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Parkinsons Disease
Definition:
Parkinson's disease is a progressive disorder of the nervous system that affects
movement. It develops gradually, sometimes starting with a barely noticeable tremor in
just one hand. But while a tremor may be the most well-known sign of Parkinson's
disease, the disorder also commonly causes stiffness or slowing of movement.
In the early stages of Parkinson's disease, your face may show little or no
expression, or your arms may not swing when you walk. Your speech may become soft
or slurred. Parkinson's disease symptoms worsen as your condition progresses over
time. As symptoms get worse, people with the disease may have trouble walking,
talking, or doing simple tasks. They may also have problems such as depression, sleep
problems, or trouble chewing, swallowing, or speaking.
There is no lab test for PD, so it can be difficult to diagnose. Doctors use a
medical history and a neurological examination to diagnose it.
PD usually begins around age 60, but it can start earlier. It is more common in
men than in women. There is no cure for PD. A variety of medicines sometimes help
symptoms dramatically. Surgery and deep brain stimulation (DBS) can help severe
cases. With DBS, electrodes are surgically implanted in the brain. They send electrical
pulses to stimulate the parts of the brain that control movement.
Pathophysiology:

Parkinsons disease is primarily associated with the gradual loss of cells in the
substantia nigra of the brain. This area is responsible for the production of dopamine.
Dopamine is a chemical messenger that transmits signals between two regions of the
brain to coordinate activity. For example, it connects the substantia nigra and the corpus
striatum to regulate muscle activity.
If there is deficiency of dopamine in the striatum the nerve cells in this region
fire out of control. This leaves the individual unable to direct or control movements.
This leads to the initial symptoms of Parkinsons disease. As the disease progresses,
other areas of the brain and nervous system degenerate as well causing a more
profound movement disorder.
The exact cause for the loss of cells is unknown. Possible causes include both
genetic and environmental factors.
Genetic factors that raise the risk of Parkinsons disease
Certain genes have been found that may be associated with Parkinsons disease.
At least 15-20% of Parkinsons disease patients have a close relative who has
parkinsonian symptoms. There may be more than one genetic factor in causation of
Parkinsons disease. In addition genetic factors may be combined with environmental
factors as well.
Parkinsons is seen at an early age in individuals with mutations in genes for
parkin, PINK1, LRRK2, DJ-1, and glucocerebrosidase, among others. So far at least
nine genetic mutations have been identified as increasing a persons risk of developing
Parkinsons disease.
The National Human Genome Research Institute (NHGRI) and the National
Institute of Neurological Disorders and Stroke (NINDS) pinpointed a gene on
chromosome 4 called the alpha synculein gene that is associated with Parkinsons in
some families. This mutated or changed gene however, may account for only a small
proportion of the total number of Parkinsons disease cases but is associated with a
significant proportion of familial Parkinsons disease with an onset before the age of 60.
Alpha-synculein is the main component of Lewy bodies, which are found in cells
of all patients with Parkinson's disease. In patients with a mutated gene for alpha
synculein an altered protein product is formed. This protein accumulates in the cell and
attracts other proteins in order to form a deposit which leads to the damage of the
neuron.
Free radicals
These are unstable molecules produced during normal chemical reactions in the
body. When they interact with other molecules they have the ability to damage tissues
like neurons.
Aging
With age there is a normal decline of the dopamine producing neurons, which
leads to the premature loss of dopamine.
Environmental toxins
Several toxins like illegal drugs contaminated with a chemical called MPTP may
cause severe Parkinson-like symptoms. It was found that once MPTP crossed into the
brain it started killing brain cells.

Possible toxins could include pesticides and herbicides used in farming, toxins
released by industrial plants and air pollution related to road traffic.
]
Alpha-synculein is the main component of Lewy bodies, which are found in cells of all
patients with Parkinson's disease. In patients with a mutated gene for alpha synculein an
altered protein product is formed. This protein accumulates in the cell and attracts other
proteins in order to form a deposit which leads to the damage of the neuron.

Free radicals
These are unstable molecules produced during normal chemical reactions in the body. When
they interact with other molecules they have the ability to damage tissues like neurons.

Aging
With age there is a normal decline of the dopamine producing neurons, which leads to the
premature loss of dopamine.

Environmental toxins
Several toxins like illegal drugs contaminated with a chemical called MPTP may cause severe
Parkinson-like symptoms. It was found that once MPTP crossed into the brain it started
killing brain cells.
Possible toxins could include pesticides and herbicides used in farming, toxins released by
industrial plants and air pollution related to road traffic.

Management:
The goal of medical management of Parkinson disease is to provide control of signs
and symptoms for as long as possible while minimizing adverse effects. Studies
demonstrate that a patient's quality of life deteriorates quickly if treatment is not
instituted at or shortly after diagnosis.
Symptomatic and neuroprotective therapy
Pharmacologic treatment of Parkinson disease can be divided into symptomatic and
neuroprotective (disease modifying) therapy. At this time, there is no proven
neuroprotective or disease-modifying therapy.
Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI), remains
the gold standard of symptomatic treatment for Parkinson disease. Carbidopa inhibits
the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for
greater levodopa distribution into the central nervous system. Levodopa provides the
greatest antiparkinsonian benefit for motor signs and symptoms, with the fewest
adverse effects in the short term; however, its long-term use is associated with the
development of motor fluctuations (wearing-off) and dyskinesias. Once fluctuations
and dyskinesias become problematic, they are difficult to resolve.

Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment of early
disease. These drugs provide mild symptomatic benefit, have excellent adverse effect
profiles, and, according to a Cochrane review, have improved long-term outcomes in
quality-of-life indicators by 20-25%.
Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic benefit and
delay the development of dyskinesia compared with levodopa. Proactively screen
patients receiving oral dopamine agonists for adverse events. A review of the Cochrane
and PubMed databases from 1990 to 2008 found that these agents caused a 15%
increase in adverse events such as somnolence, sudden-onset sleep, hallucinations,
edema, and impulse control disorders (eg, pathologic gambling, shopping, and Internet
use; hypersexuality; and hoarding). Note that patients may be reluctant to mention these
events or may not attribute them to their treatment.
Symptomatic anti-Parkinson disease medications usually provide good control of motor
signs of Parkinson disease for 4-6 years. After this, disability often progresses despite
best medical management, and many patients develop long-term motor complications,
including fluctuations and dyskinesias. Additional causes of disability in late disease
include postural instability (balance difficulty) and dementia. Thus, symptomatic therapy
for late disease requires different strategies.
Neuroprotective therapy aims to slow, block, or reverse disease progression; such
therapies are defined as those that slow underlying loss of dopamine neurons. Although
no therapy has been proven to be neuroprotective, there remains interest in the longterm effects of MAO-B inhibitors. Other agents currently under investigation include
creatine and isradipine.
The younger the patient, the more emphasis the authors place on long-term
considerations to guide early treatment. Young patients have a longer life expectancy
and are more likely to develop motor fluctuations and dyskinesias. For older patients
and those with cognitive impairment, less emphasis is placed on long-term
considerations; instead, the focus is on providing adequate symptomatic benefit in the
near term, with as few adverse effects as possible.
For patients who have motor fluctuations and dyskinesias that cannot be adequately
managed with medication manipulation, surgery is considered. The principal surgical
option is deep brain stimulation (DBS), which has largely replaced neuroablative lesion
surgeries. Levodopa/carbidopa intestinal gel infusion is available in some countries and
is in clinical trials in others, including the United States.
Nonmotor symptoms
It is now recognized that in Parkinson disease, nonmotor symptoms may be as
troublesome as, or more troublesome than, motor symptoms. Nonmotor symptoms can
be categorized as autonomic, cognitive/psychiatric, and sensory and may include
depression, dementia, hallucinations, rapid eye movement (REM) sleep behavior
disorder (RMD), orthostatic hypotension, and constipation. Nonmotor symptoms can
also fluctuate, especially depression, pain, numbness, paresthesia/dysesthesia,
akathisia, and restless-legs syndrome. Recognition of nonmotor symptoms of Parkinson
disease is essential for appropriate management.

Screen Parkinson disease patients for depression, and treat it when present. An
evidence-based guideline from the American Academy of Neurology (AAN) reports that
physician recognition of depression is low in Parkinson disease, at less than 30% of
clinically proven cases. There are many factors that confound its diagnosis in these
patients; and depression has the single largest effect on the quality of life of patients
with Parkinson disease.
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of
Parkinson disease. Recommendations included the following :

Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction

Polyethylene glycol may be considered to treat constipation
Modafinil should be considered for patients who subjectively experience
excessive daytime somnolence
For insomnia, evidence is insufficient to support or refute the use of levodopa to
improve objective sleep parameters that are not affected by motor symptoms;
evidence is also insufficient to support or refute the use of melatonin for poor sleep
quality
Levodopa/carbidopa should be considered to treat periodic limb movements of
sleep in Parkinson disease, but there are insufficient data to support or refute the use
of nonergot dopamine agonists to treat this condition or that of restless-legs syndrome
Methylphenidate may be considered for fatigue (note: methylphenidate has the
potential for abuse and addiction)
Evidence is insufficient to support or refute specific treatments of orthostatic
hypotension, urinary incontinence, anxiety, and RMD