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"...the disease...the man... the world go together and cannot be considered separately as things in themselves. An adequate concept or characterization of a man...would embrace all that happened to him, all that affected him, and all that he has affected..."
Dr. Oliver Sacks in Awakening
What is Parkinson's Disease?

Parkinson's disease is a degenerative neurological disease. Degenerative means "declining in quality"- thus, the disease increases in severity over time; neurologic refers to the nervous system. Parkinson's disease can also be described as a chronic, progressive neurologic disease. This means that Parkinson's does not go away, and it gradually gets worse.

Neurons in the substantia nigra (small area located deep within the brain, one on left side and one on the right side) are primarily affected. When this happens the brains ability to generate body movements is disrupted and this causes the symptoms of Parkinson’s disease.

Named after physican James Parkinson





Signs and Symptoms
Symptoms are not noticeable until about 80 percent of the substantia nigra cells have died.This is because the human nervous system has multiple safety factors that are able to take over the activities of the dying cells.

Early signs and symptoms
  • Symptoms on only one side
  • Mild Tremor
    • sometimes is dismissed as just a sign of anxiety or aging
  • Internal Tremor
    • half of patients feel trembling in an arm or leg
    • has enough force that patient can feel it but not enough to cause visible movement
  • Sexual Effects
  • Pain and other Sensory Effects
    • aches and pains around the neck, shoulders, arms, legs or lower back
    • 10% develop frozen shoulder(painful, stiff shoulder)
    • numbness, tingling, burning, coldness or aching in arms, legs, abdomen or pelvic regions
    • are not constant
  • Foot Cramps
    • in early morning
    • sometimes painful
    • all toes curl downward/all toes but big toe curl down and big toe bends up
  • Masked Face
    • decreased frequency of blinking
  • Voice Changes
    • becomes softer
  • Loss of Hand Dexterity
    • difficulity
      • using computer keyboard
      • taking keys or wallet out of their pocket
      • applying makeup
      • fasten a top shirt button or buttons on sleeves
      • beating eggs
      • brushing teeth
    • problems with flow of their handwritting
      • slower
      • words shrink as they go
  • Stooped Posture
  • Difficulties in walking and other Whole body Movements
    • natural arm swing is lost in one side
      • is stuck at their side
      • only moves if they think about it
    • feel like one leg is dragging (slight limp)
    • difficulty
      • getting out of chirs and sofas
      • getting in and out of a car
  • Felling out of Balance
    • loss of balance and falling are rare at this stage
    • develop unsteadiness
    • difficulty
      • turing around quickly
      • standing on one foot (even for just a few seconds)
  • Depression
    • lose interest in other things
    • have little energy
    • sleep disturbances
  • Anxiety
    • worry what other will think if they shake or show other symptoms
    • panic attacks
  • Apathy
    • no longer want to continue old activities or start new ones
    • become socialy withdrawn


Moderate Parkinson's
  • Tremor
    • resting tremor
      • more sever when a person's hands are at rest
      • sometimes disappears when hands are moving
    • becomes more noticeable over time
    • emotional excitement makes it worse
    • affected by sleep
      • disappears when fully asleep
      • moments before waking up it returns
  • Rigidity
    • causes stiffness of muscles
    • might be responsible for
      • increasing neck, back and limb pain
      • hand awkwardness
      • clumsiness
  • Pain
    • foot spasms
    • frozen shoulder
  • Foot Cramps
    • foot and leg cramps
      • muscle spasms
      • occure more fequently when medication levels are low
  • Akinesia or Bradykinesia
    • slowness of movement(bradykinesia)
    • eventually can not move at all (akinesia)
  • Social Isolation and Communication Problems
    • due to loss of facial expressions and reduced volume of speech
    • no longer appear to be friendly
  • Body Language
    • gesturing difficul
  • Voice
    • monotone
    • slight slurring of speech
  • Handwritting
    • becomes slow and difficult
    • hard to rea
  • Drooling and Swallowing Difficulties
    • appear after having the disease for two to four years
    • nocturnal drooling
    • have trouble swalling pills
    • may cough or choke after eating or drinking
    • leads to weight loss
  • Postural Instability
    • fall down occasionally with no warning
  • Difficultiy Walking
    • start to walk slower
    • cant keep up with other
    • feel like feet are glued to floor
  • Stooped Posture
    • head and neck lean forward
  • Autonomic System Impairment
    • problems with
      • digestion
      • teperature control,
      • gland sectetions
      • hormones
  • Disruption of sleep Patterens
    • become sleepy during the day even if sleeps well at night
    • may fall asleep in social situations and at meals
    • sometimes can not sleep at all at night
  • Skin Rash
    • skin around scalp, nose and mouth develope an oily, scaly, reddened appearance
    • responds quite well to tar-based shampoos
  • Inner Restlessness
    • so uncomfortable that a person must get up and walk around


Problem Areas in Advanced Parkinson’s Disease
  • Tremor
    • usually becomes less troubling
  • Rigidity and slowness of movement
    • extremely slow movement
  • Pain
    • Caused by
      • muscles becoming more rigid
      • changes in muscle tone
      • getting more ordinary disorders such as
        • arthritis
        • bursitis
        • tendonitis
  • Voice
    • fast
    • slurred
    • hesitant
    • very soft
  • Handwritting
    • becomes illegible
    • is so slow it is usless as a convenient form of communication
  • Swalowing and drooling problems
    • begin to drool during the day
  • Autonomic system impairments
    • badder control and urinary difficulties
    • consitpation
    • sexual dysfunction
    • fainting after rising
Characteristic signs and symptoms of Parkinson’s disease (TRAP)
T
Tremor
Involuntary trembling of the limbs
R
Rigidity
Stiffness of the muscles
A
Akinesia
Lack of movement or slowness in initiating and maintaining movement
P
Postural instability
Characteristic bending of flexion of the body, associated with difficulty in maintaining balance and disturbances in gait

And bradykinesia (slowness of movement)


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Behavioral Changes
  • Depression
    • largely due to changes in the neurochemistry of the brain
  • Anxiety
    • difficulty with job performance and socialization
  • Apathy
    • social withdrawn
    • loss of interests
  • Fatigue
    • sleepy during the day
  • Vivid Dreams
    • nightmares become very frightening
    • confuse what is real and what is a dream
    • nightmare accompanied by thrashing movements
    • talk or scream out loud
  • Visual Hallucinations
    • many think they see their parents who have died years ago
    • see small elfllike children, pet and insects
  • Delusions (false beliefs)
    • think that they have had money stolen
    • believe their spiuse is having an affair
    • feel unfairly persecuted


Young-Onset Parkinson's Disease

  • When symptoms appear in a person older than thirty but younger than fifty
  • symptoms are usually the same except
    • a tremor is now an early symptom
    • are more likely to develop drug-induced motor symptoms in the first year
  • hard to diagnose
  • harder to cope with since
    • still have a carrer
    • maybe want to start a family/add to theirs



Causes
Parkinson's disease is caused by many factors, but the main cause of the disease involves the substantia nigra and dopamine. The substantia nigra is a very small area located deep within the brain on both the right and left sides of the brain. The substantia nigra accounts for an extremely small percentage of the brain's weight, but because of its important electrochemical connections with motor centers, it is a vital component in how we move. The specific neurotransmitter, the chemicals that the brain uses to communicate communication from one neuron to another neuron, produced and used by substantia nigra is dopamine. When the cells of the substantia nigra degenerate and die, dopamine is lost and dopamine relayed messages to other motor centers cannot go through, and is therefore the primary cause of the motor symptoms in Parkinson's disease.

While the loss of dopamine-producing cells is the primary neurochemical disturbance in Parkinson's, the neurochemical disturbances are not limited to the cells of the substantia nigra and to the loss of dopamine. Other small nuclear centers within the brain are also affected by the degeneration. In Parkinson's disease, as the concentrations of dopamine in the brain decline, so do concentrations of other neurotransmitters such as norepinephrine and serotonin, although changes in these other neurotransmitters are not nearly as significant as the loss of dopamine.

Because the brain's neurotransmitters-especially dopamine-are so important to the central nervous system's control of the muscles, when the neurotransmitters are lost, the muscles act strangely. The central mechanism that controls muscle tone is altered. Tremors are produced due to the muscles rapidly tightening and releasing. At times, muscles could tighten up and become stiff and rigid. Inadequate communication between the brain and the muscles will cause movement to be slow and therefore muscles are not able to make quick, fluid, and spontaneous movements. The central mechanism that controls muscle tone does not require function adequately for the delicate interplay of muscles requires to help us stand, walk, and balance. In addition, because Parkinson's deisease also affects the autonomic nervous system (the largely unconsscious system that controls our body temperature, digestive system, sexual function, and bladder control, among other functions), these systems may also act oddly.

Parkinson's is sometimes termed idiopathic (cause unknown) because although we do know that neurochemical disturbance causes the symptoms of Parkinson's, researchers do not know what causes the neurodegeneration even after extensive research has been conducted.




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Treatment
Drug Therapies
Levodopa: Levodopa is the immediately preceding chemical, or precusor (a chemical that can be metabolized into another chemical), from which dopamine is made. Levodopa was first used in the 1960s and continues to be the most significant and dramatic development in the treatment of people with Parkinson's disease. The drug allowed wheelchair-bound patients and those having trouble performing everyday activities to regain the ability to function normally. Some believed that levodopa was the cure for Parkinson's disease, but were faced with the reality that levodopa provided dramatic symptomatic relief even as the underlying disease continued to progress. A problem with levodopa therapy is that the body converted the levodopa into dopamine in the bloodstream, which prevents levodopa from reaching the brain, where it is needed, but also caused severe nausea and vomiting. To solve this problem and allow levodopa to reach the brain intact, treatment was developed that combines levodopa with a peripheral dopa decarboxylase inhibitor (DDI), which blocks the body's natural conversion of levodopa to dopamine in the bloodstream. DDIs cannot enter the blood-brain barrier so when levodopa reaches the brain, it can enter the brain to be converted into dopamine unaffected by the DDI, which is left behind in the bloodstream. Levodopa can be taken alone, but as stated before, it will cause severe nausea and vomiting, therefore levodopa is usually prescribed with a DDI. This pairing of levodopa and DDI is known as "levodopa therapy." Another limitation of levodopa therapy is that the dopamine-producing nerve cells on the substantia nigra become less able to convert levodopa into dopamine. To stimulate the dopamine receptors, people with moderate or advanced Parkinson's disease take a dopamine receptor agonist along with a DDI/levodopa medication.

Dopa Decarboxylase Inhibitor (DDI): DDIs block the body's natural conversion of levodopa to dopamine in the bloodstream. The two most commonly used DDIs today are carbidopa and benserazide. The combination of levodopa and carbidopa is known by the trade name of Sinemet, and the combination of levodopa and benserazide is known as Prolopa or Madopar. There is very little difference in the pharmacologic properties of the two DDIs. The dose of these two drugs are designated as a fraction: the numerator is the amount of carbidopa in each tablet, and the denominator is the amount of levodopa. For example, 25/100 would signify that there is 25 milligrams of carbidopa and 100 milligrams of levodopa. Carbidopa/levodopa is also sold in a controlled-release formulation known as Sinemet CR, available in does of 25/100 or 50/200. Controlled-release formulations of Sinemet provide a slower release of levodopa into the bloodstream; this produces a somewhat longer duration of action. Some Parkinson's symptoms arise just as the levodopa is wearing off, and Sinemet CR's controlled release can help smooth them out. These symptoms include motor fluctuations, end-of-dose wearing-off fluctuations or on/off fluctuations, and nighttime immobility and sleep disruption. Carbidopa/levodopa can also be administered as a homemade liquid preparation, which is effective for people who are having a lot of trouble with on/off fluctuations. In liquid form, the drug is quickly and easily absorbed in the digestive tract; the disadvantage is that people must take the liquid preparation about every hour. Levodopa is best absorbed through the digestive tract on an empty stomach.


Primary Drugs Used to Relieve Symptoms of Parkinson's Disease
Drugs for Motor Symptoms
Levodopa
Levodopa plus peripheral dopa decarboxylase inhibitors (DDIs)
Dopamine receptor agonists
Levodopa plus COMT inhibitors (catechol-O-methyltransferase inhibitors)
MAO inhibitors (monoamine oxidase inhibitors)
Anticholinergics
Amantadine
Drugs for Other Symptoms
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
Benzodiazepines
Sedatives
Atypical antipsychotic agents
Stool softeners
Fiber-rich preparations

Drugs That Enhance Levodopa and Dopamine
As Parkinson's disease progresses the amount of neurons are fewer and are unable to handle the metabolic conversion of levodopa to dopamine. Some cells may try to handle the metabolic conversion, but the cells release the dopamine immediately, without the normal control or storage exercised by normally functioning dopaminergic neurons. Today, the development of drugs that mimic dopamine and drugs that inhibit the breakdown of dopamine in the body have helped prevent the problem of too little neurons.

Agonists: A dopamine receptor agonist is a drug that mimics the activity of dopamine at the dopamine receptor. Some potential advantages include the alleviation of Parkinson's symptoms and the possibility of a smoother effect, since the drug does not have to be metabolized by the very neurons that are affects by the disease process. There are four types of dopamine receptor agonists: bromocriptine (1970s), peroglide (1980s), pramipexole (Mirapex, 1997), and ropinirole (Requip, 1997). Each receptor agonist work using the same general mechanism, but they are not all the same. Each of the four agonists can be combined with carbidopa/levodopa. All four agonists can also produce the side effects lethargy, dizziness, low blood pressure, swollen ankles, and psychiatric disturbances. The agonist must be started at a very low dosage and then very slowly titrated up. This slow increase may avoid such side effects as dizziness and nausea.
Catechol O-methyltransferase (COMT) Inhibitors: The first COMT inhibitor was approved by the FDA in 1998 and was called tolcapone. The second inhibitor was approved in 1999 as entacapone. COMT inhibitors, as well as monoamine oxidase (MAO) inhibitors, operate on enzyme systems to increase the amount of dopamine available to the brain's motor control system. COMT inhibitors are particularly helpful for people with motor fluctuations, such as those effected with Parkinson's disease. COMT inhibitors help prolong the "on" time and reduce the "off" time for dopamine in the brain. Both COMT inhibitors may have some troubling side effects, such as dizziness, nausea, fatigue, orthostatic hypotension, dyskinesia, and hallucinations. Side effects are often manageable by reducing the levedopa dosage. Some side effects require special attention, such as diarrhea. About 5 to 10 percent of those taking a COMT inhibitor develop diarrhea and should stop taking the drug. Liver malfunction is another side effect that may develop with those taking tolcapone. Entacapone does not have these liver toxicity problems and liver monitoring is not necessary for people using this drug.
Monoamine Oxidase (MAO) Inhibitors: MAO inhibitors have been around longer than COMT inhibitors, a number of them have been developed as anti-depressants. The MAO system of enzymes is divided into subsidiary systems called MAO-A and MAO-B. The MAO-A inhibitors and the nonselective MAO inhibitors- those that inhibit either the MAO-A or the MAO-B system-relieve depression apparently by increasing the amount of dopamine and norepinephrine in the brain. Those taking the older MAO inhibitors must avoid eating certain foods in order to prevent the so called cheese effect. When combined with the MAO-A inhibitors or the nonselective MAO inhibitors, a compound called tyramine, common in aged cheese, red wines, and beer, can be transformed into a chemical that can elevate blood pressure to dangerously high levels. The problem also occurs if these MAO inhibitors are given levodopa, so they are generally not used in treating Parkinson's disease. Those taking MAO-B inhibitors, such as selegiline, do not need to be worried about the cheese effect and do not need to be worried about eating certain foods.
Anticholinergics: Anticholinergics are used to block the acetylcholine system and bring the two neurotransmitter systems back into balance, thus relieving symptoms. Anticholinergics are made from the herb belladonna, the belladonna alkaloids were used in the late nineteenth and early twentieth centuries as major therapy for the symptoms of Parkinson's disease. Anticholinergic medications include a wide variety of compounds, such as trihexyphenidyl, benzotropine, procyclidine, ethopropazine, and biperiden. They are mainly used to reduce the resting tremor of Pakinson's disease. To help with drooling and controlling saliva, a low dose of an anticholinergic medication such as Artane, Cogentin, or Partisan may be used. Although anticholinergics help treat the tremors that subside with Parkinson's disease, many patients do not use them because of the adverse side effects that follow. Some side effects include mouth dryness, constipation, or visual blurring.
Amantadine: Several hypotheses have arisen to why amantadine is effective in Parkinson's disease. One hypothesis is that amantadine may interfere with the reuptake of dopamine or it may promote the release of dopamine, which is necessary for patients of Parkinson's. Any drug that enhances dopamine tend to relieve symptoms of the disease, so it is no different with amantadine. Amantadine is often used in the early Parkinson's disease to relieve mild stiffness, slowness, and minor gait abnormalities. Most studies show that the usefulness of amantadine lasts only ten to twleve weeks, but for some patients the benefits received by the medication lasts much longer. Amantadine also carries anticholinergic effects as well. Just like anticholinergics and every other medication, amantadine is no exception to side effects. Amantadine should not be used for people who have abnormal functioning kidneys as they may develop a toxic buildup of the drug. Amantadine may also cause a personality change in a person, feelings of fogginess may occur, unexpected malaise, forgetfulness, and occasionally hallucinations and confusion. Personality changes induced by amantadine can be eliminated by stopping the medication. Some other minor side effects of amantadine include livedo reticularis, a skin disease, which typically has a blotchy or mottled, red, streaky pattern. Amantadine can also cause the swelling of the ankles, and a mild discomfort with a feeling of tightness in the affected area.

Drugs for the Other Symptoms of Parkinson's
Those affected by Parkinson's disease often need medication to relieve symptoms other than the characteristc symptoms of tremor, rigidity, slowness, and other problems with walking and balance. Evidence shows that Parkinson's disease can cause some depression, anxiety, sleep disruption, muscle cramps, and constipation. Some of these problems can be handled by making changes in lifestyles, but if that does not woork, or if these other symptoms have become severe, drugs are available to help.

Depression: In Parkinson's disease, the brain systems that degenerate include some parts of the brain involved in emotion, so depression may be an effect of the disease itself, or a sign of difficulty with adjustment to chronic symptoms, or a combination of both. A number of medications can be used to treat depression, such as the tricyclic antidepressants (TCAs). Amitriptyline (Elavil) and nortriptyline (Pamelor) are examples of TCAs. TCAs tend to sedate people, so they can also help people have sleep disturbances. The side effects include dry mouth and excessive sleepiness, and there could be changes in behavior such as memory dysfunction or confusion. Venlafaxine (Effexor), a newer bicyclic antidepressant, is better tolerated and very effective for depression in people with Parkinson's disease. Also used to treat depression are newer antidepressants called selective serotonin reuptake inhibitors (SSRIs). Some examples of SSRIs are fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). SSRIs are also believed to relieve anxiety as well. There is a rare occurance of SSRIs worsening the signs of Parkinson's disease or causing symptoms of parkinsonism in people who had no previous symptoms.
Anxiety: Sometimes, people with Parkinson's disease may develop anxiety, develop social phobias, or have panic attacks. Anxiety may be the result of both the biochemical changes in the brain and the stress of coping with Pakinson's symptoms. SSRIs are effective in alleviating the anxiety one may feel. As well as SSRIs, drugs classified as anxiolytics may be used for people who compplain of nervousness. The most common treatment used for anxiety are benzodiazepines, which include diazepam (Valium), lorazepam (Ativan), and alprazolam (Xanax). They may also me helpful as musscle relaxants or to induce sleep. The major disadvantage of taking benzodiazepines is that regular usuage results in both tolerance of the drug's effects and physical dependence on the drug. Side effects of this drug include sleepiness, forgetfulness, and mild confusion.
Psychotic Symptoms: When a person loses the ability to distinguish reality from dreams or hallucinations, physicians diagnose this as psychotic behavior. People with Parkinson's disease usually develp psychosis as a result of drugs or something drug related. Fortunately, there are many ways to solving this problem, including carefully reducing dosage of certain medications, discontinuing some medications, or adding atypical antipsychotic agents such as quetiapine (Seroquel), or clozapine (Clozaril). Atypical antipsychotics can suppress psychotic symptoms but are less likely to make parkinsonism worse than the typical antipsychotics.
Muscle cramps: Many people with Parkinson's disease experience stiff and rigid feelings in their muscles and request muscle relaxants. For dystonic muscle spasm, baclofen (Lioresal), a special type of muscle relaxant, may be helpful both at bedtime and intermittently throughout the day, but we prefer to adjust the levels of medication. Dystonic cramps occur particularly in the early morning when dopamine levels in the brain are low. Dystonic spasms that occur at night or in the early morning can often be eliminated by taking Sinemet CR at bedtime. If the spasms occur exclusively after waking at the same time every morning, another successful approach is to set the alarm for one or two hours earlier, take a dose of bidopa/levodopa, and then go back to bed. When you do this, the levels of brain dopamine are usually high enough to prevent the dystonic spasm.
Constipation: Constipation is the most common alteration of bowel habits in people with Parkinson's disease because of the potential causes of constipation: normal aging, the Parkinson's degeneration of motor control of muscles in the lower digestive tract, increased sedentary habits, and antiparkinson medications. Lifestyle changes is the best defense against constipation. There are fiber rich medications that people can take such as Metamucil or Konsyl and stool softeners such as Colace. Stronger medications such as lactulose syrup, Dulcolax tablets/suppositories, milk of magnesia, or enemas may or may not be needed. Severe constipation can be a medical emergency and on rare occasion can lead to bowel obstruction.



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Bibliography
Lang, Anthony E., Lisa Shulman, and William J. Weiner. Parkinson's Disease: A Complete Guide for Patients & Families. Baltimore, Maryland: Johns Hopkins University Press, 2001.

Dorros, Sidney.Parkinson's:A Patient's View.Washington, D.C.:Seven Locks Press, 1989.