What is myasthenia gravis?

Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by varying degrees ofweakness of
the skeletal (voluntary) muscles of the body. The name myasthenia gravis, which is Latin and Greek in origin, literally
means "grave muscle weakness." With current therapies, however, most cases of myasthenia gravis are not as "grave"
as the name implies. In fact, for the majority of individuals with myasthenia gravis, life expectancy is not lessened by the
disorder.

The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after
periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing,
talking, and swallowing are often, but not always, involved in the disorder. The muscles that control breathing and neck
and limb movements may also be affected.

What causes myasthenia gravis?

Myasthenia gravis is caused by a defect in the transmission of nerve impulses to muscles. It occurs when normal
communication between the nerve and muscle is interrupted at the neuromuscular junction - the place where nerve cells
connect with the muscles they control. Normally when impulses travel down the nerve, the nerve endings release a
neurotransmitter substance called acetylcholine. Acetylcholine travels through the neuromuscular junction and binds to
acetylcholine receptors which are activated and generate a muscle contraction.

In myasthenia gravis, antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction
which prevents the muscle contraction from occurring. These antibodies are produced by the body's own immune
system. Thus, myasthenia gravis is an autoimmune disease because the immune system - which normally protects the
body from foreign organisms - mistakenly attacks itself.

What is the role of the thymus gland in myasthenia gravis?

The thymus gland, which lies in the upper chest area beneath the breastbone, plays an important role in the
development of the immune system in early life. Its cells form a part of the body's normal immune system. The gland is
somewhat large in infants, grows gradually until puberty, and then gets smaller and is replaced by fat with age. In adults
with myasthenia gravis, the thymus gland is abnormal. It contains certain clusters of immune cells indicative of lymphoid
hyperplasia - a condition usually found only in the spleen and lymph nodes during an active immune response. Some
individuals with myasthenia gravis develop thymomas or tumors of the thymus gland. Generally thymomas are benign,
but they can become malignant.

The relationship between the thymus gland and myasthenia gravis is not yet fully understood. Scientists believe the
thymus gland may give incorrect instructions to developing immune cells, ultimately resulting in autoimmunity and the
production of the acetylcholine receptor antibodies, thereby setting the stage for the attack on neuromuscular
transmission.

What are the symptoms of myasthenia gravis?

Although myasthenia gravis may affect any voluntary muscle, muscles that control eye and eyelid movement, facial
expression, and swallowing are most frequently affected. The onset of the disorder may be sudden. Symptoms often
are not immediately recognized as myasthenia gravis.

In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and
slurred speech may be the first signs. The degree of muscle weakness involved in myasthenia gravis varies greatly
among patients, ranging from a localized form, limited to eye muscles (ocular myasthenia), to a severe or generalized
form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in
type and severity, may include a drooping of one or both eyelids (ptosis), blurred or double vision (diplopia) due to
weakness of the muscles that control eye movements, unstable or waddling gait, weakness in arms, hands, fingers,
legs, and neck, a change in facial expression, difficulty in swallowing andshortness of breath, and impaired speech
(dysarthria).

Who gets myasthenia gravis?

Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects young adult women (under
40) and older men (over 60), but it can occur at any age.

In neonatal myasthenia, the fetus may acquire immune proteins (antibodies) from a mother affected with myasthenia
gravis. Generally, cases of neonatal myasthenia gravis are transient (temporary) and the child's symptoms usually
disappear within 2-3 months after birth. Other children develop myasthenia gravis indistinguishable from adults.
Myasthenia gravis in juveniles is common.

Myasthenia gravis is not directly inherited nor is it contagious. Occasionally, the disease may occur in more than one
member of the same family.

Rarely, children may show signs of congenital myasthenia or congenital myasthenic syndrome. These are not
autoimmune disorders, but are caused by defective genes that produce proteins in the acetylcholine receptor or in
acetylcholinesterase.

How is myasthenia gravis diagnosed?

Unfortunately, a delay in diagnosis of one or two years is not unusual in cases of myasthenia gravis. Because weakness
is a common symptom of many other disorders, the diagnosis is often missed in people who experience mild weakness
or in those individuals whose weakness is restricted to only a few muscles.

The first steps of diagnosing myasthenia gravis include a review of the individual's medical history, and physical and
neurological examinations. The signs a physician must look for are impairment of eye movements or muscle weakness
without any changes in the individual's ability to feel things. If the doctor suspects myasthenia gravis, several tests are
available to confirm the diagnosis.

A special blood test can detect the presence of immune molecules or acetylcholine receptor antibodies. Most patients
with myasthenia gravis have abnormally elevated levels of these antibodies. However, antibodies may not be detected
in patients with only ocular forms of the disease.

Another test is called the edrophonium test. This approach requires the intravenous administration of edrophonium
chloride or Tensilon(r), a drug that blocks the degradation (breakdown) of acetylcholine and temporarily increases the
levels of acetylcholine at the neuromuscular junction. In people with myasthenia gravis involving the eye muscles,
edrophonium chloride will briefly relieve weakness. Other methods to confirm the diagnosis include a version of nerve
conduction study which tests for specific muscle "fatigue" by repetitive nerve stimulation. This test records weakening
muscle responses when the nerves are repetitively stimulated. Repetitive stimulation of a nerve during a nerve
conduction study may demonstrate decrements of the muscle action potential due to impaired nerve-to-muscle
transmission.

A different test called single fiber electromyography (EMG), in which single muscle fibers are stimulated by electrical
impulses, can also detect impaired nerve-to-muscle transmission. EMG measures the electrical potential of muscle
cells. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated
electrical stimulation compared to muscles from normal individuals.Computed tomography (CT) may be used to identify
an abnormal thymus gland or the presence of a thymoma.

A special examination called pulmonary function testing - which measures breathing strength - helps to predict whether
respiration may fail and lead to a myasthenic crisis.

How is myasthenia gravis treated?

Today, myasthenia gravis can be controlled. There are several therapies available to help reduce and improve muscle
weakness. Medications used to treat the disorder include anticholinesterase agents such
asneostigmine and pyridostigmine, which help improve neuromuscular transmission and increase muscle strength.
Immunosuppressive drugs such asprednisone, cyclosporine, and azathioprinemay also be used. These medications
improve muscle strength by suppressing the production of abnormal antibodies. They must be used with careful medical
followup because they may cause major side effects.

Thymectomy, the surgical removal of the thymus gland (which often is abnormal in myasthenia gravis patients), reduces
symptoms in more than 70 percent of patients without thymoma and may cure some individuals, possibly by re-
balancing the immune system. Other therapies used to treat myasthenia gravis include plasmapheresis, a procedure in
which abnormal antibodies are removed from the blood, and high-dose intravenous immune globulin, which temporarily
modifies the immune system and provides the body with normal antibodies from donated blood. These therapies may
be used to help individuals during especially difficult periods of weakness. A neurologist will determine which treatment
option is best for each individual depending on the severity of the weakness, which muscles are affected, and the
individual's age and other associated medical problems.

What are myasthenic crises?

A myasthenic crisis occurs when the muscles that control breathing weaken to the point that ventilation is inadequate,
creating a medical emergency and requiring a respirator for assisted ventilation. In patients whose respiratory muscles
are weak, crises - which generally call for immediate medical attention - may be triggered by infection, fever, or an
adverse reaction to medication.

What is the prognosis?

With treatment, the outlook for most patients with myasthenia gravis is bright: they will have significant improvement of
their muscle weakness and they can expect to lead normal or nearly normal lives. Some cases of myasthenia gravis
may go into remission temporarily and muscle weakness may disappear completely so that medications can be
discontinued. Stable, long-lasting complete remissions are the goal of thymectomy. In a few cases, the severe
weakness of myasthenia gravis may cause a crisis (respiratory failure), which requires immediate emergency medical
care. (see above).

What research is being done?

Within the Federal Government, the National Institute of Neurological Disorders and Stroke (NINDS), one of the Federal
Government's National Institutes of Health (NIH), has primary responsibility for conducting and supporting research on
myasthenia gravis.

Much has been learned about myasthenia gravis in recent years. Technological advances have led to more timely and
accurate diagnosis, and new and enhanced therapies have improved management of the disorder. Much knowledge
has been gained about the structure and function of the neuromuscular junction, the fundamental aspects of the thymus
gland and of autoimmunity, and the disorder itself. Despite these advances, however, there is still much to learn. The
ultimate goal of myasthenia gravis research is to increase scientific understanding of the disorder. Researchers are
seeking to learn what causes the autoimmune response in myasthenia gravis, and to better define the relationship
between the thymus gland and myasthenia gravis.

Today's myasthenia gravis research includes a broad spectrum of studies conducted and supported by NINDS. NINDS
scientists are evaluating new and improving current treatments for the disorder. One such study is testing the efficacy of
intravenous immune globlin in patients with myasthenia gravis. The goal of the study is to determine whether this
treatment safely improves muscle strength. Another study seeks further understanding of the molecular basis of
synaptic transmission in the nervous system. The objective of this study is to expand current knowledge of the function
of receptors and to apply this knowledge to the treatment of myasthenia gravis.

Pathophysiology

A juvenile thymus. It shrinks with age.

Myasthenia gravis is an autoimmune channelopathy: it features antibodies directed against the body's own proteins.
While various similar diseases have been linked to immunologic cross-reaction with an infective agent, there is no
known causative pathogen that could account for myasthenia. There is a slight genetic predisposition:
particular HLA types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to
75% of patients have an abnormality of the thymus; 25% have a thymoma, a tumor (either benign or malignant) of the
thymus, and other abnormalities are frequently found. The disease process generally remains stationary after
thymectomy (removal of the thymus).

The acetylcholine receptor.

In MG, the auto-antibodies most commonly against the nicotinic acetylcholine receptor(nAChR),[6] the receptor in
the motor end plate for the neurotransmitter acetylcholine that stimulates muscular contractions. Some forms of the
antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors, either
by complement fixation or by inducing the muscle cell to eliminate the receptors through endocytosis.

The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into plasma cells by T-helper cell
stimulation. In order to carry out this activation, T-helpers must first be activated themselves, which is done by binding of
the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment (epitope) resting within the major
histocompatibility complex of an antigen presenting cells. Since the thymus plays an important role in the development
of T-cells and the selection of TCR myasthenia gravis is closely associated with thymoma . The exact mechanisms are
however not convincingly clarified although resection of the thymus (thymectomy) in MG patients without a thymus
neoplasm often have positive results.

In normal muscle contraction, cumulative activation of the nAChR leads to influx of sodium ions which in turn causes the
depolarization of muscle cell and subsequent opening of voltage gated sodium channels. This ion influx then travels
down the cell membranes via T-tubules and, via calcium channel complexes leads to the release of calcium from
the sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are high enough will it contract.
Decreased numbers of functioning nAChRs therefore impairs muscular contraction by limiting depolarization. In fact,
MG causes the motor neuron action potential to muscular twitch ratio to vary from the non-pathological one to one ratio.
It has recently been realized that a second category of gravis is due to auto-antibodies against the MuSK
protein (muscle specific kinase), atyrosine kinase receptor which is required for the formation of the neuromuscular
junction. Antibodies against MuSK inhibit the signaling of MuSK normally induced by its nerve-derived ligand, agrin. The
result is a decrease in patency of the neuromuscular junction, and the consequent symptoms of MG.

People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of MG, but
both the symptoms and the titer disappear when drug administration is discontinued.

MG is more common in families with other autoimmune diseases. A familial predisposition is found in 5% of the cases.
This is associated with certain genetic variations such as an increased frequency of HLA-B8 and DR3. People with MG
suffer from co-existing autoimmune diseases at a higher frequency than members of the general population. Of
particular mention is co-existing thyroid disease where episodes of hypothyroidism may precipitate a severe
exacerbation.

The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research in which might eventually lead to
new treatment options.[7]

Diagnosis

Myasthenia can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both normal
variants and other neurological disorders.[4] A thorough physical examination can reveal easy fatiguability, with the
weakness improving after rest and worsening again on repeat of the exertion testing. Applying ice to weak muscle
groups characteristically leads to improvement in strength of those muscles. Additional tests are often performed, as
mentioned below. Furthermore, a good response to medication can also be considered a sign of autoimmune
pathology.

[edit]Physical examination

Muscle fatigability can be tested for many muscles.[11] A thorough investigation includes:

 looking upward and sidewards for 30 seconds: ptosis and diplopia.

 looking at the feet while lying on the back for 60 seconds
 keeping the arms stretched forward for 60 seconds
 10 deep knee bends
 walking 30 steps on both the toes and the heels
 5 situps, lying down and sitting up completely
 "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds)
start to separate and the sclera starts to show[4]

[edit]Blood tests

If the diagnosis is suspected, serology can be performed in a blood test to identify certain antibodies:
 One test is for antibodies against the acetylcholine receptor.[4] The test has a
reasonable sensitivity of 80–96%, but in MG limited to the eye muscles (ocular myasthenia) the test may be negative in
up to 50% of the cases.

 A proportion of the patients without antibodies against the acetylcholine receptor have antibodies
against the MuSK protein.[12]

 In specific situations (decreased reflexes which increase on facilitation, co-existing autonomic

features, suspected presence of neoplasm, especially of the lung, presence of increment or facilitation on repetitive
EMG testing) testing is performed for Lambert-Eaton syndrome, in which other antibodies (against a voltage-
gated calcium channel) can be found.

[edit]Neurophysiology

Muscle fibers of patients with MG are easily fatigued, and thus do not respond as well as muscles in healthy individuals
to repeated stimulation. By repeatedly stimulating a muscle with electrical impulses, the fatiguability of the muscle can
be measured. This is called the repetitive nerve stimulation test. In single fiber electromyography, which is considered to
be the most sensitive (although not the most specific) test for MG,[4] a thin needle electrode is inserted into a muscle to
record the electric potentials of individual muscle fibers. By finding two muscle fibers belonging to the same motor unit
and measuring the temporal variability in their firing patterns (i.e. their 'jitter'), the diagnosis can be made.

[edit]Edrophonium test

Photograph of a patient showing right partial ptosis (left picture). The left lid shows compensatory pseudo lid retraction
because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation). Right picture: after
an edrophonium test, note the improvement in ptosis.

The "edrophonium test" is infrequently performed to identify MG; its application is limited to the situation when other
investigations do not yield a conclusive diagnosis. This test requires theintravenous administration of edrophonium
chloride (Tensilon, Reversol) or neostigmine (Prostigmin), drugs that block the breakdown of acetylcholine
by cholinesterase (cholinesterase inhibitors) and temporarily increases the levels of acetylcholine at the neuromuscular
junction. In people with myasthenia gravis involving the eye muscles, edrophonium chloride will briefly relieve
weakness.[13]

[edit]Imaging

A chest CT-scan showing a thymoma (red circle).

A chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton syndrome due to
a lung tumor) and comorbidity. It may also identify widening of themediastinum suggestive of thymoma, but computed
tomography (CT) or magnetic resonance imaging (MRI) are more sensitive ways to identify thymomas, and are
generally done for this reason.[14]
[edit]Pulmonary function test

Spirometry (lung function testing) may be performed for the assessing of respiratory function if there are concerns about
a patient's ability to breathe adequately. The forced vital capacity may be monitored at intervals in order not to miss a
gradual worsening of muscular weakness. Acutely,negative inspiratory force (NIF) may be used to determine adequacy
of ventilation. Severe myasthenia may cause respiratory failure due to exhaustion of the respiratory muscles.[15]

[edit]Pathological findings

Muscle biopsy is only performed if the diagnosis is in doubt and a muscular condition is
suspected. Immunofluorescence shows IgGantibodies on the neuromuscular junction. (Note that it is not the antibody
which causes myasthenia gravis that fluoresces, but rather asecondary antibody directed against it.) Muscle electron
microscopy shows receptor infolding and loss of the tips of the folds, together with widening of the synaptic clefts. Both
these techniques are currently used for research rather than diagnostically.[7]

Treatment

Treatment is by medication and/or surgery. Medication consists mainly of cholinesterase inhibitors to directly improve
muscle function andimmunosuppressant drugs to reduce the autoimmune process. Thymectomy is a surgical method to
treat MG. For emergency treatment,plasmapheresis or IVIG can be used as a temporary measure to remove antibodies
from the blood circulation.

[edit]Medication

Neostigmine, chemical structure.

 Acetylcholinesterase inhibitors: neostigmine and pyridostigmine can improve muscle function by

slowing the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is
therefore around longer to stimulate its receptor. Usually doctors will start with a low dose, e.g. 3x20mg pyridostigmine,
and increase until the desired result is achieved. If taken 30 minutes before a meal, symptoms will be mild during eating.
Side effects, like perspiration and diarrhea can be countered by addingatropine. Pyridostigmine is a short-lived drug with
a half-life of about 4 hours.


Azathioprine, chemical structure.

 Immunosuppressive drugs: prednisone, cyclosporine, mycophenolate mofetil and azathioprine may

be used. It is common for patients to be treated with a combination of these drugs with a cholinesterase inhibitor.
Treatments with some immunosuppressives take weeks to months before effects are noticed. Other immunomodulating
substances, such as drugs that prevent acetylcholine receptor modulation by the immune system, are currently being
researched.[16]

[edit]Plasmapheresis and IVIG

If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the putative antibody from the
circulation. Also, Intravenous immunoglobulins (IVIG) can be used to bind the circulating antibodies. Both of these
treatments have relatively short-lived benefits, typically measured in weeks.[17]

[edit]Surgery
Main article: thymectomy

Thymectomy, the surgical removal of the thymus, is essential in cases of thymoma in view of the potential neoplastic
effects of the tumor. However, the procedure is more controversial in patients who do not show thymic abnormalities.
Although some of these patients improve following thymectomy, some patients experience severe exacerbations and
the highly controversial concept of "therapeutic thymectomy" for patients with thymus hyperplasia is disputed by many
experts and efforts are underway to unequivocally answer this important question.

There are a number of surgical approaches to the removal of the thymus gland: transsternal (through the sternum, or
breast bone), transcervical (through a small neck incision), and transthoracic (through one or both sides of the chest).
The transsternal approach is most common and uses the same length-wise incision through the sternum (breast
bone)used for most open-heart surgery. The transcervical approach is a less invasive procedure that allows for removal
of the entire thymus gland through a small neck incision. There has been no difference in success in symptom
improvement between the transsternal approach and the minimally invasive transcervical approach.[18]However for
patients with a thymoma it is important that all the tissue is removed as thymic tissue can regrow. Thymomas can be
malignant and are thought to be the onset of other diseases as well. For this reason, many surgeons will only
recommend the full sternotomy approach to a thymectomy.

Thymoma is relatively rare in younger (<40) patients, but paradoxically especially younger patients with generalized MG
without thymoma benefit from thymectomy. Of course, resection is also indicated for those with a thymoma, but it is less
likely to improve the MG symptoms.
 What is Parkinson's disease?

Parkinson's disease is the second most common neurodegenerative disorder and the most common movement
disorder. It is characterized by progressive loss of muscle control, which leads to trembling of the limbs and head while
at rest, stiffness, slowness, and impaired balance. As symptoms worsen, it may become difficult to walk, talk, and
complete simple tasks.

The progression of Parkinson's disease and the degree of impairment vary from individual to individual. Many people
with Parkinson's disease live long productive lives, whereas others become disabled much more quickly. Premature
death is usually due to complications such as falling-related injuries or pneumonia.

In the United States, about 1 million people are affected by Parkinson's disease and worldwide about 5 million. Most
individuals who develop Parkinson's disease are 60 years of age or older. Parkinson's disease occurs in approximately
1% of individuals aged 60 years and in about 4% of those aged 80 years. Since overall life expectancy is rising, the
number of individuals with Parkinson's disease will increase in the future. Adult-onset Parkinson's disease is most
common, but early-onset Parkinson's disease (onset between 21-40 years), and juvenile-onset Parkinson's disease
(onset before age 21) also exist.

Descriptions of Parkinson's disease date back as far as 5000 BC. Around that time, an ancient Indian civilization called
the disorder Kampavata and treated it with the seeds of a plant containing therapeutic levels of what is today known as
levodopa. Parkinson's disease was named after the British doctor James Parkinson, who in 1817 first described the
disorder in great detail as "shaking palsy."

What causes Parkinson's disease?

A substance called dopamine acts as a messenger between two brain areas - the substantia nigra and the corpus
striatum - to produce smooth, controlled movements. Most of the movement-related symptoms of Parkinson's disease
are caused by a lack of dopamine due to the loss of dopamine-producing cells in the substantia nigra. When the amount
of dopamine is too low, communication between the substantia nigra and corpus striatum becomes ineffective, and
movement becomes impaired; the greater the loss of dopamine, the worse the movement-related symptoms. Other cells
in the brain also degenerate to some degree and may contribute to non-movement related symptoms of Parkinson's
disease.

Although it is well known that lack of dopamine causes the motor symptoms of Parkinson's disease, it is not clear why
the dopamine-producing brain cells deteriorate. Genetic and pathological studies have revealed that various
dysfunctional cellular processes, inflammation, and stress can all contribute to cell damage. In addition, abnormal
clumps called Lewy bodies, which contain the protein alpha-synuclein, are found in many brain cells of individuals with
Parkinson's disease. The function of these clumps in regards to Parkinson's disease is not understood. In general,
scientists suspect that dopamine loss is due to a combination of genetic and environmental factors.
Pathophysiology

The basal ganglia is a group of brain structures innervated by the dopaminergic system and considered the main
affected location in PD.[13]The symptoms of Parkinson's disease result from the greatly reduced activity of dopamine-
secreting cells due to cell death in the pars compacta region of the substantia nigra.[13] The characteristic pathological
finding in PD is Lewy bodies.

[edit]Physiology

Connections of the basal ganglia in the normal state.

Connections of the basal ganglia in Parkinson's disease, resulting from decreased activity of thepars compacta region of
the substantia nigra. Larger and smaller arrows refer to pathways with increased and decreased activity, respectively, in
Parkinson's disease.
Model of the circuits of the basal ganglia in the normal state (left) and PD (right). Substantia nigra is seen at
bottom right. Pictures show 2 coronal slices that have been superimposed to include the involved basal ganglia
structures. + and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in
effect. Green arrows refer to excitatory glutamatergic pathways,red arrows refer to inhibitory GABAergic pathways
and turquoise arrows refer to dopaminergicpathways that are excitatory on the direct pathway and inhibitory on the
indirect pathway. Dis-inhibitory pathways are in effect excitatory on the feedback to the cortex, while dis-dis-inhibitory
pathways are inhibitory.

There are five major pathways in the brain interconnecting different brain areas and the basal ganglia. These are the
motor, oculo-motor, associative, limbic and orbitofrontalcircuits, with names indicating the main projection area of the
circuit.[13] All of them are affected in PD and their disruption likely explains much of the symptomatology of the disease
since these circuits are involved in a wide variety of functions including movement, attention or learning.[13] Scientifically,
the motor circuit is the best known.[13]

A model of the motor circuit and its alteration with PD has been of great influence since 1980, even if some limitations
which have led to its modification have been pointed out.[13]This model divides the efferent neurons from the striatum in
two different projection systems.[13] The direct pathway connects theputamen directly with the structure globus pallidus
pars interna (GPi) - substantia nigra pars reticulata (SNr), and facilitates movement by reducing the output of the basal
ganglia.[13]The indirect pathway consists of three links, first a projection from the putamen to GPe; second a projection
from GPe to thesubthalamic nucleus (STN); and third a projection from STN to SNr. The indirect pathway, as opposed
to the direct, inhibits movement by increasing activity in the basal ganglia.[13] According to this model in PD dopamine
reduction brings functional consequences related to motor symptoms of the disease. The most important consequence
is an increased activity in the indirect pathway, leading to an excessive inhibition of movement and thus
to hypokinetic symptoms.[13] On the other hand it is believed levodopa administrations leads to a reduction of the basal
ganglia output, which if excessively marked, produces dyskinesias.[13]Similarly it has been proved that lesion or blockade
of the STN or GPi lead to a reduced hyperactivity of the basal ganglia and to an improvement of symptoms.
[13]
Evidences partially conflicting with the model led to the inclusion of the interaction between further connections and
neurotransmitters with the aim of better reflecting the complexity of the basal ganglia in healthy subjects, their disruption
in PD, and the effect produced by the treatments for the disease.[13] Some of these enhancements are included in the
image above.

[edit]Pathology

A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson's Disease, as proposed by Braak
and colleagues. B. Localization of the area of significant brain volume reduction in initial PD compared with a group of
participants without the disease in a neuroimaging study which concluded that brain stem damage may be the first
identifiable stage of PDneuropathology.[14]

The main pathological characteristic of PD is cell death in the substantia nigra and more specifically the ventral part of
the pars compacta, affecting up to 70% of the cells by death time.[12] The mechanisms by which the brain cells in
Parkinson's are lost are varied.[15] One mechanism consists of an abnormal accumulation of the protein alpha-
synuclein bound toubiquitin in the damaged cells. This protein accumulation forms inclusions called Lewy bodies.
[12]
According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first
appear in the olfactory bulb, medulla oblongata and pontine tegmentum, individuals at this stage being asymptomatic.
As the disease evolves, Lewy bodies later attain the substantia nigra, areas of the midbrain and
basal prosencephalon and finally reach areas of theneocortex.[12] Other cell-death mechanisms
include proteosomal and lysosomal system dysfunction, and reduced mitochondrial activity.[15] Iron accumulation in the
substantia nigra is also typically observed in conjunction with the protein inclusions. It may be related to oxidative
stress, protein aggregation and neuronal death, although mechanisms are not fully understood.

What are the symptoms of Parkinson's disease?

The primary symptoms of Parkinson's disease are all related to voluntary and involuntary motor function and usually
start on one side of the body. Symptoms are mild at first and will progress over time. Some individuals are more
affected than others. Studies have shown that by the time that primary symptoms appear, individuals with Parkinson's
disease will have lost 60% to 80% or more of the dopamine-producing cells in the brain. Characteristic motor symptoms
include the following:

• Tremors: Trembling in fingers, hands, arms, feet, legs, jaw, or head. Tremorsmost often occur
while the individual is resting, but not while involved in a task. Tremors may worsen when an individual is excited, tired,
or stressed.

• Rigidity: Stiffness of the limbs and trunk, which may increase during movement. Rigidity may
produce muscle aches and pain. Loss of fine hand movements can lead to cramped handwriting (micrographia) and
may make eating difficult.

• Bradykinesia: Slowness of voluntary movement. Over time, it may become difficult to initiate
movement and to complete movement. Bradykinesia together with stiffness can also affect the facial muscles and result
in an expressionless, "mask-like" appearance.

• Postural instability: Impaired or lost reflexes can make it difficult to adjust posture to maintain
balance. Postural instability may lead to falls.
• Parkinsonian gait: Individuals with more progressive Parkinson's disease develop a distinctive
shuffling walk with a stooped position and a diminished or absent arm swing. It may become difficult to start walking and
to make turns. Individuals may freeze in mid-stride and appear to fall forward while walking.

Secondary symptoms of Parkinson's disease

While the main symptoms of Parkinson's disease are movement-related, progressive loss of muscle control and
continued damage to the brain can lead to secondary symptoms. These vary in severity, and not every individual will
experience all of them. Some of the secondary symptoms include:

• anxiety, insecurity, and stress

• confusion, memory loss, and dementia (more common in elderly individuals)

• constipation

• depression

• difficulty swallowing and excessive salivation

• diminished sense of smell

• increased sweating

• male erectile dysfunction

• skin problems

• slowed, quieter speech, and monotone voice

• urinary frequency/urgency

What other conditions resemble Parkinson's disease?

In its early stages, Parkinson's disease can resemble a number of other conditions with Parkinson-like symptoms known
as Parkinsonism. These conditions include multiple system atrophy, progressive supranuclear palsy, corticobasal
degeneration, Lewy body dementia, stroke,encephalitis (inflammation of the brain), andhead trauma. Alzheimer's
disease and primary lateral sclerosis can also be mistaken for Parkinson's disease. Other similar conditions include
essential tremor, dystonic tremor, vascular Parkinsonism, and drug-induced Parkinsonism.

How is Parkinson's disease diagnosed?

An early and accurate diagnosis of Parkinson's disease is important in developing good treatment strategies to maintain
a high quality of life for as long as possible. However, there is no test to diagnose Parkinson's disease with certainty
(except after the individual has passed away). A diagnosis of Parkinson's disease - especially in the early phase - can
be challenging due to similarities to related movement disorders and other conditions with Parkinson-like symptoms.
Individuals may sometimes be misdiagnosed as having another disorder, and sometimes individuals with Parkinson-like
symptoms may be inaccurately diagnosed as having Parkinson's disease. It is therefore important to re-evaluate
individuals in the early phase on a regular basis to rule out other conditions that may be responsible for the symptoms.
A neurologist who specializes in movement disorders will be able to make the most accurate diagnosis. An initial
assessment is made based on medical history, a neurological exam, and the symptoms present. For the medical
history, it is important to know whether other family members have Parkinson's disease, what types of medication have
been or are being taken, and whether there was exposure to toxins or repeated head trauma in the past. A neurological
exam may include an evaluation of coordination, walking, and fine motor tasks involving the hands.

Several guidelines have been published to assist in the diagnosis of Parkinson's disease. These include the Hoehn and
Yahr scale and the Unified Parkinson's Disease Rating Scale. Tests are used to measure mental capacity, behavior,
mood, daily living activities, and motor function. They can be very helpful in the initial diagnosis, to rule out other
disorders, as well as in monitoring the progression of the disease to make therapeutic adjustments. Brain scans and
other laboratory tests are also sometimes carried out, mostly to detect other disorders resembling Parkinson's disease.

The diagnosis of Parkinson's disease is more likely if:

1. at least two of the three major symptoms are present (tremor at rest, muscle rigidity, and
slowness);

2. the onset of symptoms started on one side of the body;

3. symptoms are not due to secondary causes such as medication or strokes in the area controlling
movement; and

4. symptoms are significantly improved with levodopa (see below).

What is the treatment for Parkinson's disease?

There is currently no treatment to cure Parkinson's disease. Several therapies are available to delay the onset of motor
symptoms and to ameliorate motor symptoms. All of these therapies are designed to increase the amount of dopamine
in the brain either by replacing dopamine, mimicking dopamine, or prolonging the effect of dopamine by inhibiting its
breakdown. Studies have shown that early therapy in the non-motor stage can delay the onset of motor symptoms,
thereby extending quality of life.

The most effective therapy for Parkinson's disease is levodopa (Sinemet), which is converted to dopamine in the brain.
However, because long-term treatment with levodopa can lead to unpleasant side effects (a shortened response to
each dose, painful cramps, and involuntary movements), its use is often delayed until motor impairment is more severe.
Levodopa is frequently prescribed together with carbidopa (Sinemet), which prevents levodopa from being broken down
before it reaches the brain. Co-treatment with carbidopa allows for a lower levodopa dose, thereby reducing side
effects.

In earlier stages of Parkinson's disease, substances that mimic the action of dopamine (dopamine agonists), and
substances that reduce the breakdown of dopamine (monoamine oxidase type B (MAO-B) inhibitors) can be very
efficacious in relieving motor symptoms. Unpleasant side effects of these preparations are quite common, including
swelling caused by fluid accumulation in body tissues, drowsiness, constipation, dizziness, hallucinations, andnausea.

For some individuals with advanced, virtually unmanageable motor symptoms, surgery may be an option. In deep brain
stimulation (DBS), the surgeon implants electrodes to stimulate areas of the brain involved in movement. In another
type of surgery, specific areas in the brain that cause Parkinson's symptoms are destroyed.

An alternative approach currently being explored is the use of dopamine-producing cells derived from stem cells. While
stem cell therapy has great potential, more research is required before such cells can become of therapeutic value in
the treatment of Parkinson's disease.
In addition to medication and surgery, general lifestyle changes (rest and exercise), physical therapy, occupational
therapy, and speech therapy may be beneficial.
Ali was diagnosed with Parkinson's disease in 1984,[27][28] a disease for which those subject to severe head
trauma, such as boxers, are many times more susceptible.