disease, Parkinson disease
with Demnentia (PDD) and Dementia with Lewy Bodies (DLB)
might be most accurately conceptualized as a spectrum, with
a discrete area of overlap between each of the three
disorders. The natural history and role of Lewy bodies is
very little understood.
Patients often begin with
typical Parkinson's disease symptoms which persist for some
years; these Parkinson-Plus diseases can only be diagnosed
when other symptoms become apparent with the passage of
time. These Parkinson-Plus diseases usually progress more
quickly than typical ideopathic Parkinson disease. The usual
anti-Parkinson's medications are typically either less
effective or not effective at all in controlling symptoms;
patients may be exquisitely sensitive to neuroleptic
medications like haldol. Administration of such drugs is
dangerous, even lethal, Additionally, the cholinesterase
inhibiting medications have shown preliminary efficacy in
treating the cognitive, psychiatric, and behavioral aspcects
of the disease, so correct differential diagnosis is
important.
Pathology
The primary symptoms of
Parkinson's Disease are due to excessive muscle contraction.
Acetylcholine affects muscle
contraction via the five cholinergic receptors : m1, m2, m3,
m4, and m5. The receptors m1, m3 and m5 are stimulatory. The
receptors m2 and m4 are inhibitory. The combined stimulatory
effect of m1, m3 and m5 is more powerful in total than the
combined inhibitory effect of m2 and m4. So the overall
effect of acetylcholine is to stimulate muscle contraction.
Dopamine affects muscle
contraction via the five dopamine receptors : D1, D2, D3,
D4, and D5. The receptors D2, D3 and D4 are inhibitory. The
receptors D1 and D5 are stimulatory. The combined inhibitory
effect of D2, D3 and D4 is more powerful in total than the
combined stimulatory effect of D1 and D5. So the overall
effect of dopamine is to inhibit muscle contraction.
Parkinson's Disease
consequently occurs when the effect of dopamine is less than
that of acetylcholine. Dopamine deficiency rather than
acetylcholine excess is normally responsible for this
occurring.
Distribution of Neural
Degeneration in the Brain
The most striking gross
pathologic abnormality in Parkinson disease (PD) is loss of
pigmentation in an area of the midbrain called the
substantia nigra pars compacta. This depigmentation
corresponds to loss of neuromelanin-containing,
dopamine-producing neurons. In the past, most of the
symptoms of PD have been attributed to neuron loss in this
region.
Pathologic abnormalities have also been noted in other
regions of the brain. The Dutch neuropathologist Heiko Braak
has described a progressive, upward involvement of brain
structures, starting in the dorsal motor nucleus of the
vagus nerve in the brainstem, progressing over time to
involve midbrain, limbic, and finally neocortical neurons.
Based on this work, Braak and his colleagues have proposed
the following neuropathological staging system for PD:
Pre-clinical (no symptoms of
PD). Neural degeneration confined to
brainstem.
- Stage 1: Dorsal motor
nucleus of the vagus nerve
- Stage 2:
Locus ceruleus and
raphe nucleus
Clinical (symptomatic).
Progressive involvement of midbrain, limbic structures, and
cortex.
Stage 3: substantia nigra,
amygdala, basal forebrain (esp. nucleus basalis of Meynert),
ventral tegmental area, among others
Stage 4: stria terminalis, intralaminar thalamic nuclei,
insular cortex, temporal mesocortex, anterior cingulate
gyrus
Stage 5: neocortical higher-order sensory association areas
and prefrontal fields
Stage 6: first-order sensory association areas, premotor
fields, primary neocortical fields
Although there is still some
degree of controversy surrounding this staging system, the
broad areas of brain involved do seem to account for the
myriad motor and non-motor symptoms found in PD. Braak and
colleagues have embarked on the work of systematically
correlating pathologic stage of PD with clinical
manifestations. Recently, his team published work
correlating the incidence and severity of dementia with
pathologic stage of PD.[4]
The Lewy Body
Historically, the Lewy body
has been the microscopic pathologic hallmark of Parkinson
disease. Lewy bodies are found in the cytoplasm of neurons,
and are composed of densely aggregated filaments. These
filaments contain ubiquitin and alpha-synuclein.
Patients with parkin mutations (PARK2, see below) do not
have Lewy bodies. Such patients develop a syndrome that
closely resembles the sporadic form of PD; however, they
tend to develop symptoms at a much younger age. Whether the
Lewy body itself causes neurodegeneration; or whether it is
a protective response by damaged neurons is the focus of
current research.
Pathophysiology: A Complex
Interaction Between Genetics and Environment
The cause of neuron loss
Parkinson's disease is not fully understood(idiopathic).
There are, however, many theories.
Genetic
Parkinson disease (PD) is
thought to be caused by some combination of genetic and
environmental factors. Up to one third of PD cases run in
families. The rest are apparently sporadic cases.
Inheritance may be Mendelian, i.e., autosomal recessive,
autosomal dominant, or x-linked. Mitochondrial inheritance
has been postulated but not proven. Most familial cases,
however, follow no clear inheritance pattern.
An affected individual is
three to four times more likely than an unaffected
individual to have a close relative with PD. Having a first
degree relative (parent or sibling) with PD doubles or
triples an individual's risk of PD relative to the general
population.
In recent years, a number of
specific genetic mutations causing PD have been discovered.
However, these account for a minority of PD cases.
Genetic forms that have been
identified include:
Mitochondrial
DNA mutations may also play a role in PD. Dysfunction in
mitochondrial Complex I has been found in autopsy specimens
and platelets from PD patients. Certain mitochondrial DNA
haplogroups have been associated with increased
susceptibility for disease. However, no kindred has been
identified that demonstrates a clear pattern of
mitochondrial inheritance.
Toxins
One theory holds that the
disease may result in many or even most cases from the
combination of a genetically determined vulnerability to
environmental toxins along with exposure to those toxins.
This hypothesis is consistent with the fact that Parkinson's
disease is not distributed homogenously throughout the
population: rather, its incidence varies geographically. The
toxins most strongly suspected at present are certain
pesticides and industrial metals. MPTP is used as a model
for Parkinson's as it can rapidly induce parkinsonian
symptoms in human beings and other animals, of any age.
Other toxin-based models employ PCBs,paraquat (a herbicide)
in combination with maneb, a fungicide rotenone (an
insecticide), and specific organochlorine pesticides
including dieldrin and lindane. Numerous studies have found
an increase in Parkinson disease in persons who consume
rural well water; researchers theorize that water
consumption is a proxy measure of pesticide exposure. In
agreement with this hypothesis are studies which have found
a dose-dependent an increase in PD in persons exposed to
agricultural chemicals.
Almost all of the PD-causing toxins act on the mitochondrial
complex I of the electron transfer chain, and sporadic PD
cases have been found to have a partial loss of activity of
this enzyme complex. Studies in cybrids have found that
mitochondrial DNA, rather than nuclear DNA, is responsible
for the dysfunction. Most recently, microheteroplasmic
mutations in one of the mitochondrial complex I genes, ND5,
were found to be sufficient to diagnose sporadic PD
correctly in 27 out of 28 cases. While additional studies
are needed, mitochondrial microheteroplasmic mutations may
be the cause of the majority of PD cases.
However, the ubiquity of
agricultural chemical exposures makes it difficult to gauge
the true extent of the problem. In the current state of
knowledge about the origins of the disease, it appears that
family history of the disease and (especially) multiple
episodes of head-trauma-induced unconsciousness increase
individual risk more than does pesticide exposure, but
research is continuing.
Head trauma
Past episodes of head trauma
are reported more frequently by sufferers than by others in
the population.A
methodologically strong recent study [Bower 2003] found that
those who have experienced a head injury are four times more
likely to develop Parkinson’s disease than those who have
never suffered a head injury. The risk of developing
Parkinson’s increases eightfold for patients who have had
head trauma requiring hospitalization, and it increases
11-fold for patients who have experienced severe head
injury.
While emotional or psychological
trauma can precipitate the initial symptoms or aggravate
existing symptoms, this is probably not the actual cause of
the disorder. However, psychological trauma during periods
of developmental susceptibility cannot be definitely
excluded as triggers.
Other Associations
-
Prior history of an affective
disorder
Loss of dopamine-secreting
cells
The symptoms of Parkinson's
disease result from the loss of dopamine-secreting (dopaminergic)
cells and subsequent loss of melanin, secreted by the same
cells, in the pars compacta region of the substantia nigra
(literally "black substance"). These neurons project to the
striatum and their loss leads to alterations in the activity
of the neural circuits within the basal ganglia that
regulate movement, in essence an inhibition of the direct
pathway and excitation of the indirect pathway.
The direct pathway facilitates movement and the indirect
pathway inhibits movement, thus the loss of these cells
leads to a hypokinetic movement disorder. The lack of
dopamine results in increased inhibition of the ventral
lateral nucleus of the thalamus, which sends excitatory
projections to the motor cortex, thus leading to hypokinesia.
There are four major dopamine pathways in the brain; the
nigrostriatal pathway, referred to above, mediates movement
and is the most conspicuously affected in early Parkinson's
disease. The other pathways are the mesocortical, the
mesolimbic, and the tuberoinfundibular. These pathways are
associated with, respectively: volition and emotional
responsiveness; desire, initiative, and reward; and sensory
processes and maternal behavior. Disruption of dopamine
along the non-striatal pathways is the likely explantion for
much of the neuropsychiatric pathology associated with
Parkinson's disease.
Brain cells producing other brain chemicals such as GABA,
norepinephrine, serotonin and acetylcholine exhibit damage
in Parkinson's disease, accounting for some of the wide
array of symptoms. It is not known whether this damage is a
primary disease process, or secondary to loss of normal
dopaminergic stimulation.
The mechanism by which the brain cells in Parkinson's are
lost appears to center on an abnormal accumulation of the
protein alpha-synuclein bound to ubiquitin in the damaged
cells.alpha-synuclein-ubiquitin complex cannot be directed
to the proteosome. This protein accumulation forms
proteinaceous cytoplasmic inclusions called Lewy bodies.
Excessive accumulations of iron, which are toxic to nerve
cells, are also typically observed in conjunction with the
protein inclusions.
The precise mechanism whereby aggregates of alpha-synuclein
damage the cells is not known. The aggregates may be merely
a normal reaction by the cells as part of their effort to
correct a different, as-yet unknown, insult. It does appear
that alpha-synuclein aggregation is enhanced by the presence
of dopamine and the byproducts of dopamine production. Based
on this mechanistic hypothesis, a transgenic mouse model of
Parkinson's has been generated by introduction of human
wild-type α-synuclein into the mouse genome under control of
the platelet-derived-growth factor-β promoter.
Treatment
Pharmacological Treatment
The treatment of Parkinson's
disease mainly relies on replacing dopamine with levodopa
(L-DOPA) or mimicking its action with dopamine agonists such
as pramipexole, ropinirole, pergolide or bromocriptine.
Treatment of the symptoms by supplementing dopamine is not
successful due to the presence of dopa decarboxylase in the
body.
Levodopa and Polypharmic
Contributors
Levodopa was discovered as a
Parkinson's treatment by
Arvid Carlsson. L-DOPA is a dopamine precursor that is
transfomed into dopamine by dopa-decarboxylase, present in
the pre-synaptic terminals of dopaminergic neurons present
in the basal ganglia. However, only 1-5% of L-DOPA makes
it's way to this target site. The remaining 95% of the
remaining L-DOPA is converted to dopamine in the periphery
by enzymes and is rapidly absorbed into the bloodstream
where it causes side effects including nausea and dizzyiness.
L-DOPA is mostly inert. The desired effects (and side
effects) result when L-DOPA is converted to Dopamine.
Therapy
for Parkinson disease typically requires an evolving regimen
of multiple medications. Medicating to control the side
effects of other medications contributes to polypharmacy. To
treat the side effects caused by the L-DOPA in the plasma, a
drug needed to be developed to successfully inhibit the dopa
decarboxylase outside of the central nervous system. Such
drugs need to be large molecules that are hydrophillic. The
drug,
carbidopa, does this and reduces the effective dose of
L-DOPA by 75%. Together, L-DOPA is marketed with carbidopa
in one pill as Sinemet.
Naturally, L-DOPA would be
converted by catechol-o-methyltransferace (COMT) to
3-ortho-methyl-dopa which does not yield any clinical
benefits. To compliment Sinemet, Talcopone (Tasmar), was
developed. Talcopone inhibits the COMT enzyme, thereby
prolonging the effects of L-Dopa. This too has side effects.
Tolcapone has been linked to possibile of liver failure and
has been pulled from the market in Canada. It is still
available in the United States.
A similar drug, entacapone
was released in 2000 and has similar efficasy but has not
been shown to cause significant alterations of liver
function.
* Levodopa and diet
Foods rich in proteins can
reduce the uptake of levodopa, because some
amino acids compete with levodopa for cellular receptor
sites. This can usually be dealt with by offsetting
medication and meal times: consuming the majority of
required proteins towards the evening allows patients to use
dopamine medication more effectively during the morning and
mid-day when mobility is more critical.
Dopamine Agonists
Other treatments, such as
the Dopamine-agonists, bromocriptine (Parlodel), pergolide (Permax),
pramipexole (Mirapex) and ropinirole (Repip) exist and are
moderately effective. These have their own side effects
including those listed above in addition to somnolence,
hallucinations and /or insomnia. There are also some reports
of people suddenly falling asleep while on these agonists.
As a result, sinemet is the standard of current treatment.
MAO-B Inhibitor
Selegiline (Eldepryl)
appears to slow down the progression of the disease by
inhibiting monoamine oxidase-B (MAO-B), which has an
affinity for dopaminergic neurons. It also inhibits the
breakdown of dopamine secreted by the remaining 20% of
dopaminergic neurons in the basal ganglia.
Sidenotes:
- By-products of selegiline
include amphetamine and methamphetamine - each can have
side effects that kill Dopaminergic neurons, thus worsen
the clinical case.
- Use of L-DOPA in
conjunction with Selegiline has increased mortality rates
that have not been effectively explained.
Surgical Interventions
Surgical interventions are
an active area of current research, and
deep brain stimulation is presently the most popular and
effective such treatment. In the future, implantation of
cells genetically engineered to produce dopamine or stem
cells that transform into dopamine-producing cells may
become available.
Even these, however, will
not constitute cures because they do not address the
widespread loss of several different types of cells in the
brain and even for the dopamine-producing cells, do not
re-establish all of the original connections with
neighboring brain cells. A true cure will have to detect the
earliest signs of the disorder before they cause important
symptoms and will intervene in the process that damages the
brain cells in the first place.
Dopamine deficiency is
central, but deficits of serotonin, norepinephrine, and
acetylcholine are also typical. The depression and anxiety
states that predominate when serotonin and norepinephrine
are deficient are often treated with selective serotonine
reuptake inhibitors (SSRIs) like Paxil, Zoloft, or Celexa;
there is emerging evidence that the SSNRI (selective
serotonin and norepinephrine reuptake inhibitor) Effexor may
be particularly effective in Parkinson's disease because it
augments two deficient neurotransmitters. Amphetimine-like
drugs (Ritalin, Concerta) are being prescribed with
increasing frequency to treat the Attention Deficit Disorder
(ADD)-like attention problems that are almost universal in
Parkinson's disease. Finally, there is emerging evidence to
suggest that drugs that inhibit the reuptake of
acetylcholine, developed as treatments for Alzheimer's
dementia, may also improve memory and executive function in
Parkinson's disease.
The patient and physicians
are confronted with the behavioral and cognitive
consequences of disruptions in at least five
neurotransmitters; in addition to the four above, GABA is
also disrupted. The inevitable cost, risk, and sheer
unpleasantness of such complex medication regimens drives
both doctors and patients to advocate for better and more
comprehensive therapies.
The best evidence is that
analytic and synthetic reasoning are relatively spared, even
in advancing Parkinson's disease. However, the evidence that
executive function impairment begins early and is
progressive is growing rapidly. Coupled with the observation
that more than 70 percent of Parkinson disease patients meet
the criteria for at least one psychiatric diagnosis (most
commonly anxiety or depression, with apathy also
significant), the picture that emerges is one of
considerable neuropsychological disability in individuals
with preserved reasoning and awareness.
Because reasoning and
awareness are operative, most patients can and should
participate in their own care. This is correct from a legal
and moral perspective of respect for the dignity and
autonomy of individual patients, but it is also good medical
practice. The formation of a "therapeutic alliance" between
the patient and the physician ensures the optimal exchange
of information, and amplifies the effectiveness of medical
interventions.
The liberty to exercise
preferences, even in regard to seemingly trivial details,
has been shown to preserve the intellectual and emotional
integrity of very physically compromised individuals.
Patients have both a legal and a moral right to participate
in their own care to the fullest extent possible.
The cumulative prevalence of
dementia (substantially disabling defects in memory and
reasoning) in Parkinson disease is still being debated, but
the estimates range from 40 to 80 percent; more careful
analysis seems to support the higher estimates. . With this
fact in mind, patients, families, caregivers and medical
personnel should work together to outline clear and
pragmatically possible ways to preserve the dignity and
choices of patients even when they cannot speak clearly for
themselves.
Dietary
Nutrients have been used in
clinical studies and are widely used by people with
Parkinson's Disease in order to partially treat Parkinson's
Disease or slow down its deterioration. The L-dopa precursor
L-tyrosine was shown to relieve an average of 70% of
symptoms.
Ferrous iron, the essential cofactor for L-dopa biosynthesis
was shown to relieve between 10% and 60% of symptoms in 110
out of 110 patients. More limited
efficacy has been obtained with the use of THFA, NADH, and
pyridoxine - coenzymes and coenzyme precursors involved in
dopamine biosynthesis. Vitamin C and Vitamin E in large
doses are commonly used by patients in order to lessen the
cell damage that occurs in Parkinson's Disease. This is
because the enzymes Superoxide Dismutase and Catalase
require these vitamins in order to nullify the superoxide
anion, a toxin commonly produced in damaged cells. Coenzyme
Q10 has more recently been used for similar reasons.
Other
Regular physical exercise
and/or therapy are beneficial to the patient and essential
for maintaining and improving mobility, flexibility, balance
and a range of motion, and for a better resistance against
many of the secondary symptoms and side effects. There is
increasing evidence that exercise is both neuroprotective
against the development of Parkinson's disease, and also
ameliorative of both severity of symptoms, and also possibly
of progression. "Alternative" exercise modalities such as
yoga, tai chi, and dance may also hold promise as
rehabilitation therapies, due to their integration of
movement, thought, feeling, and sensory experience. Exercise
has also been shown to effectively improve mild-moderate/
depression,
Secondary parkinsonism
Secondary parkinsonism
(or briefly parkinsonism)
is a term used for a symptom
constellation that is similar to that of Parkinson's disease
but is caused by other disorders or medications. Major
reasons for secondary parkinsonism are stroke, encephalitis,
narcotics, toxins such as manganese or carbon monoxide
poisoning, traumatic brain injury, and normal pressure
hydrocephalus.
There are other idiopathic (of unknown cause) conditions as
Parkinson's disease that may cause parkinsonism. In these
conditions the problem is not the deficient production of
dopamine but the inefficient binding of dopamine to its
receptors located on globus pallidus.
Prognosis
Most older studies have
noted increased mortality in patients with Parkinson disease
(PD). However, the 2005 Rotterdam Study, which prospectively
followed a large cohort of participants, noted only a modest
decrease in survival in patients without dementia. A 2004
community-based cohort study of 245 PD patients demonstrated
similar findings in patients with clinically definite PD.
The most commonly reported cause of death in PD patients is
pneumonia. Swallowing difficulties may lead to aspiration of
food, causing aspiration pneumonia (a specific form of
pneumonia caused by gastric acid, food and digestive tract
bacteria). A weak cough secondary to respiratory muscle
stiffness may increase susceptibility to infection.
Onset of dementia doubles
the odds of death. Depression more than doubles the odds
ratio.[30]
However, people may live for 20 to 30 years with the
condition.
Notable Parkinson's
sufferers
One famous sufferer of
young-onset Parkinson's is Michael J. Fox, who has written a
book about his experience of the disease. The film
Awakenings (starring Robin Williams and Robert De Niro and
based on genuine cases reported by Oliver Sacks) deals
sensitively and largely accurately with a similar disease,
postencephalitic parkinsonism; the state of the art in
treatment remains roughly the same as it was at the time of
the events depicted, the 1960s, although patients with
postencephalitic parkinsonism lose benefit from their
medication far faster than do patients with Parkinson's
disease. Other famous sufferers include Pope John Paul II,
former US Attorney General Janet Reno, boxer Mohammad Ali,
and, allegedly, dictator Adolf Hitler.
Young Onset Parkinson's
Disease
Parkinson’s disease also
affects young people. Anyone affected before the age of 40
is diagnosed with Young Onset Parkinson’s Disease, more
commonly known as YOPD. A common face of YOPD is Michael J.
Fox. He was diagnosed in his young thirties and has become
an advocate for Parkinson’s research. Although YOPD is rarer
than adult Parkinson’s disease, it still affects about 50
thousand Americans. This makes up about 20% of all
Parkinson’s cases.
The cause is also unknown,
like that of PD. Since there is no cure for PD and it is
inevitably progressive, medications simply decrease the
effects. The symptoms remain the same as adult PD, but
simply allow more progression since the life span is longer.
Key features for diagnosis are stiffness, rest tremor,
slowness of movements, difficulty with dexterity, and
walking or balance problems. Tremors or the drag of a foot
are usually the first signals of symptoms. Some episodes
involve the extremities, while others involve the entire
body. It is similar to watching someone have a seizure.
There is nothing to be done during this time, other than
letting nature take its course. These incidents are more
likely to occur while the person is at rest and rarely occur
during an active part of the day unless the individual is
under a significant amount of stress. Also, another signal
that is associated with YOPD is very freezing of the body.
This is usually triggered by the person’s thought of
changing stride while walking. This tends to be more common
in individuals who have advanced stages of the disease.
Rigidity of the limbs becomes an increasing problem as the
disease carries on. Problems swallowing also affect many
patients.
As cells degenerate, the
production of dopamine is put off balance. Patients are
often described as “short circuiting.” Symptoms don’t
usually occur until at least 60% of the cells have died off.
This means that the disease has been damaging the patient’s
mind for years before they have any idea. Replacement of the
dopamine becomes less and less effective, because the cells
are continually dying off. Many factors many contribute to
the likelihood of acquiring this disease.
Some of which include living
in rural areas where pesticides are used, drinking well
water, along with genetics. There is a problem of common
misdiagnoses due to the young age. Symptoms will continue to
persist if the diagnosis is incorrect. There is a broad
spectrum of severity of this disease. Patients can
constantly be plagued with spasms and shaking, while others
symptoms are less noticeable. Young patients usually respond
very quickly to medication treatments. There will be a
period that the patient will be almost back to normal due to
treatment. However, young patients develop complications of
treatment more quickly. These fluctuations sometimes cause a
wiggling movement while the patient is sitting down. This
occurs about a year or two after the treatment has been
instituted. Missing doses will catch up to the patient very
quickly. They will soon notice their muscles tightening and
a slowing of their body. There is a fine line from the time
where the medication allows the body to move normally, to
when the effects become shorter and cause too much movement
in the body. This is when the body will be in constant,
uncontrollable motions. Some patients don’t respond well to
drug therapy. For these patients, surgery has become an
option. A small hole is drilled in the skull and part of the
thalamus is frozen. This causes the tremors to be more
controllable. This does not mean that the disease is under
control, but simply that one symptom is temporarily
suppressed.
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